Clinical trial NCT03872388
Conditions: Anatomic Stage IIB Breast Cancer AJCC v8 Anatomic Stage III Breast Cancer AJCC v8 Anatomic Stage IIIA Breast Cancer AJCC v8 Anatomic Stage IIIB Breast Cancer AJCC v8 Anatomic Stage IIIC Breast Cancer AJCC v8 Estrogen Receptor Negative HER2/Neu Negative Inflammatory Breast Carcinoma Progesterone Receptor Negative Prognostic Stage IIB Breast Cancer AJCC v8 Prognostic Stage III Breast Cancer AJCC v8 Prognostic Stage IIIA Breast Cancer AJCC v8 Prognostic Stage IIIB Breast Cancer AJCC v8 Prognostic Stage IIIC Breast Cancer AJCC v8 Stage IIB Breast Cancer AJCC v6 and v7 Stage III Breast Cancer AJCC v7 Stage IIIA Breast Cancer AJCC v7 Stage IIIB Breast Cancer AJCC v7 Stage IIIC Breast Cancer AJCC v7 Triple-Negative Breast Carcinoma
Sponsor: M.D. Anderson Cancer Center
Start date: 2019-09-23; Completion date: 2023-10-19
Enrollment: 6 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase II trial studies how well atorvastatin works in treating patients with stages IIb-III triple negative breast cancer who did not achieve a pathologic complete response to neoadjuvant chemotherapy. Pathologic complete response is the lack of all signs of cancer in tissue samples removed during surgery after upfront chemotherapy. Atorvastatin is used for the treatment of high cholesterol and may reduce the risk of triple negative breast cancer from coming back. Triple-negative breast cancer is a type of breast malignancy that is comprised of cancer cells that do not have estrogen receptors, progesterone receptors, or large amounts of HER2/neu protein. Patients with TNBC do not have established systemic therapies such as anti-estrogens or HER2-targeting agents to reduce recurrence after surgery, and residual cancer found at surgery is associated with higher relapse rate.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the proportion of patients with undetectable circulating tumor cells (CTCs) at 6 months in patients with stage IIB/III triple negative breast cancer (TNBC) who did not achieve a pathologic complete response a (pCR) or Residual Cancer Burden-I (RCB-I) after receiving neoadjuvant chemotherapy (NAC) with and without atorvastatin therapy.

SECONDARY OBJECTIVES:

I. To determine if baseline fasting lipid profile level (low density lipoprotein cholesterol \[LDL-C\]) and/or change in serum lipid levels are a predictive biomarker of change in the proportion of patients with CTCs.

II. To assess effect of biomarkers on atorvastatin treatment response, defined as CTCs, circulating tumor deoxyribonucleic acid (DNA) (ctDNA), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum Interleukin-6 (IL-6) and other inflammatory cytokines, for the purpose of identifying the optimal patient population for future larger scale adjuvant studies.

III. To determine if baseline fasting lipid profile level (LDL-C) and/or change in serum lipid levels are associated with 2-year relapse free survival (RFS) rate.

IV. To determine if baseline CRP and/or change in serum lipid levels are a predictive biomarker of change in the proportion of patients with CTCs.

V. To determine if baseline C-reactive protein (CRP) and/or change in CRP are associated with 2-year RFS rate.

VI. To determine if baseline absolute number of CTCs and/or CTC change are associated with 2-year RFS rate.

VII. To estimate the 2-year RFS rate of patients with TNBC who did not achieve pCR with and without atorvastatin therapy.

VIII. To describe the toxicity and adverse events profile of atorvastatin treatment when given concurrently with standard doses of radiotherapy to the chest wall and regional nodes.

EXPLORATORY OBJECTIVES:

I. To evaluate the correlation between multiplexed imaging biomarkers in the normal or tumor tissue taken at the time of surgery, and response to atorvastatin-induced CTC changes or with measured outcomes.

OUTLINE: Patients are assigned to 1 of 2 groups.

GROUP I: Patients receive standard of care atorvastatin orally (PO) once daily (QD) for up to 24 months. A physical exam is performed, and blood drawn at 3, 6, 12, 18 and 24 months after starting standard of care treatment or at any time the disease appears to get worse.

GROUP II: Patients not eligible to receive atorvastatin, will be enrolled into non-statin observation group with/without capecitabine treatment.

Arms: arm 1: Patients receive standard of care atorvastatin PO QD for up to 24 months. arm 2: Patients not eligible to receive atorvastatin, will be enrolled into non-statin observation group with/without capecitabine treatment.
Interventions: intervention 1: Atorvastatin intervention 2: Capecitabine
Intervention descriptions: intervention 1: Patients will receive Atorvastatin per ASCVD guidelines dosed as either a moderate intensity (20mg/day) or high intensity statin (80mg/day). Tablets are available in either 20mg or 80mg and will be dispensed as per standard of care for up to 24 months as part of the study.

Patients may also receive capecitabine concurrently with Atorvastatin per physician discretion as standard of care. Standard of care dosing of Capecitabine is a 21 day cycle consisting 14 days on and 7 days off. The starting dosing will be per physician discretion, but may be up to 2500mg/m2 per day. intervention 2: Patients not eligible to receive atorvastatin in group II will be enrolled into non-statin observation group with/without capecitabine treatment. Capecitabine administration will be dosed as per standard of care. Standard of care dosing of Capecitabine is a 21 day cycle consisting 14 days on and 7 days off. The starting dosing will be per physician discretion, but may be up to 2500mg/m2 per day.

Protocol documents:
Prot_SAP_000.pdf: 
Product:  Atorvastatin 
1 
Protocol/Amendment No.: 2018-0550 
PI: Carlos H. Barcenas, MD  
Date:  01/10/2023 
 
 
SPONSOR: The University of Texas MD Anderson Cancer Center 
 
TITLE: Atorvastatin in triple-negative breast cancer (TNBC) patients who did not achieve 
a pathologic complete response (pCR) after receiving neoadjuvant chemotherapy; a 
multicenter pilot study 
 
Principal Investigator:  Carlos H. Barcenas, MD, MS 
Co-principal Investigator(s): Susan Gilchrist, MD  
Collaborating Statistician: Yu Shen, PhD; Diane Liu, MS 
Clinical Collaborators: Vicente Valero, MD; Michael Stauder, MD  
Laboratory Collaborators: James M. Reuben, PhD; Wendy A. Woodward, MD, PhD  
 
Department:  
 
Breast Medical Oncology 
Phone: 
 
 
713-792-2817 
Fax: 
 
 
 
713-794-4385 
Research Nurse: 
 
Angela Alexander 
 
Version Status: 
 
01/10/2023 
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PI: Carlos H. Barcenas, MD  
Date:  01/10/2023 
 
 
  
                                                TABLE OF CONTENTS 
1.0 
TRIAL SUMMARY.................................................................................................... 4 
         1.1  Study Schemas .……………………………………………………………………..5  
2.0 
OBJECTIVE(S) & HYPOTHESIS (ES) ................................................................... 6 
3.0 
BACKGROUND & RATIONALE ............................................................................ 8 
3.1 
Need for Adjuvant Therapies for Patients with TNBC ....................................... 8 
 Statins as Possible Adjuvant Therapy for Breast Cancer based on Retrospective 
Datasets of Statins in Breast Cancer ..................................................................... 8 
 Preclinical and Clinical Trial Data of statins in breast cancer .............................. 10 
 Rationale for Dose Selection/Regimen/Modification ........................................... 13 
 Rationale for Correlatives ..................................................................................... 18 
 Study Endpoint...................................................................................................... 18 
4.0 
METHODOLOGY ................................................................................................... 19 
4.1 
Entry Criteria ........................................................................................................ 19 
 Inclusion Criteria .................................................................................................. 20 
 Exclusion Criteria ................................................................................................. 20 
4.2 
Treatment Plan ..................................................................................................... 22 
 Dose Selection: ..................................................................................................... 22 
 Toxicities and Dose Modification: Atorvastatin ................................................... 22 
 Toxicities and Dose Modification: Atorvastatin and Radiation Therapy (RT) .... 26 
4.3 
Concomitant Medications/Vaccinations (allowed & prohibited) ..................... 25 
 Acceptable Concomitant Medications .................................................................. 26 
 Prohibited Concomitant Medications ................................................................... 26 
4.4 
Rescue Medications & Supportive Care ............................................................. 27 
4.5 
Subject Withdrawal/Discontinuation Criteria ................................................... 27 
4.6 
Criteria for Disease Control ................................................................................. 27 
4.6.1. Response will not be considered evaluable in the following categories: .............. 28 
5.0 
STUDY FLOW CHART .......................................................................................... 28 
6.0 
COLLATERAL RESEARCH ................................................................................. 29 
6.1 
Biomarker assessments ......................................................................................... 29 
 Blood samples ....................................................................................................... 29 
 Tumor samples ...................................................................................................... 32 
7.0 
SAFETY MONITORING AND REPORTING ..................................................... 31 
7.1 
Adverse Event ....................................................................................................... 31 
7.2 
Serious Adverse Event Reporting (SAE) ............................................................ 33 
 Internal SAE reporting .......................................................................................... 33 
        7.2.1.2 Guidelines for participating Cancer Network Sites to report SAEs ……………32 
 Evaluating Adverse Events ................................................................................... 33 
8.0 
STATISTICAL CONSIDERATION AND ANALYSIS PLAN ............................ 33 
9.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 34 
9.1 
Product used in the study ..................................................................................... 34 
9.2 
Packaging and Labeling Information ................................................................. 34 
9.3 
Clinical Supplies Disclosure ................................................................................. 34 
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Product:  Atorvastatin 
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Protocol/Amendment No.: 2018-0550 
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Date:  01/10/2023 
 
 
9.4 
Storage and Handling Requirements .................................................................. 34 
10.0 
DATA MANAGEMENT .......................................................................................... 35 
10.1 
Data collection for this study including: ............................................................. 35 
10.2 
Data confidentiality plan ...................................................................................... 35 
11.0 
MULTICENTER STUDY MANAGEMENT PLAN    .......................................... 35 
      11.1   Research Sample Distribution …………………………………………………..36 
12.0 
REFERENCES .......................................................................................................... 37 
13.0 
SAMPLE COLLECTION INSTUCTION ............................................................. 39 
 
 
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1.0 TRIAL SUMMARY 
Abbreviated Title 
Atorvastatin as adjuvant therapy in TNBC patients which did not achieve 
pCR 
Trial Phase 
Pilot Study 
Clinical Indication 
Role of Atorvastatin in TNBC in the adjuvant setting 
Trial Type 
Open labeled, non- randomized, multicenter 
Type of control 
TNBC patients who were not recommended to receive Atorvastatin by 
ASCVD 
Route of administration 
Oral 
Trial Blinding 
No 
Treatment Groups  
Two 
Number of trial subjects 
80 
Estimated duration of trial 
3 years 
Duration of Participation 
2 years 
 
 
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Protocol/Amendment No.: 2018-0550 
PI: Carlos H. Barcenas, MD  
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1.1 Study Schemas:  
 
 
 
 
 
 
 
 
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2.0 OBJECTIVE(S) & HYPOTHESIS (ES) 
Central Hypothesis:  
 
Adjuvant statin therapy is effective in reducing the risk of recurrence in TNBC patients who did 
not achieve a pCR to neoadjuvant chemotherapy. 
 
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PI: Carlos H. Barcenas, MD  
Date:  01/10/2023 
 
 
Primary Objective:  
• To determine the proportion of patients with undetectable circulating tumor cells (CTCs)  
at 6 months in patients with stage IIB/III TNBC who did not achieve a pCR or Residual 
Cancer Burden-I (RCB-I) after receiving neoadjuvant chemotherapy (NAC) with and 
without atorvastatin therapy. 
Secondary Objectives:  
• To determine if baseline fasting lipid profile level (LDL-C) and/or change in serum lipid 
levels are a predictive biomarker of change in the proportion of patients with CTCs. 
• To assess effect of biomarkers on atorvastatin treatment response, defined as CTCs, 
circulating tumor DNA (ctDNA), erythrocyte sedimentation rate (ESR), C-reactive 
protein (CRP), serum Interleukin-6 (IL-6) and other inflammatory cytokines, for the 
purpose of identifying the optimal patient population for future larger scale adjuvant 
studies. 
• To determine if baseline fasting lipid profile level (LDL-C) and/or change in serum lipid 
levels are associated with 2-year relapse free survival (RFS) rate.  
• To determine if baseline CRP and/or change in serum lipid levels are a predictive 
biomarker of change in the proportion of patients with CTCs. 
• To determine if baseline C-reactive protein (CRP) and/or change in CRP are associated 
with 2-year RFS rate. 
• To determine if baseline absolute number of CTCs and/or CTC change are associated with 
2-year RFS rate. 
• To estimate the 2-year RFS rate of patients with TNBC who did not achieve pCR with and 
without atorvastatin therapy. 
• To describe the toxicity and adverse events profile of atorvastatin treatment when given 
concurrently with standard doses of radiotherapy to the chest wall and regional nodes. 
 
Exploratory Objectives 
• To evaluate the correlation between multiplexed imaging biomarkers in the normal or 
tumor tissue taken at the time of surgery, and response to atorvastatin-induced CTC 
changes or with measured outcomes. 
• To evaluate whether adjuvant xeloda treatment changes CTC counts and other 
inflammatory biomarkers.  
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3.0 BACKGROUND & RATIONALE 
3.1 
Need for Adjuvant Therapies for Patients with TNBC 
TNBC is a subtype of breast cancer that affects approximately 15% of breast cancer patients and 
was, until recently, defined as having estrogen receptor (ER) and progesterone receptor (PR) <10% 
positivity by IHC, and Her2 normal, which is 0 or 1+ by IHC, or HER2 2+ by IHC and negative 
by FISH or HER2 negative by FISH if IHC is not performed. More recently, the hormone receptor 
expression cutoff was changed to <1% to qualify as TNBC, although the clinical relevance of this 
has been questioned and patients with 1-9% ER and PR positivity rates are still often managed 
similar to patients with ER and PR <1%. While we have adjuvant treatments for hormone receptor 
positive breast cancer with endocrine therapy that have resulted in significant survival 
improvements, there are currently no approved adjuvant treatments for patients with TNBC. 
TNBC is the most aggressive subtype of breast cancer, and these worse outcomes are most 
pronounced among patients who did not achieve a pCR after neoadjuvant chemotherapy, as shown 
in Figure 1 [1, 2]. Efficacious adjuvant treatments with acceptable toxicity profiles are therefore 
needed for these breast cancer patients who are at highest risk of relapse. One of those efforts 
recently reported was treatment with adjuvant capecitabine [3]. This study reported that disease-
free survival was longer in the group treated with capecitabine than the group without treatment 
(HR 0.7; 95%CI 0.53-0.92). Among the subgroup of patients with TNBC, disease-free survival 
remained significantly better in capecitabine group (HR 0.58 p5%CI 0.39-0.87).   
  
 
 
 Statins as Possible Adjuvant Therapy for Breast Cancer based on Retrospective 
Datasets of Statins in Breast Cancer 
Statins, 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are 
cholesterol-lowering agents that have been long established as agents that significantly reduce 
Figure 1 [1] 
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PI: Carlos H. Barcenas, MD  
Date:  01/10/2023 
 
 
cardiovascular events and overall mortality. They are more recently being recognized to have 
tumor protective effects, which in combination with their favorable toxicity profile makes statins 
a potential candidate for adjuvant therapy of patients with TNBC. Statin use after diagnosis has 
been shown to be associated with improved breast cancer relapse-free survival and lower breast 
cancer mortality in large nationwide and single-institution cohorts [4-9]. Figure 2 summarizes 
findings of several of these studies [10].  
 
The initial report of the protective effect of statin use came from a cohort study of 1945 early stage 
breast cancer survivors participating in the Life After Cancer Epidemiology (LACE) study [6]. 
Pharmacy records showing post-diagnosis statin use in the Kaiser Permanente health plan that 
these patients were enrolled in showed a trend towards decreased risk of recurrence HR 0.67 (0.39-
1.13) if > 100 days statin use was recorded, and HR 0.38 (0.12-1.19) if > 2 years of statin use was 
recorded, with average exposure to statin use of 1.96 years and average follow-up of 7 years from 
diagnosis. Lovastatin was the primary statin used in 84.4% of patients in this study, followed by 
simvastatin in 10.9% of patients. Another United States (US) study by Chae et al retrospectively 
assessed statin use in 703 patients with stage II or III breast cancer diagnosed between 1999 and 
2005 [5]. Use of any statin for greater than 6 months was associated with lower recurrence rate 
(adjusted HR 0.48-0.82), with prescriptions for atorvastatin and simvastatin accounting for 60% 
and of 17%, respectively. The largest US study of 4,216 patients with stage I or II breast cancer 
enrolled in the Group Health health-care delivery found that use of lipophilic statins (atorvastatin, 
simvastatin, lovastatin, fluvastatin, and cerivastatin) was associated with a trend towards decreased 
recurrence, HR 0.76 (0.54-1.05) [7]. The largest and strongest evidence of benefit of statin use 
comes from a nationwide Danish prospective cohort study that included 18,769 patients diagnosed 
with stage I-III breast cancer between 1996 and 2003 [4]; in this study, simvastatin use was 
associated with decreased breast cancer relapse at 10 years after diagnosis (adjusted HR 0.70, 95% 
CI 0.57-0.86, and absolute relapse reduction of 10%).  
 
 
 
 
Figure 2. Association between statin use and the risk of breast cancer recurrence [10]   
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Protocol/Amendment No.: 2018-0550 
PI: Carlos H. Barcenas, MD  
Date:  01/10/2023 
 
 
Our group provided additional support for this protective effect in 723 primary inflammatory 
breast cancer (IBC) patients, in whom we showed that use of atorvastatin at the time of initial 
evaluation was significantly associated with prolonged relapse-free survival (HR 0.48, 95% CI 
0.28-0.84) [8]. Of note, simvastatin use was not found to be significantly associated with improved 
outcomes in this study but the limited patient number (total of 73 patients were on statin therapy) 
may have limited the power of this analysis. In addition to its association with overall decreased 
relapse rates, statin use and simvastatin use in particularly has been studied as a radiosensitizing 
agent. Our group retrospectively studied this in 519 stage III inflammatory breast cancer patients 
who had adjuvant radiation treatment and found that statin use was associated with decreased 
locoregional relapse (adjusted HR 0.40, 95% CI 0.16-1.00) [11], with 2 year and 5 year local 
control rates of 76% and 69%, respectively in the no-statin group compared to 92% and 85%, 
respectively, in the statin group. We further showed that in this cohort locoregional control was 
strongly related to HDL plasma level (discussed in more detail below, Wolfe, IJROBP 2015) and 
that the expression of the HDL cholesterol transporter ABCA1 dictates radio-responsiveness to 
HDL in vitro (Wolfe et al, IJROBP, in press). These retrospective findings justify our central 
hypothesis (Section 2.0) and support our proposal of this clinical trial. These studies additionally 
provide strong hypothesis based leads for the biomarkers studies proposed below. 
 
 Preclinical and Clinical Trial Data of statins in breast cancer 
3.1.2.1 Preclinical Data  
 
The scientific rationale for studying statins, inhibitors of HMG CoA-reductase, in patients with 
TNBC is supported by preclinical in vitro and in vivo data demonstrating the efficacy of these 
agents in preventing breast cancer growth and progression, respectively. Our group has shown in 
in vitro viability assays that therapeutic levels of simvastatin decrease proliferation of TNBC 
(SUM 159, MDA-231, SUM 149) cell lines [12] via cell cycle arrest in G1 phase, a process that is 
reversed by adding mevalonate, a cholesterol pathway component downstream to the effect of 
statin. These effects on proliferation are seen after just 24 hours of pre-treating with simvastatin 
and appear between 48 hours and 8 days after treatment. Simvastatin caused impaired migration 
of these TNBC cell lines, as tested by the Boyden chamber migration assay, and the migratory 
ability of simvastatin treated cells was rescued again by addition of mevalonate. Effect of 
simvastatin on TNBC cancer stem cells was also assessed, since these cells have been hypothesized 
to be metastasis-initiating cells. First, the mammosphere formation assay, which correlates to 
cancer stem cell self-renewal capacity was used and showed that primary sphere formation was 
reduced 75-78% in the TNBC cell lines tested after simvastatin pre-treatment. Additionally the 
spheres that were formed were smaller compared to control DMSO treated cells. Self-renewal 
properties were restored with mevalonate addition.  Mouse models using orthotopic injection of 
green fluorescent protein–labeled SUM 149 cells showed a decreased rate in primary tumor 
formation 20 weeks after injection of cells, from 95% with cells treated with DMSO solution to 
67% with cells treated with therapeutic concentration of simvastatin (p=0.04). There was also a 
decreased rate of metastasis, from 86% with DMSO solution treated cells to 22% with simvastatin 
treatment (p=0.04). To more closely simulate a clinically relevant environment, mice were injected 
with TNBC cell lines in the tail and then after 1 week, half the mice were given drinking water 
containing simvastatin while the other half received water alone. Corroborating the other in vivo 
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experiments, metastasis rate decreased from 70% in control to 20% in simvastatin treated mice 
(p=0.06). Of note, we also showed that simvastatin enhances sensitivity of TNBC and 
inflammatory breast cancer cell lines to radiation treatment. 
 
Several mechanisms have been shown to mediate statin induced decrease in proliferation and 
metastatic potential of breast cancer cells. Several groups have shown that simvastatin causes 
increased expression of the tumor suppressor PTEN and subsequent downregulation of PI3K 
pathway components such as phosphorylated Akt [12-15]. In support of this the Akt inhibitor 
LY294002 has been shown to augment the effect of simvastatin in TNBC cell lines [13]. Our group 
performed proteomic analyses of signaling pathways in the study detailed above and showed 
significant decreases in levels of FOXO3a (pS318) and Akt (pS473) with simvastatin treatment. 
FOXO3a is a tumor suppressor protein that is targeted for degradation by phosphorylation by Akt, 
and was found to be a downstream mediator of the effects of simvastatin. Simvastatin was found 
to decrease phosphorylation of FOX03a and thereby prevent degradation and allow for tumor 
suppressive ability of FOXO3a [12]. Further investigation with knockdown and overexpression 
studies confirmed that FOXO3a, a tumor suppressor transcription factor, mediates simvastatin’s 
antitumor effects and that the decreased proliferation and migratory ability induced by simvastatin 
is negated by knocking out FOXO3a expression. The relevance of FOXO3a expression to breast 
cancer metastases and importance as a possible target with statin treatment was evaluated with 
analysis of 1479 breast cancer patients in 8 publicly available datasets, and showed that decreased 
FOXO3a correlates to decreased metastasis free survival in patients with TNBC.  
 
Other suggested intracellular mechanisms include inhibition of NF-kB transcription factor [15-18] 
and promotion of apoptosis. NF-kB proteins are a family of transcription factors that are involved 
in control of many normal cellular processes, such as immune and inflammatory responses, 
development, cellular growth, and apoptosis. The NK-kB system is dysregulated in a number of 
disease states such as cancer. Simvastatin was shown to inhibit the DNA binding and 
transcriptional activities of NF-kB [15] with resultant downstream effect on PTEN (increased 
transcription) as well as anti-apoptosis protein BCL-XL (decreased transcription) [15, 17-19]. In 
addition to suppression of anti-apoptotic protein BCL-XL, simvastatin has been shown to 
upregulate pro-apoptotic c-Jun N-terminal kinase (JNK), death receptor-5, and CCAAT/enhancer 
binding protein homologous protein pathway, leading to simvastatin induced apoptosis. Both NF-
kB and apoptotic processes were shown to be dependent on HMG-CoA reductase activity as the 
effects of simvastatin were reversed with addition of mevalonate [16, 19]. 
 
The mevalonate and cholesterol pathways appears to mediate many of the anti-tumor effects of 
simvastatin as many of the above processes are negated with addition of mevalonate. Statins are 
inhibitors of HMG CoA reductase and this enzyme is the rate limiting step of cholesterol 
precursors such as farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) [20]. 
These 2 proteins are responsible for translocation of Ras and Rho, respectively, to the cell 
membrane. Ras is a GTPase that is an important component of intracellular signaling and is 
frequently dysregulated in human cancers. Delocalization of RhoA from the cell membranes 
results in disorganization of actin fibers and disappearance of focal adhesion sites, which is 
reversed after statin treatment with adding GGPP back to cell media. The mevalonate pathway 
also provides metabolites for post-translational modifications that have been found to stimulate 
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histone deacetylases and DNA methyltransferase that affect cancer signaling pathways through 
epigenetic changes [21]. Genome wide RNAi analysis showed that inhibition of multiple 
components of the mevalonate pathway potentiates statin induced apoptosis [22].  
 
Systemic cholesterol reduction has also been suggested to be an important antitumor-mediating 
mechanism [23] of statin treatment. Our group showed that VLDL increases and HDL decreases 
mammosphere formation in IBC cell lines SUM 149 (TNBC) and KPL4. Retrospective analysis 
of IBC cohorts supported this effect by showing that higher VLDL values >30 mg/dL and low 
HDL values < 60 mg/dL predicted for lower 5-year overall survival. For hormone receptor positive 
breast cancer, it was shown that 27-hydroxycholesterol is a primary metabolite of cholesterol as 
well as an ER and liver X receptor ligand and was found to cause ER-dependent growth and LXR-
dependent metastasis in mouse models of breast cancer. 
 
Statins have been well established to have anti-inflammatory properties and decrease high 
sensitivity CRP (shCRP) and ESR in cardiac patients. Statin immunomodulatory roles are only 
beginning to be understood, however, particularly in the cancer setting where the importance of 
immune surveillance and immunotherapeutics are now fully being realized. Suppression of TNF-
a induced IL-6 secretion has been demonstrated in MCF-7 breast cancer cell lines after treatment 
with pitavastatin [16]. Our group has also shown that simvastatin suppresses recruitment of 
macrophages to tumor via IL-6 inhibition (data not published). Statin effect on tumor associated 
macrophages (TAM) was also seen in a melanoma mouse model in which a long acting liposomal 
encapsulated formulation of simvastatin mediated potent antitumor activity through a reduction in 
TAM induced oxidative stress and production of hypoxia-inducible factor 1 α (HIF-1 α) in tumors 
(Alupei MC). Additionally, in healthy individuals as well as acute coronary syndrome patients, 
statins have been shown to increase frequency of CD4+FOXP3+ regulatory T cells [24, 25].  
 
Based on these findings, we hypothesize that atorvastatin has antitumor effects and improve 
recurrence free survival in patients with TNBC who did not achieve a pCR after preoperative 
chemotherapy. 
 
3.1.2.2 Clinical Data 
 
Several pre-surgical window of opportunity trials have been completed or are underway evaluating 
the efficacy of neoadjuvant statin treatment in breast cancer patients. Bjarnadottir et al showed in 
50 patients with primary invasive breast cancer that treatment with 2 weeks of atorvastatin 80 mg 
before surgery led to a statistically significant decrease in Ki-67 by 7.6% and increase in HMG-
CoA reductase [26]. This group then performed another phase II trial to explore mechanisms of 
reduced Ki-67 expression in 42 patients with primary invasive breast cancer and again did a 2 
week window of opportunity study with atorvastatin 80 mg for 2 prior to surgery [27]. They found 
that there was significant decrease in cyclin D1 and increase in tumor suppressive protein p27. A 
similarly designed phase 2 trial with fluvastatin in stage 0/1 breast cancer showed a decrease in 
Ki-67 and increase in markers of apoptosis with cleaved caspase-3 in high grade patients only [28]. 
Additional pre-surgical studies are underway to assess effect of simvastatin on proliferation and 
apoptosis in basal subtype of primary breast cancer (NCT00807950), effect of rosuvastatin on 
proliferation in hormone receptor positive breast cancer (NCT02483871), assessment of 
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mechanisms of action of atorvastatin in reducing Ki-67 (NCT02416427), and efficacy of 
combination of statin treatment with metformin (NCT01980823) again assessed by change in Ki-
67. No unexpected toxicities aside from what is known from treatment of cardiovascular patients 
have been reported in these studies.  
 
In addition to studies in primary breast cancer, additional studies have evaluated statin therapy in 
patients at high risk of developing breast cancer. Patients with BRCA 1, BRCA 2, CDH1, or TP53, 
personal history of breast cancer, or lifetime risk >20% by Claus model were treated with 40 mg 
lovastatin for 6 months and had mammographic density and breast duct cytology assessed [29]. 
The study showed technical feasibility and that the drug was well tolerated but showed no 
significant change in endpoints. Another trial underway is a single arm phase 2 of simvastatin for 
24-48 weeks in patients with DCIS or stage I-III breast cancer to prevent second new breast cancer, 
assessing changes in biomarkers such as hsCRP, AKT and p-AKT, cyclin D2, Twist, and 
contralateral tumor density (NCT00334542). Chemoprevention of atorvastatin is being evaluated 
in a randomized phase II trial of 100 patients at high risk of breast cancer treating, treating patients 
with 1 year atorvastatin and measuring change in breast density (NCT00914017). Another 
atorvastatin chemoprevention trial instead is administering 3 months of drug in patients with DCIS 
or LCIS and measuring Ki-67 on breast biopsies as a biomarker trial (NCT00637481). Simvastatin 
is also being tested in this setting in a phase II trial of patients at high risk for non-hormone receptor 
responsive breast cancer, assessing markers such as Ki-67 in ductal lavage as endpoint [30].  
 
The improvement in proliferation markers seen in the above completed studies highlight that statin 
therapy has biological activity in breast cancer patients. Notably, the studies listed above are trials 
with either laboratory biomarker or imaging endpoints without clinical evaluation of efficacy. 
Additionally, due to easier feasibility, they have evaluated patients in pre-surgical settings but not 
in the adjuvant setting of high risk patients where there is currently a critical need for effective and 
well tolerated treatments. The trial detailed in this protocol, therefore, is an important first step to 
understanding clinical activity of statin treatment in breast cancer management, identifying 
biomarkers of this clinical response, studying efficacy in the adjuvant setting where there is 
currently a lack of data on statin treatment, and addressing a high patient subpopulation for whom 
adjuvant treatments are critically needed.  
 
Given support of biologic effect seen in above clinical studies, we hypothesize that adjuvant statin 
use can be effective in reducing the risk of recurrence in TNBC patients who did not achieve a 
pCR to neoadjuvant chemotherapy, a breast cancer subpopulation for which we do not have 
standard of care adjuvant treatment options and is at high risk for relapse. We propose to administer 
atorvastatin to this patient cohort in a phase 2 trial to assess clinical and biologic efficacy as well 
as identify biomarkers of response. 
   
 Rationale for Dose Selection/Regimen/Modification  
The American College of Cardiology and American Heart Association released new lipid 
guidelines in 2018 with recommendations on statin use for lipid management as shown in Figure 
3 below [31]. According to these guidelines, patients are eligible for either moderate intensity 
statin therapy or high intensity statin therapy based on age, presence of diabetes, clinical 
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atherosclerotic cardiovascular disease risk (ASCVD), elevated 10 year ASCVD risk score based 
on an online risk calculator (http://tools.acc.org/ASCVD-Risk-Estimator/), and baseline lipid 
profile. Clinical ASCVD consists of ACS, those with history of MI, stable or unstable angina or 
coronary other arterial revascularization, stroke, transient ischemic attack (TIA), or peripheral 
artery disease (PAD) including aortic aneurysm, all of atherosclerotic origin. Figure 3 shows the 
classification of available statin drugs by level of intensity. For our study we will be employing 2 
dose levels so that we appropriately treat patients based on lipid guidelines. We will use 
atorvastatin 20 mg as our moderate intensity statin and atorvastatin 40 mg as our high intensity 
statin. The use of atorvastatin for choice of statin treatment in this study is supported by evidence 
of biologic activity demonstrated in pre-surgical window of opportunity breast cancer trials as 
described in 3.1.2.2. 
All TNBC patients who are not receiving statin therapy and do not have a known contraindication 
to statin therapy will be eligible to participate in this study. Baseline lipids and risk factors will be 
assessed at time of initiation of study. For patients who are recommended to receive statins based 
on the most recent 2018 lipid guidelines, the algorithm illustrated in Figure 4 (Primary prevention) 
and Figure 5 (Secondary prevention) will be applied and patient will be started on moderate 
intensity atorvastatin 20 mg or high intensity atorvastatin 80 mg by mouth daily as described. Of 
note, though the majority of preclinical work done in our lab is based on simvastatin, our 
retrospective study of IBC patients and pre-surgical window of opportunity breast cancer trials as 
described in 3.1.2.2 support that the anti-breast cancer effect is seen with atorvastatin in addition 
to other statins. Importantly, unlike simvastatin which is only a moderate intensity statin, 
atorvastatin can be dosed both as a moderate intensity as well as high intensity statin as needed to 
comply with standard of care cardiovascular guidelines (http://tools.acc.org/ASCVD-Risk-
Estimator/).  
 
  
High Intensity 
Moderate Intensity 
Low Intensity 
LDL-C Lowering 
>=50% 
30-49% 
<30% 
Statins 
Atorvastatin 40mg/80mg 
Rosuvastatin 20mg/40mg 
Atorvastatin 10mg/20mg 
Rosuvastatin 5mg/10mg 
Simvastatin 20-40mg 
Simvastatin 10mg 
  
  
Pravastatin 40mg/80mg  
Lovastatin 40mg/80mg 
Fluvastatin XL 80mg 
Fluvastatin 40mg BID 
Pitavastatin 1-4mg 
Pravastatin 10-20mg 
Lovastatin 20mg 
Fluvastatin 20-40mg 
 
 
 
 
Figure 3 Dose recommendation for each risk category  
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Figure 4 ASCVD risk stratification algorism (Secondary prevention) [31] 
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Figure 4 Dose recommendation for each risk category [31] 
 
 
 
Figure 5 ASCVD risk stratification algorism (Secondary prevention) [31] 
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 Rationale for Correlatives 
1) We will measure CTCs and ctDNA as a burden of metastatic cells and will assess their 
changes during statin treatment. CTCs can be found in human blood when cancers undergo 
metastatic dissemination and spread to distant organs [32]. Our previous work 
demonstrated that circulating tumor cells at the end of neoadjuvant chemotherapy in 
patients with TNBC are predictive of worse outcomes, including 2 year recurrence rate 
[33]. CTCs have been reported as a surrogate marker for tumor response and linked to 
shorter survival in metastatic breast, prostate and colorectal lung cancer patients [32, 34-
38]. We will therefore also calculate changes in CTCs and ctDNA during treatment and 
correlate to 2 year RFI. These correlatives will therefore both assist in evaluating efficacy 
of statin treatment as well as developing and testing these platforms to monitor adjuvant 
treatment in breast cancer patients.  
2) We will test serial serum lipid profiles, markers of inflammation: ESR, high sensitivity 
CRP, IL-6, and immune profiling, and evaluate if these behave as biomarkers of response 
to atorvastatin treatment. Please see section 3.1.2 for preclinical work supporting the 
rationale for testing of these studies. 
3) Up to 5 unstained slides of tumor and normal tissue from the mastectomy specimen will be 
used for multiplexed imaging of hypothesis based biomarkers and staining correlated to 
clinical outcomes as well as other correlatives. We will include imaging such as, but not 
limited to IL6R, gp130, cholera toxin for lipid rafts, multi-marker labelling of macrophages 
and stem cells. 
4) Additional blood samples and mastectomy tumor formalin fixed paraffin embedded slides 
will be banked for future testing of additional studies pending the above studies. Additional 
tests that may be run in the future include components of the cancer signaling pathways 
shown to mediate statin effects as detailed in section 3.1.2 and components of the 
mevalonate/HMG Co-A reductase pathway. 
 Study Endpoint  
This is a multicenter pilot study including MD Anderson Cancer Network sites. The primary 
endpoint is the proportions of patients with undetectable CTC at 6 months in patients with stage 
IIB/III TNBC who did not achieve a pCR nor had a residual cancer burden (RCB)-I after 
neoadjuvant chemotherapy with and without atorvastatin; we will enroll patients who had an 
RCB-II or RCB-III (if TNBC), or non-pCR (if IBC). The positive outcome is defined either 
CTC’s remaining non-detected when baseline CTC is not detected or reduction of the absolute 
number in CTCs when baseline CTC is detected. If positive outcome is observed with 
atorvastatin in more than 6 patients among the first 30 patients enrolled, the next step in this 
clinical study is to enroll 50 additional patients to assess CTC changes in patients who were 
treated either with atorvastatin (N=18) or without atorvastatin (N=32). CTC change is defined 
either a CTC measurement becoming negative in patients who have baseline positive CTCs, or a 
CTC measurement becoming positive in patients who have a baseline negative CTC.   
 
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The secondary endpoints will align with the secondary objectives to understand the underlying 
biology of atorvastatin-induced changes and potential associations with the clinical outcome of 
interest, 2-year RFS. For this reason, study treatment will continue for 2 years in order to explore 
the kinetics and magnitude of pharmacodynamic changes in biomarkers including inflammation 
markers (C-reactive protein, ESR, serum IL-6 and other cytokines), CTCs and lipid profiles over 
the course of the study. The patients on the study who will not receive atorvastatin will be 
followed and provide longitudinal data on the natural behavior of inflammation and lipid 
pathways in patients with TNBC including triple negative IBC. 
The exploratory objective that relates to patients in cohort 4 who will not receive xeloda or have 
already completed prior to the determination of need for atorvastatin is added to learn about the 
changes in CTCs and inflammatory biomarkers as a result of xeloda.  Xeloda is currently a 
standard of care based on the CREATE-X study, yet no CTC work has been published showing 
if CTCs are eliminated by this type of chemotherapy. 
 
4.0 METHODOLOGY 
4.1 
Entry Criteria 
Informed consent from each subject must be obtained prior to enrolling at the clinic visit or 
remotely (electronic informed consent). The method of obtaining and documenting the informed 
consent and the contents of the consent must comply with ICH-GCP and all applicable 
regulatory requirements. Informed consent for this study may only be obtained by the Principal 
Investigator or the assigned designee. This delegation will be included on a protocol delegation 
log that will be signed by the site’s PI. Informed Consent Forms for enrolled patients and for 
patients who are enrolled but not eligible to receive study treatment (screening failures) will be 
maintained at the study site. The site investigator will maintain a screening log to record details 
of all patients screened and to confirm eligibility or record reasons for screening failure, as 
applicable.  
 
All participants must be registered in the Clinical Oncology Research (CORe) system at MD 
Anderson with the correct corresponding institution and investigator.  This will result in a unique 
study number being assigned to each patient. Patients must not start protocol intervention prior to 
the registration in CORe. 
 
To register a patient, participating Cancer Network Site should upload the following documents 
into the institutionally approved cloud-based storage folder: 
• Signed informed consent and documentation of the informed consent process 
• HIPAA authorization form (if separate from the informed consent document) 
• Completed eligibility checklist with supporting source documents for each criterion 
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Patients will be registered in CORe by 2 steps by a member of the Cancer Network Research 
Team and an email receipt will be sent to the participating Cancer Network Site including the 
registration details and assigned protocol patient identification number (PPID#). 
 
 Inclusion Criteria 
1. Is willing and able to provide written informed consent for the trial. 
2. Is a female or male and ≥ 18 years of age at diagnosis of TNBC (including patients with a 
clinical diagnosis of triple negative inflammatory breast cancer).  
3. Has histological confirmation of breast carcinoma. 
4. Have stage IIB or III disease as defined by the American Joint Committee on Cancer version 
7 or 8. 
5. Has confirmed TNBC, defined as having estrogen and progesterone receptor <10% 
positivity by IHC and HER2 normal, which is 0 or 1+ by IHC and negative by FISH if 
performed or HER2 2+ by IHC and negative by FISH or HER2 negative by FISH if IHC is  
not performed.  
6. Received neoadjuvant chemotherapy and did not achieve pCR nor had an RCB-I (we will 
enroll patients with an RCB-II or RCB-III) following neoadjuvant chemotherapy. Since the  
RCB index has not been validated in IBC, any amount of residual disease will be allowed.  
pCR is defined as: 
a) the absence of residual invasive cancer on hematoxylin and eosin evaluation of the 
complete resected breast specimen and all sampled regional lymph nodes following 
completion of neoadjuvant systemic therapy (i.e., ypT0/Tis ypN0 in the current AJCC 
staging system).  
Or  
 
b) the absence of residual invasive and in situ cancer on hematoxylin and eosin evaluation 
of the complete resected breast specimen and all sampled regional lymph nodes 
following completion of neoadjuvant systemic therapy (i.e., ypT0 ypN0 in the current 
AJCC staging system) 
7. Has a performance status of 0-1 on the ECOG Performance Scale. 
8. Has adequate organ function as determined by the following laboratory values:  
ANC ≥ 1,500 /mcL, Platelets ≥ 100,000 /mcL, Hgb ≥ 8 g/dL, creatinine levels < 2.0 x ULN, 
Total bilirubin ≤ 1.5 x ULN, ALT and AST ≤ 3.0 x ULN  
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9. Subjects of childbearing potential should be willing to use effective methods of birth control 
or be surgically sterile, or abstain from heterosexual activity for the course of the study 
through at least 4 months after the last dose of study drug. Subjects of childbearing potential 
are those who have not been surgically sterilized or have not been free from menses for > 1 
year. Effective methods of birth control include 1). Use of hormonal birth control methods: 
pills, shots/injections, implants (placed under the skin by a health care provider), or patches 
(placed on the skin); 2). Intrauterine devices (IUDs); 3). Using 2 barrier methods (each 
partner must use 1 barrier method) with a spermicide.   Males must use the male condom 
(latex or other synthetic material) with spermicide.  Females must choose either a 
Diaphragm with spermicide, or Cervical cap with spermicide, or a sponge (spermicide is 
already in the contraceptive sponge).  
10. Within 12 months from completion of definitive surgery after neoadjuvant chemotherapy at 
the time of consent.  
11. Willing to take statin for minimum of two years. 
 Exclusion Criteria 
1. Has not recovered from adverse events due to prior therapies, i.e. monoclonal antibody, 
chemotherapy, targeted small molecule therapy, radiation therapy, or surgery.  
- 
Note:  Subjects with ≤ Grade 2 neuropathy, alopecia and general disorders and 
administration site conditions (per CTCAE version 4.0) are an exception to this 
criterion and may qualify for the study. 
2. Has a known malignancy (other than breast cancer) except basal cell carcinoma or 
squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone 
potentially curative therapy.   
3. Has known psychiatric or substance abuse disorders and assessed by attending physician 
that would interfere with cooperation with the requirements of the trial. 
4. Has received prior therapy with a statin within past 6 months or is currently receiving statin 
therapy.  Patients who previously received a statin more than 6 months prior to beginning 
study therapy and who discontinued treatment for reasons other than severe toxicity or 
allergic reaction are eligible. 
5. Is currently receiving another anti-lipidemic agent other than statin: fibric acid derivatives 
(i.e. fenofibrate, gemfibrozil), bile acid sequestrants (i.e. cholestyramine, colestipol), 
Ezetimibe, niacin, Lovaza (omega-3-acid ethyl esters), red yeast rice, Orlistat, phytosterol, 
and lomitapide.  
6. Known hypersensitivity to statin or any component of the formulation. 
7. Active liver disease or unexplained persistent elevations of serum transaminases, defined 
as elevated transaminases > 3x ULN on at least 2 separate occasions 1 week apart. 
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8. Pregnancy or women who may become pregnant and not on acceptable form of 
contraception. Lactating women. 
9. Has evidence of distant metastasis.  
10. Record of myocardial infarction within 6 months before starting therapy, symptomatic 
congestive heart failure (New York Heart Association > class II), unstable angina, or 
unstable cardiac arrhythmia requiring medication. 
11. Chronic steroid use as this may prevent any immunomodulatory roles of statin treatment, 
defined as anticipating need of supraphysiologic dose of steroids for at least 12 weeks while 
on study.     
 
4.2 
Treatment Plan 
• After surgery, the attending physician will determine the need for adjuvant xeloda and 
radiation, and decide the sequence of these. Based on this information, the patient will be 
enrolled into cohorts 1-4 as applicable. 
• Patient will have a consultation with study cardiologist who will determine the need for 
statin treatment based on ASCVD criteria and clinical judgement. If the patient is planned 
for adjuvant xeloda, the cardiology consult (and baseline labs) will be done at the end of 
xeloda, prior to when atorvastatin would be considered.   
• All patients who are recommended for high- or moderate-intensity statin assessed by 
cardiologist will start atorvastatin with the dose recommended in the guideline (Figures 3, 
4, and 5.) 
• All patients who do not meet the criteria for statin treatment based on ASCVD risk 
stratification and/or clinical judgement will be followed and have blood collected at the 
same time points without statin treatment.  
• All patients enrolled in Cohort I and Cohort II whoever are eligible for atorvastatin 
treatment will start atorvastatin treatment with radiation therapy; and all patients enrolled 
in Cohort III whoever are eligible for atorvastatin treatment will start atorvastatin 
treatment after the completion of xeloda treatment; and all patients enrolled in Cohort IV 
whoever eligible for atorvastatin treatment will start atorvastatin treatment after 
cardiology consultation 
• After 2 years treatment or follow up, patients will be off study, but may continue statin 
treatment based on physician discretion.  
 
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 Dose Selection:  
Atorvastatin 20 mg or 40 mg will be administered by mouth daily depending on whether 
the patient requires high intensity statin (atorvastatin 40 mg) based on cardiovascular risk 
factors (3.1.3) or moderate-intensity (atorvastatin 20 mg). 
 
  Toxicities and Dose Modification: Atorvastatin  
• Adverse events (both non-serious and serious) associated with statin exposure may occur 
shortly after the first dose or several months after the last dose of treatment. Statin therapy 
must be withheld for drug-related toxicities and severe or life-threatening adverse events 
as per Table 2 below.  
 
• The most commonly observed significant adverse reactions and associated frequencies are 
diarrhea (7-14%), arthralgias (9-12%), nasopharyngitis (13%), hemorrhagic stroke (2%), 
insomnia (5%), diabetes mellitus (6%), nausea (7%), dyspepsia (6), urinary tract infection 
(7-8%), elevated serum transaminase (</- 2%), limb pain (9%), myalgias (4-8%), 
musculoskeletal pain (5%), muscle spasms (4-5%), and pharyngolaryngeal pain (3-4%).  
 
• Other rare and significant toxicities seen in < 2% of patients include abdominal pain, 
abnormal hepatic function tests, alopecia, anaphylaxis, anemia, angioedema, anorexia, 
cholestasis, cholestatic jaundice, cognitive dysfunction (reversible), confusion (reversible), 
depression, elevated glycosylated hemoglobin (HbA1c), epistaxis, eructation, erythema 
multiforme, gynecomastia, hematuria, hepatic failure, hepatitis, hyperglycemia, 
hypoesthesia, increased creatinine phosphokinase, increased serum alkaline phosphatase, 
increased serum glucose, jaundice, joint swelling, muscle fatigue, myasthenia, myopathy, 
myositis, neck stiffness, nightmares, pancreatitis, paresthesia, peripheral edema, peripheral 
neuropathy, 
rhabdomyolysis, 
rupture 
of 
tendon, 
Stevens-Johnson 
syndrome, 
thrombocytopenia, and toxic epidermal necrolysis 
Hepatotoxicity 
If serious hepatotoxicity with clinical symptoms and/or hyperbilirubinemia/jaundice occur during 
treatment, atorvastatin therapy should be discontinued. If alternate etiology is not identified, 
atorvastatin should be permanently discontinued. If alternate etiology is identified and corrected, 
atorvastatin can be restarted once liver function tests return to normal values. Excessive ethanol 
consumption should be avoided as this can potentiate adverse hepatic effects of statin therapy. 
Myopathy/Rhabdomyolysis 
Patients should be instructed to report unexplained muscle pain, tenderness, weakness, or brown 
urine, particularly if accompanied by malaise or fever. Manage according to Table 2. 
Baseline hypothyroidism, Vitamin D, etc. should be tested and corrected if found to be abnormal 
to minimize risk of statin induced myopathy. Concurrent use of medications (see section 6.3.2) 
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that potentiate myopathy such as CYP3A4 inhibitors of fibrates should be avoided. Uncomplicated 
myalgia immune-mediated necrotizing myopathy (IMNM) associated with HMG-CoA reductase 
inhibitors use has also been reported.  
Renal Impairment 
No dose changes are required for renal impairment but this increases risk of myopathy so patient 
should be closely monitored. 
Pregnancy and Lactation 
Studies in animals and pregnant women have shown evidence of fetal abnormalities and use is 
contraindicated in women who are or may become pregnant. There are reports of congenital 
anomalies following maternal use of HMG-CoA reductase inhibitors in pregnancy. Cholesterol 
biosynthesis may be important in fetal development; serum cholesterol and triglycerides increase 
normally during pregnancy. HMG-CoA reductase inhibitors should be discontinued prior to 
pregnancy (ADA 2013). The manufacturer recommends administration to women of childbearing 
potential only when conception is highly unlikely and patients have been informed of potential 
hazards. 
It is not known if atorvastatin is excreted in breast milk. Due to the potential for serious adverse 
reactions in a nursing infant, use while breast-feeding is contraindicated by the manufacturer. 
Table 2    Dose Modification Guidelines for Statin Related Adverse Events: 
Toxicity 
Severity 
Management including Treatment Discontinuation 
Myopathy 
Mild 
symptoms 
Continue without change in statin treatment. . Evaluate 
patient for other conditions that may increase the risk for 
muscle symptoms (i.e. hypothyroidism, reduced renal or 
hepatic function, rheumatologic disorders such as 
polymyalgia rheumatica, steroid myopathy, vitamin D 
deficiency, or primary muscle diseases). Measure CK and 
follow algorithm as detailed in CK section below. 
Moderate 
symptoms 
Evaluate for other conditions that may increase risk for 
muscle symptoms. Discontinue use until symptoms can 
be evaluated. Hold treatment until symptom resolution. 
Upon resolution, resume the original dose of atorvastatin. 
If muscle symptoms recur, dose reduce or change to 
alternate statin (pravastatin). If symptoms re-occur at 
lower dose, change to alternate statin. Measure CK and 
assess for rhabdomyolysis.  
Severe 
symptoms 
Discontinue use until symptom resolution. Re-challenge 
at lower dose or alternate statin (pravastatin). If re-occurs 
at lower dose, change to alternate statin. Measure CK and 
assess for rhabdomyolysis. 
CK elevation 
< 10x ULN 
Continue statin at same dose with close monitoring of 
symptoms. Workup for secondary causes and treat as 
indicated. 
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Toxicity 
Severity 
Management including Treatment Discontinuation 
>10x normal 
Evaluate for rhabdomyolysis (creatinine, myoglobinuria, 
and treat if patient has). If no rhabdomyolysis, repeat 1 
week later and discontinue if persistently > 10x ULN. 
Workup for secondary causes and treat as indicated.  
Rhabdomyolysis 
n/a 
Permanently discontinue. Treat with hydration, etc. per 
guidelines. 
Hepatic injury 
Bilirubin > 1.5 
ULN or 
clinical 
evidence of 
hepatotoxicity 
Discontinue treatment. If alternate etiology is not 
identified, atorvastatin should be permanently 
discontinued. If alternate etiology is identified and 
corrected, atorvastatin can be restarted once liver function 
tests return to normal values. 
AST or ALT 
1-3x ULN 
Continue same dose and type of statin and monitor 
closely. 
AST or ALT 
> 3x ULN  1 
week apart 
Repeat 1 week later. If still elevated at 3x ULN, dose 
reduce or discontinue treatment. Workup for other causes 
of liver injury and restart statin if LFTs improve or 
alternate etiology identified. 
Type 2 diabetes 
mellitus (new 
diagnosis) or 
hyperglycemia 
T2DM or  
3-4 
Recommend standard of care management of patients if 
this is discovered. Refer to primary care physician. No 
change in statin dose or type indicated. 
Kidney injury 
3-4 
Evaluate for rhabdomyolysis and permanently 
discontinue if workup supports this. Otherwise, continue 
at present dose. Monitor closely for statin associated 
adverse events.  
Cognitive Impairment 
 
If felt to be related to statin treatment, hold and see if 
symptoms improve in 3 weeks. Can then restart treatment 
if improvement. Workup for alternate etiologies. 
All Other Drug-
Related Toxicity1 
Grade 1 or 2 
No change in statin dose or type indicated. 
 
3  
Hold statin if deemed by investigator to be related to 
statin therapy only. Defer to PI regarding re-introduction 
of statin upon improvement to grades 1/2 toxicity. 
4 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
1Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  
Permanently discontinue study drug for persistent Grade 2 adverse reactions for which treatment with study drug has been 
held, that do not recover to Grade 0-1 within 12 weeks of the last dose. 
 
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons not 
related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, and/or 
holidays). Subjects should be placed back on study therapy within 3 weeks of the scheduled 
interruption. The reason for interruption should be documented in the patient's study record. 
 
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 Toxicities and Dose Modification: Atorvastatin and Radiation Therapy (RT) 
Radiation therapy will be performed as per standard of care at each institution (i.e. once or twice 
per day, with a total dose of about 60-66Gy over 4-6 weeks). Statin administration will commence 
prior to, with/after starting radiation, after collecting baseline blood sample based on whichever 
cohort the patient is enrolled in. 
 
Statin therapy must be withheld during radiation for the following adverse events: 
 
Confluent moist desquamation, defined as presence of a single region of moist 
desquamation that exceeds 100 cm2 in area (this is specified because chest wall radiotherapy 
with bolus to 50 Gy followed by boost to total dose of 60-66 Gy commonly leads to smaller 
areas of desquamation even in the absence of sensitizing agents). 
* Note that areas of moist desquamation smaller than 100cm2 in area will be scored as Grade 
2 radiation dermatitis for the purposes of this study, but bleeding induced by minor trauma 
or abrasion will be considered Grade 3 and scored as a DLT 
 
 Any toxicity requiring a radiotherapy delay exceeding 1 week 
If statin therapy is withheld during RT, it may be started again 2 weeks after completion of RT 
provided that no criteria described above in section 4.2.2 has been met. 
 
Each patient receiving RT will be followed for evaluation of toxicity according to each site’s 
institutional policies. The recommendation is to follow for twelve weeks with weekly assessments 
throughout the approximate six-week course of radiotherapy and at a six-week post completion 
visit. Cancer Network Sites patients are required to undergo all treatments, follow-up 
appointments, and adverse events management at their consenting facility to collect the protocol 
required data. 
 
4.3 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications specifically prohibited in the exclusion criteria are not allowed during the ongoing 
trial.  If there is a clinical indication for one of these or other medications specifically prohibited 
during the trial, discontinuation from trial therapy may be required.  The final decision on any 
supportive therapy rests with the investigator and/or the subject's primary physician. 
  
 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be administered 
at the discretion of the investigator in keeping with the community standards of medical care. 
Concomitant medication will be recorded as standard of care in clinic database.  
 Prohibited Concomitant Medications  
• Statins are substrates of CYP3A4 (major), P-glycoprotein, and SLCO1B1. They are 
also inhibitors of CYP2C8 (weak), CYP2C9 (weak), and CYP2D6 (weak). They 
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thereby can weakly interfere with metabolism of other drugs and vice versa. Subjects 
are prohibited from receiving the following therapies during the study: acipimox, 
azithromycin, 
bezafibrate, 
ciprofibrate, 
colchicine, 
fenofibrate, 
gemfibrozil, 
ketoconazole, voriconazole, naloxegol, niacin, niacinamide, ombitasvir, paritaprevir, 
ritonavir, and dasabuvir, raltegravir, red yeast rice, aprepitant, boceprevir, bile acid 
sequestrants, clarithromycin, cobicistat, conivaptan, cyclosporine, cyproterone , 
daclatasvir, danazol, dasatinib, efavirenz, dronedarone, erythromycin, diltiazem, 
fluconazole, fosaprepitant, itraconazole, ivacaftor, luliconazole, mifepristone, 
netupitant, 
ombitasvir, 
paritaprevir, 
ritonavir, 
and 
dasabuvir, 
osimertinib, 
posaconazole, protease inhibitors, quinine, ranolazine, sacubitril, simeprevir, 
stiripentol, telaprevir, telithromycin, ticagrelor, tipranavir, verapamil, fusidic acid, 
large quantities of grapefruit juice, amiodarone, antacids, bexarotene, bosentan, 
deferasirox, enzalutamide, fosphenytoin, etravirine, mitotane, osimertinib, phenytoin, 
rifamycin derivatives, siltuximab, St Johns Wort, tocilizumab, edoxaban, ledipasvir, 
prucalopride, rifaximin, silodosin, aliskiren, digoxin, midazolam, verapamil, 
aripiprazole, dofetilide, nimodipine, pimozide, lomitapide, flibanserin, eltrombopag, 
teriflunomide, lanthanum 
• Atorvastatin may decrease concentration of dabigatran so caution should be used 
during concomitant use. Statin treatment can enhance the adverse effects of 
daptomycin. Consider temporarily stopping statin prior to daptomycin. If used together, 
regular (i.e., at least weekly) monitoring of CK concentrations is recommended. 
Atorvastatin can also enhance toxic effects of cimetidine and spironolactone and 
requires close monitoring. 
• Chronic use of supraphysiologic doses of steroids as this can mitigate any 
immunomodulatory effects of statin treatment. 
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial.  Subjects may receive other 
medications that the investigator deems to be medically necessary. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
4.4 
Rescue Medications & Supportive Care 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Supportive care should therefore be provided as part of standard of care. 
Of note patients should be encouraged to hydrate if having symptoms of myopathy. If evidence 
of rhabdomyolysis, patients will likely need to be admitted for intravenous hydration. 
 
4.5 
Subject Withdrawal/Discontinuation Criteria 
In this study, statin administration will continue until one of the following conditions is 
observed. 
 
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4.5.1. Disease progression 
Disease progression will be defined as biopsy-confirmed recurrence of cancer either locally or at 
any distant site. 
 
4.5.2 Noncompliance:   
If the patient is not able to compliant with the treatment schedule in the absence of toxicity, the 
study treatment should be discontinued for the patient. Noncompliance is defined as an 
unscheduled dose interruption lasting ≥14 days without a documented reason agreed upon by the 
investigator for patient safety. 
 
4.5.3. Sustained side effects: 
Study treatment will be discontinued for patients who have sustained toxic effects that are 
attributed to the study drug and require a dose interruption lasting more than 12 weeks.  
 
4.5.4. Initiation of new anticancer treatment:   
In patients for whom the investigator, in his or her judgment, determines new treatment for breast 
cancer is warranted, the study treatment may be discontinued.   
 
4.5.5. Patient withdraws consent.  
In the event that a patient withdraws consent, the reason(s) for withdrawal must be documented. 
Patients must be informed that their participation in the study is voluntary and that they may choose 
not to take part in the study or to stop taking part at any time. If a patient chooses not to take part 
in the study or to stop at any time, his/her future medical care or medical benefits will not be 
affected.  
 
4.5.6. Patient has completed 24 months of treatment.  
 
4.5.7. If the patient requires or is using any prohibited medication listed on section 4.3.2 during 
study therapy period.  
 
4.6 
Criteria for Disease Control  
The secondary purpose of this study is to estimate recurrence rate with addition of statin therapy 
to adjuvant treatment of patients with TNBC who did not achieve a pCR after neoadjuvant 
chemotherapy.  
 
4.6.1. Response will not be considered evaluable in the following categories: 
4.6.1.1. Early Deaths: Patients who die within the first 2 weeks of the initiation of drug therapy 
owing to concurrent disease. These cases will be considered treatment failures in the intent-to-treat 
analysis. 
4.6.1.2. Lost to Follow-up:  Patients for whom there is inadequate information to judge tumor 
response because of loss of contact with our institution (>2 months after a missed appointment) 
and with referring physician in spite of repeated attempts to locate them. These cases will be 
considered treatment failures in the intent-to-treat analysis. 
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4.6.1.3. Major Protocol Violation:  Patients who significantly deviate from the treatment program 
by either adding or deleting another agent or another therapeutic maneuver or by modifying 
schedule substantially (delay treatment ≥14 days without administration reason) of the drug under 
evaluation. Patients who did not fulfill the requirements outlined under Patient Eligibility are also 
included in this category. 
5.0 STUDY FLOW CHART 
Trial Period: 
Screening 
Pre-
xeloda 
Baselineh 
Baseline 
(pre-
statin) 
During  
RTf 
3M 
 
6M, 12 M, 18M, 24M or 
disease progression 
Scheduling Window (Week): 
 
 
± 2 
 
± 4 
± 6 
Informed Consent 
x 
 
 
 
 
 
Inclusion/Exclusion Criteria 
x 
 
 
 
 
 
Demographics and Breast Cancer History a 
x 
 
 
 
 
 
Concomitant Medication Review per SOC 
x 
 
x 
 
x 
x 
Physical Exam b 
x 
 
X 
 
x 
x 
Adverse Events b 
x 
 
X 
 
x 
x 
ECOG Performance Status b  
x 
 
x 
 
x 
x 
Pregnancy Test – Urine or Serum β-HCG 
(for women with childbearing potential) c 
x 
 
 
 
 
 
CBC, comprehensive metabolic profile d 
x 
 
x 
 
x 
x 
Lipid profile e 
 
 
x 
 
x 
x 
Archived initial diagnostic breast biopsy 
tissue and/or surgical specimens (block or 
unstained slides) obtained at any time prior 
to study treatment 
x 
 
 
 
 
 
Correlative Studies Blood Collection f 
 
x 
x 
x 
x 
x 
Cardiology consult g 
 
 
x 
 
 
 
Optional collection of 5 to 20 slides if 
tumor sample collected as part of SOC on 
disease progression, if the site is accessible 
 
 
 
 
 
x 
Disease Progression Status 
x 
 
x 
 
x 
x 
 
a. Demographics include patient’s age, gender and race. Medical history includes primary breast 
cancer pathological diagnosis, ER/PR/HER2 status, prior therapies, procedures for breast 
cancer, other medical problems present, and review of systems. 
b. Complete physical exam during the screening period. This will not be repeated if done within 
30 (+/- 3) days before the start of treatment. During treatment Physical Exam as clinically 
indicated prior to trial treatment administration.  Adverse events and ECOG performance status 
assessment can be done within 30 (+/- 3) days of the treatment.  
c. Serum or urine pregnancy test must be performed per standard of care only for women of 
reproductive potential. A woman is considered to be of “reproductive potential” if she has had 
menses at any time in the preceding 12 consecutive months. A source document must be 
available for post-menopausal subjects (i.e., no menses for 12 months without an alternative 
medical cause), women with permanent sterilization (e.g., hysterectomy, bilateral 
salpingectomy and bilateral oophorectomy, or tubal ligation) and/or age over 55. 
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d. Hematologic and biochemical profiles (CBC, albumin, alkaline phosphatase, ALT, AST, LDH, 
fasting blood sugar, phosphorus, potassium, sodium, total bilirubin, total protein, BUN, 
creatinine) as standard of care (will not be repeated if done within 30 (+/- 3 days) days before 
the start of treatment). During treatment, an earlier evaluation will be performed if clinically 
indicated. 
e. HDL, LDL, VLDL, triglycerides, total cholesterol. (Refer to 6.1.1 in details.). Baseline lipid 
panel will be done after xeloda for patients receiving xeloda while on study.  
f. Peripheral blood and serum for correlative studies (Refer to 6.1.1 in details). Correlative 
studies blood collection during radiation will be done 2 weeks (+/- 5 days) after starting the 
radiation.  Participating Cancer Network sites will refer to the lab manual for blood and tumor 
sample collection, storage, package, and shipment instructions.  
g. Cardiology consult will be done to determine whether patients are recommended to be on high- 
or intermediate dose of statin based on ASCVD criteria (Figures 3 and 4) 
h. For patients who agree to the optional blood collection before xeloda, the blood will be drawn 
prior to beginning therapy. Participating Cancer Network sites will refer to the lab manual for 
blood and tumor sample collection, storage, package, and shipment instructions. 
 
 
6.0 CORRELATIVE STUDIES BLOOD COLLECTION AT PRE-XELODA TIMEPOINT IS AN 
OPTIONAL PROCEDURE IF APPLICABLE. COLLATERAL RESEARCH  
Correlative research will be performed on biologic specimens from patients enrolled.  Peripheral 
blood will be collected prior to beginning statin therapy as a baseline, at 3 months (+/- 4 weeks), 
6 months (+/- 6 weeks), 12 months (+/- 6 weeks), 18 months (+/- 6 weeks), and 24 months (+/- 6 
weeks) and/or at the time of disease recurrence, whichever occurs first. For patients who agree to 
the optional blood collection before xeloda, the blood will also be drawn prior to beginning therapy. 
Original tumor tissue’s block or unstained slides (archived initial diagnostic breast biopsy tissue 
and/or surgical specimens) prior to treatment (5 to 20 formalin fixed paraffin embedded slides from 
mastectomy) will be collected and banked for future studies if available. If available, up to twenty 
slides from formalin fixed paraffin embedded samples will also be collected and banked for future 
studies from time of progression if tumor biopsied as part of routine clinical care. These samples 
will be used to perform correlative studies aimed at identifying predictive markers and to enhance 
understanding of disease biology.   
6.1 
Biomarker assessments 
Tumor tissue and peripheral blood will be collected prior to therapy and at selected time points on 
treatment.  Residual sample material available after completion of the designated analyses may be 
used in the future for identification of additional predictive markers or to enhance understanding 
of disease biology. If biomarker samples are drawn but study drug is not administered, samples 
will be retained.  A description of each assay system is described below. 
 Blood samples  
Collection and processing 
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All blood tubes will be labeled only with the patients’ unique study number.  Samples #1 collected 
at all facilities will be sent to Epic; samples #2 and #4 will be sent to local diagnostic lab as SOC; 
sample #3, #5, #6 will be sent to Dr. Reuben’s Lab in MDACC. See details in section 13.  
 
Samples and Assays 
1) For circulating tumor cell analysis, blood samples will be collected in 10mL Cell-Free DNA 
BCT tubes (Streck, Inc.). For detailed SOP, please see the section 13 for blood collection, 
amount, type of tube and packaging and shipping information. 
2) Lipid profile (including HDL, LDL, VLDL, triglycerides, total cholesterol) sent via standard 
of care testing of each respective institutional site laboratory. For lipid panel, Mint top tube 
will be used and 3.5mL of blood will be needed.  
3) Circulating tumor DNA:  Blood samples will be collected in 10mL Streck tubes at the time 
points shown in the Study Calendar for analysis of hotspot mutations via ddPCR.  
4) Systemic markers of inflammation: Erythrocyte sedimentation rate, high sensitivity C-reactive 
protein assays will be ordered as standard of care through the diagnostic lab. For ESR, lavender 
top tube will be used and 3.0mL of blood will be needed. For CRP, gold top tube will be used 
and 5.0 mL of blood will be needed. 
5) Soluble factors such as cytokines and chemokines present in serum collected at baseline, 
during, and after treatment will be quantified using a multiplex assay which has the capability 
to simultaneously measure multiple analytes from a single sample. The primary cytokine of 
interest is IL-6 but additional cytokines in the assay such as IL-2 and TNFa may be assessed. 
Red top tube with 10 ml of blood will need to be drawn and frozen at 0.5 ml aliquots and stores 
at - 80 °C. 
6) Peripheral blood mononuclear cells: 
The proportion of specific lymphocyte subsets to include T cell subsets including T-
regulatory cells, B cells, and the proportion of memory and effector T cell subsets will be 
quantified by flow cytometry. EDTA tube with 10 mL of blood will need to be drawn and 
stored at room temperature (for MD Anderson patients) or shipped overnight at 4°C. Prior 
to processing the cells for flow cytometry, plasma will be collected first to measure proteins 
using OLINK method that has panels for Inflammation, Oncology and Immune-Oncology 
(IO). 
Remaining serum and peripheral blood mononuclear cell component will be banked for future 
correlative studies that may include peripheral blood assessment of mevalonate and cancer 
signaling pathway components previously shown to mediate effects of statin therapy, additional 
immune profiling, and measurement of miR-33a/b to examine radiosensitization and toxicity. 
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 Tumor samples 
Archived initial diagnostic breast biopsy tissue and/or surgical specimens (block or unstained 
slides) obtained at any time prior to treatment will be collected from all consenting subjects and 5 
to 20 formalin fixed paraffin embedded slides will be banked.  10 to 20 formalin fixed paraffin 
embedded slides will also be collected and banked for future studies from time of progression if 
tumor biopsied as part of routine clinical care. Up to 5 of these banked slides will be used for 
proposed multiplexed imaging. Remaining slides and tissues will be banked until future time point 
for additional correlative studies, which may include assessment of HMG CoA-reductase pathway, 
signaling pathways previously shown to mediate statin effects, and immune profiling. 
 
Assays 
 
At the time of sample processing, each Tissue-Tek-OCT-frozen punch biopsy specimen will be 
sectioned via cryostat (at 4 degrees). Four 5 um section slides will cut with the cryostat--two for 
H&E staining, two for immunofluorescence analysis of gamma-H2aX foci (indicative of DNA 
double-stranded damage), two for immunofluorescence analysis of pFOXO3a (indicative of 
signaling through EGFR and essential transcription factor in radiosensitization) 
 
The remainder of the specimen will be fixed with formalin and stored for future 
immunohistochemical or immunofluorescence studies by interested investigators. 
 
7.0 SAFETY MONITORING AND REPORTING 
7.1 
Adverse Event 
Adverse events will be assessed according to the CTCAE version 4.0 from baseline onwards. All 
study patients who have received any dose of atorvastatin will be evaluable for safety. Unexpected 
adverse events including laboratory adverse events deemed clinically significant by the 
investigator will be graded and recorded in study database - Prometheus. 
 
The ongoing review of safety data will include review of clinical AEs and SAEs. The NCI-CTC 
version 4.0 will be used to grade all AEs.   
 
AEs (≥2 non-hematological and ≥3 hematological AEs) occurring after informed consent signing 
observed by the investigator or reported by the subject (whether or not attributed to atorvastatin), 
will be documented in the medical record or an appropriate source  and recorded in Prometheus 
database. Abnormal laboratory values will not be reported as AEs; however, any clinical 
consequences of the abnormality should be reported as AEs and recorded in Prometheus.  
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7.2 
Serious Adverse Event Reporting (SAE)  
 Internal SAE reporting 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or the sponsor, it results in any of the following outcomes: 
• Death 
• A life-threatening adverse drug experience – any adverse experience that places the patient, 
in the view of the initial reporter, at immediate risk of death from the adverse experience 
as it occurred. It does not include an adverse experience that, had it occurred in a more 
severe form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered a serious adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse (21 CFR 312.32). 
• Important medical events as defined above, may also be considered serious adverse events. 
Any important medical event can and should be reported as an SAE if deemed appropriate 
by the Principal Investigator. 
 
• All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the IRB in accordance with the timeframes and procedures outlined in 
“University of Texas M. D. Anderson Cancer Center Institutional Review Board Policy for 
Investigators on Reporting Unanticipated Adverse Events for Drugs and Devices”.   
 
• Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety 
reporting to MDACC IRB.  
 
• Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug, unless the participant withdraws 
consent. Serious adverse events must be followed until clinical recovery is complete and 
laboratory tests have returned to baseline, progression of the event has stabilized, or there 
has been acceptable resolution of the event. 
 
• Additionally, any serious adverse events that occur after the 30 day time period that are 
related to the study treatment must be reported to the MDA IRB office. This may include 
the development of a secondary malignancy. 
 
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7.2.1.2 Guidelines for participating Cancer Network Sites to report SAEs 
 
• Participating Cancer Network Sites are required to report SAEs within 24 hours after 
becoming aware of the event. The SAE Form created specifically by the MD Anderson 
Cancer Center will be provided to each site. Follow-up information on the SAE event may 
be requested by MD Anderson Cancer Center. SAE report information must be consistent 
with the data provided on Prometheus.  
 
• Participating Cancer Network Sites should  also report SAEs, any unanticipated death or 
adverse event occurring after a patient has discontinued or terminated study participation 
that may reasonably be related to the study to their respective IRB according to the local 
IRB’s policies and procedures and a copy of the submitted institutional SAE form should 
be uploaded in to the institutionally approved cloud-based storage folder. 
 
 
 
 Evaluating Adverse Events 
An investigator or an assigned designee will evaluate and record adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0 as standard practice per 
institution guidelines.  
 
8.0 STATISTICAL CONSIDERATION AND ANALYSIS PLAN    
We plan to enroll a total 80 stage IIb/III TNBC patients who do not achieve pCR after 
neoadjuvant systemic chemotherapy. We will have an interim analysis after 30 of enrolled 
patients are treated with atorvastatin.  The study will continue enrollment if within the first 30 
treated patients, ≥6 patients demonstrate positive outcome in CTC at 6 months, i.e., CTC remains 
non-detected if baseline CTC is not detected or CTC count has decreased if the baseline CTC is 
detected, we will then enroll up to an additional 50 patients to complete the study. 
 
With a total of up to 80 patients, we expect about 48 patients will have received the statin and 32 
will not receive the statin, we will be able to estimate the percentage of patients with negative 
CTC, i.e, no CTC present in blood, at six months after surgery with a standard error not larger 
than 7% and 9%, respectively. At the end of the study, besides estimating the proportion of 
patients with negative CTC at 6 months with 95% confidence interval, we will also describe the 
patterns of the change in CTC (from negative to positive [any CTC count in blood], positive to 
negative, positive to positive or negative to negative) in those who receive statin and those who 
do not receive statin, separately. We will also explore any pattern of CTC counts at baseline and 
at follow-ups in patient subgroup, including patients treated with different adjuvant therapies.  
 
Variables of interest including age, stage, IBC status, CTC counts and the change of CTC counts, 
lipid profile levels, ctDNA, ESR, CRP, serum IL-6 and other cytokines, adverse events, and 
imaging biomarkers will be summarized for each group (statin vs no statin) using standard 
descriptive statistics, such as mean, standard deviation, median, and range for continuous 
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variables, and frequency and proportion for categorical variables. We will evaluate the 
association between CTC counts or the change of CTC counts and other variables. Correlation 
between continuous variables will be assessed using Pearson or Spearman correlation coefficient, 
whichever is appropriate. We will define CTC response as either remaining negative CTCs at 6 
months when the baseline CTC is negative or becoming negative when baseline CTC is positive. 
The difference between the two treatment groups (statin vs no statin) or between the CTC 
response groups will be tested using Wilcoxon rank sum test for continuous variables and Chi-
squared test/Fisher’s exact test.  Recurrence-free survival (RFS) and overall survival (OS) times 
from the time of surgery will be estimated with 95% confidence intervals using the Kaplan-
Meier method and compared between the treatment groups or CTC response groups using log-
rank test. The Cox regression models may be applied to assess the effect of covariates of interest, 
including the treatment groups or CTC response groups, on survival outcomes.  Adverse events, 
grade and relationship will be tabulated by treatment arms. Other statistical methods may be 
applied when appropriate. All analysis is exploratory and the results will serve for hypothesis 
generating purpose. 
 
Inclusion of Minorities 
The study will be available to all eligible patients regardless of race, or ethnic origin. There is no 
information currently available regarding differential effects of this regimen in subsets defined by 
race or ethnicity. 
  
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
9.1 
Product used in the study 
The investigator shall take responsibility for and shall take all steps to maintain appropriate records 
and ensure appropriate supply, storage, handling, distribution and usage of product in accordance 
with the protocol and any applicable laws and regulations. The use of the Atorvastatin is standard 
of care. 
Table 1 Product Descriptions 
Product Name & Potency 
Dosage Form 
Atorvastatin 20 mg or 40 mg daily 
Tablet to be administered by mouth 
 
9.2 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
 
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9.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or designee 
are not blinded to treatment. Drug identity (name, strength) is included in the label text; random 
code/disclosure envelopes or lists are not provided. 
 
9.4 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial 
site per their institutional guidelines. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
 
10.0 DATA MANAGEMENT 
The Principal Investigator is responsible for assuring that the data entered into the database are 
complete and accurate and that data entry is performed in a timely manner. A single Prometheus 
database for all sites will be used.  
10.1 Data collection for this study including: 
1) demographic information (sex, race, and date of birth),   
2) date of initial breast cancer diagnosis, pathology report of primary breast cancer, biomarker 
status, and date and location of distant metastases at disease progression; 
3) history of breast cancer surgery, adjuvant xeloda and radiation therapy, if applicable;  
4) All AEs will be collected, however only >/=2 non-hematologic AEs and >/=3 
hematological AEs (whether or not attributed to atorvastatin) will be recorded in 
Prometheus.  Other abnormal laboratory values will not be reported as AEs; however, any 
clinical consequences of abnormality should be reported as AEs and recorded in 
Prometheus.  
5) Concomitant medication will be recorded per standard of care in clinic database, and will 
not be recorded in the study database. Participating Cancer Network Sites will upload a 
copy of the concomitant medication list(s) into the assigned cloud-folder as specified on 
the time points in the study schema.  
10.2 Data confidentiality plan 
All laboratory and clinical data gathered in this protocol will be stored in a password-protected 
database. All patient information will be handled using anonymous identifiers. Linkage to patient 
identity will be possible only after accessing a password-protected database. Access to the database 
will be available only to individuals directly involved in the study. 
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Information gathered for this study will not be reused or disclosed to any other person or entity, or 
for other research. Once the research has been completed, identifiers will be retained for as long 
as is required by law and by institutional regulations, and at that point will be destroyed. 
11.0 MULTICENTER STUDY MANAGEMENT PLAN 
     
This study is collective effort of centers including MD Anderson Cancer Center, and 
participating Cancer Network Sites. All treatments and procedures proposed in the study are 
standard of care. There is no research treatment and procedures involved. We will only collect 
research samples and clinical data, so this is a low risk study.  
 
 Participating Cancer Network Sites will adhere to the protocol, Data Quality Management Plan 
(DQMP), and conduct the study in accordance with the Institutional policies and procedures.  
  
11.1 RESEARCH SAMPLE DISTRIBUTION 
Blood samples collected in 10mL Cell-Free DNA BCT tubes (Streck, Inc.) will be transported at 
ambient temperature to the Epic Sciences central laboratory (San Diego, CA) using of a 
standardized ISO-certified shipping process as instructed in section 13.0.  
 
All other biological samples, including blood, tissue and/or slides will be sent to MDACC IBC 
lab at the below address except the blood for CTC analysis which should be sent directly to Epic 
Sciences separately. Archival tissue may be sent in batches; 
 
Lily Villarreal / IBC Lab6565 MD Anderson Blvd.   Z12.4031 B 
Houston TX 77030 
Phone: 713-792-4925 
Email: BMO_BMOCTRLab_Users@mdanderson.org 
 
Participating Cancer Network Sites will refer to the Lab Manual for Correlative studies 
collection details including how to request the lab kits, air bill, sample collection, storage, 
package, and shipping information.  
 
12.0 REFERENCES 
1. 
Liedtke C, Mazouni C, Hess KR et al. Response to neoadjuvant therapy and long-term 
survival in patients with triple-negative breast cancer. J Clin Oncol 2008; 26: 1275-1281. 
2. 
Masuda H, Brewer TM, Liu DD et al. Long-term treatment efficacy in primary 
inflammatory breast cancer by hormonal receptor- and HER2-defined subtypes. Ann Oncol 
2014; 25: 384-391. 
3. 
Masuda N, Lee SJ, Ohtani S et al. Adjuvant Capecitabine for Breast Cancer after 
Preoperative Chemotherapy. N Engl J Med 2017; 376: 2147-2159. 
4. 
Ahern TP, Pedersen L, Tarp M et al. Statin prescriptions and breast cancer recurrence 
risk: a Danish nationwide prospective cohort study. J Natl Cancer Inst 2011; 103: 1461-1468. 
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5. 
Chae YK, Valsecchi ME, Kim J et al. Reduced risk of breast cancer recurrence in patients 
using ACE inhibitors, ARBs, and/or statins. Cancer Invest 2011; 29: 585-593. 
6. 
Kwan ML, Habel LA, Flick ED et al. Post-diagnosis statin use and breast cancer 
recurrence in a prospective cohort study of early stage breast cancer survivors. Breast Cancer 
Res Treat 2008; 109: 573-579. 
7. 
Boudreau DM, Yu O, Chubak J et al. Comparative safety of cardiovascular medication 
use and breast cancer outcomes among women with early stage breast cancer. Breast Cancer Res 
Treat 2014; 144: 405-416. 
8. 
Brewer TM, Masuda H, Liu DD et al. Statin use in primary inflammatory breast cancer: a 
cohort study. Br J Cancer 2013; 109: 318-324. 
9. 
Murtola TJ, Visvanathan K, Artama M et al. Statin use and breast cancer survival: a 
nationwide cohort study from Finland. PLoS One 2014; 9: e110231. 
10. 
Ahern TP, Lash TL, Damkier P et al. Statins and breast cancer prognosis: evidence and 
opportunities. Lancet Oncol 2014; 15: e461-468. 
11. 
Lacerda L, Reddy JP, Liu D et al. Simvastatin radiosensitizes differentiated and stem-like 
breast cancer cell lines and is associated with improved local control in inflammatory breast 
cancer patients treated with postmastectomy radiation. Stem Cells Transl Med 2014; 3: 849-856. 
12. 
Wolfe AR, Debeb BG, Lacerda L et al. Simvastatin prevents triple-negative breast cancer 
metastasis in pre-clinical models through regulation of FOXO3a. Breast Cancer Res Treat 2015; 
154: 495-508. 
13. 
Park YH, Jung HH, Ahn JS, Im YH. Statin induces inhibition of triple negative breast 
cancer (TNBC) cells via PI3K pathway. Biochem Biophys Res Commun 2013; 439: 275-279. 
14. 
Klawitter J, Shokati T, Moll V et al. Effects of lovastatin on breast cancer cells: a proteo-
metabonomic study. Breast Cancer Res 2010; 12: R16. 
15. 
Ghosh-Choudhury N, Mandal CC, Ghosh-Choudhury N, Ghosh Choudhury G. 
Simvastatin induces derepression of PTEN expression via NFkappaB to inhibit breast cancer cell 
growth. Cell Signal 2010; 22: 749-758. 
16. 
Wang J, Kitajima I. Pitavastatin inactivates NF-kappaB and decreases IL-6 production 
through Rho kinase pathway in MCF-7 cells. Oncol Rep 2007; 17: 1149-1154. 
17. 
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Cancer Res 2006; 66: 8707-8714. 
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Shen YY, Yuan Y, Du YY, Pan YY. Molecular mechanism underlying the anticancer 
effect of simvastatin on MDA-MB-231 human breast cancer cells. Mol Med Rep 2015; 12: 623-
630. 
19. 
Gopalan A, Yu W, Sanders BG, Kline K. Simvastatin inhibition of mevalonate pathway 
induces apoptosis in human breast cancer cells via activation of JNK/CHOP/DR5 signaling 
pathway. Cancer Lett 2013; 329: 9-16. 
20. 
Denoyelle C, Vasse M, Korner M et al. Cerivastatin, an inhibitor of HMG-CoA 
reductase, inhibits the signaling pathways involved in the invasiveness and metastatic properties 
of highly invasive breast cancer cell lines: an in vitro study. Carcinogenesis 2001; 22: 1139-
1148. 
21. 
Karlic H, Thaler R, Gerner C et al. Inhibition of the mevalonate pathway affects 
epigenetic regulation in cancer cells. Cancer Genet 2015; 208: 241-252. 
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Protocol/Amendment No.: 2018-0550 
PI: Carlos H. Barcenas, MD  
Date:  01/10/2023 
 
 
22. 
Pandyra AA, Mullen PJ, Goard CA et al. Genome-wide RNAi analysis reveals that 
simultaneous inhibition of specific mevalonate pathway genes potentiates tumor cell death. 
Oncotarget 2015; 6: 26909-26921. 
23. 
Nelson ER, Wardell SE, Jasper JS et al. 27-Hydroxycholesterol links 
hypercholesterolemia and breast cancer pathophysiology. Science 2013; 342: 1094-1098. 
24. 
Rodriguez-Perea AL, Montoya CJ, Olek S et al. Statins increase the frequency of 
circulating CD4+ FOXP3+ regulatory T cells in healthy individuals. J Immunol Res 2015; 2015: 
762506. 
25. 
Wang ZX, Wang CQ, Li XY et al. Changes of naturally occurring CD4(+)CD25(+) 
FOXP3(+) regulatory T cells in patients with acute coronary syndrome and the beneficial effects 
of atorvastatin treatment. Int Heart J 2015; 56: 163-169. 
26. 
Bjarnadottir O, Romero Q, Bendahl PO et al. Targeting HMG-CoA reductase with statins 
in a window-of-opportunity breast cancer trial. Breast Cancer Res Treat 2013; 138: 499-508. 
27. 
Feldt M, Bjarnadottir O, Kimbung S et al. Statin-induced anti-proliferative effects via 
cyclin D1 and p27 in a window-of-opportunity breast cancer trial. J Transl Med 2015; 13: 133. 
28. 
Garwood ER, Kumar AS, Baehner FL et al. Fluvastatin reduces proliferation and 
increases apoptosis in women with high grade breast cancer. Breast Cancer Res Treat 2010; 119: 
137-144. 
29. 
Vinayak S, Schwartz EJ, Jensen K et al. A clinical trial of lovastatin for modification of 
biomarkers associated with breast cancer risk. Breast Cancer Res Treat 2013; 142: 389-398. 
30. 
Lazzeroni M, Guerrieri-Gonzaga A, Serrano D et al. Breast ductal lavage for biomarker 
assessment in high risk women: rationale, design and methodology of a randomized phase II 
clinical trial with nimesulide, simvastatin and placebo. BMC Cancer 2012; 12: 575. 
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AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on 
the Management of Blood Cholesterol. A Report of the American College of 
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2018; ••:••••–••••. DOI: 10.1161/CIR.0000000000000625. 
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survival in metastatic breast cancer. N Engl J Med 2004; 351: 781-791. 
33. 
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Chemotherapy in Stage I-III Triple-Negative Breast Cancer. Ann Surg Oncol 2015. 
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predicting overall survival in metastatic breast cancer. Clin Cancer Res 2006; 12: 6403-6409. 
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Cohen SJ, Punt CJ, Iannotti N et al. Relationship of circulating tumor cells to tumor 
response, progression-free survival, and overall survival in patients with metastatic colorectal 
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37. 
Pantel K, Riethdorf S. Pathology: are circulating tumor cells predictive of overall 
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Product:  Atorvastatin 
39 
Protocol/Amendment No.: 2018-0550 
PI: Carlos H. Barcenas, MD  
Date:  01/10/2023 
 
 
13.0 SAMPLE COLLECTION INSTRUCTION – EPIC SCIENCE CTC SAMPLE  
Blood samples will be collected in 10mL Cell-Free DNA BCT tubes (Streck, Inc.) and 
transported at ambient temperature to the Epic Sciences central laboratory (San Diego, CA) 
using of a standardized ISO-certified shipping process. Samples will be de-identified and 
labelled with Subject ID and Draw Date/Time for blood age.  
The instruction for sample collection and shipping are as below:  
 
Blood samples will be packaged in the Epic Sciences Ambient kit and the instructions are as 
below: 
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Product:  Atorvastatin 
40 
Protocol/Amendment No.: 2018-0550 
PI: Carlos H. Barcenas, MD  
Date:  01/10/2023 
 
 
 
 
 
   
   
 
 
 
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Product:  Atorvastatin 
41 
Protocol/Amendment No.: 2018-0550 
PI: Carlos H. Barcenas, MD  
Date:  01/10/2023 
 
 
 
 
Sample Shipment Instructions    
 
 
 
 
Samples and completed CTC Sample requisition form are sent via Overnight carrier with 
advanced notification: 
Ship to:  
Epic Sciences  Attn: 2018-0550/MN-017 
9381 Judicial Drive, STE 200 
San Diego, CA 92121 
Contact Phone; +1-858-356-6610 
 
Send Email to: 
partners@epicsciences.com 
Include:  
1. 
Tracking number 
2. 
Number of samples being shipped 
3. 
Date and time of each blood draw 
4. 
Case report from including white blood cell count of patient(s) 
 
 
 
 
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