Clinical trial NCT01897441
Conditions: Stage IIA Breast Cancer Stage IIB Breast Cancer Stage IIIA Breast Cancer Stage IIIB Breast Cancer Stage IIIC Breast Cancer Stage IV Breast Cancer
Sponsor: Albert Einstein College of Medicine
Start date: 2013-06-01; Completion date: 2023-10-25
Enrollment: 31 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This pilot clinical trial studies chemotherapy before surgery and tissue sample collection in patients with stage IIA-IIIC breast cancer. Drugs used in chemotherapy, such as doxorubicin hydrochloride, cyclophosphamide, and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as trastuzumab, may interfere with the ability of tumor cells to grow and spread. Giving doxorubicin hydrochloride, cyclophosphamide, paclitaxel and trastuzumab may kill more tumor cells. Collecting and storing samples of tissue from patients with breast cancer to study in the laboratory may help doctors learn more about how well patients will respond to treatment.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the effects of preoperative neoadjuvant paclitaxel and doxorubicin (doxorubicin hydrochloride)/cyclophosphamide (AC) on: senescence; invasion/motility (tumor microenvironment of metastasis \[TMEM\] and 67 kDa laminin receptor \[67LR\]).

II. To create a biospecimen repository for future studies derived from patients with breast cancer receiving standard neoadjuvant chemotherapy.

OUTLINE: Patients with human epidermal growth factor receptor 2 (HER2)-positive disease are assigned to Stratum A, and patients with HER2-negative disease are randomized to Stratum B or C.

STRATUM A: Patients receive paclitaxel intravenously (IV) over 1 hour and trastuzumab IV over 30-90 minutes weekly for 12 weeks. Beginning 2-3 weeks later, patients receive doxorubicin hydrochloride IV over 5-10 minutes and cyclophosphamide IV over 30-60 minutes every 2 weeks for 8 weeks

STRATUM B: Patients receive paclitaxel, doxorubicin hydrochloride, and cyclophosphamide as in Stratum A.

STRATUM C: Patients receive doxorubicin hydrochloride IV over 5-10 minutes and cyclophosphamide IV over 30-60 minutes every 2 weeks for 8 weeks. Patients then receive paclitaxel IV over 1 hour weekly for 12 weeks.

Patients undergo surgery 2-6 weeks after the last chemotherapy dose.

In all arms, treatment continues in the absence of unacceptable toxicity.

Arms: arm 1: Patients receive Paclitaxel 80 mg/m\^2 IV infusion over 1 hour for 12 weeks and Trastuzumab 8 mg/kg IV loading dose over 90 minutes, then 6 mg/kg IV every three weeks (after Paclitaxel when given concurrently) for a total of 17 doses over 51 weeks. Beginning 2-3 weeks after the last dose of Paclitaxel, patients receive Doxorubicin hydrochloride 60 mg/m\^2 IV over 5-10 minutes and Cyclophosphamide 600 mg/m\^2 IV infusion over 30-60 minutes every 2 weeks for 8 weeks. arm 2: Patients receive sequential Paclitaxel followed by Doxorubicin hydrochloride and Cyclophosphamide (AC) as described in Stratum A. arm 3: Patients receive sequential Doxorubicin hydrochloride and Cyclophosphamide (AC) followed by Paclitaxel. Patients receive Doxorubicin hydrochloride IV over 5-10 minutes and cyclophosphamide IV over 30-60 minutes every 2 weeks for 8 weeks. Patients then receive paclitaxel IV over 1 hour weekly for 12 weeks. arm 4: Patients receive Paclitaxel 80 mg/m\^2 IV infusion over 1 hour for 12 weeks followed by Doxorubicin hydrochloride and Cyclophosphamide (AC). Patients receive Doxorubicin hydrochloride 60 mg/m\^2 IV over 5-10 minutes and Cyclophosphamide 600 mg/m\^2 IV infusion over 30-60 minutes every 2 weeks for 8 weeks. arm 5: Patients receive Paclitaxel 80 mg/m\^2 IV infusion over 1 hour for 12 weeks and Trastuzumab 8 mg/kg IV loading dose over 90 minutes, then 6 mg/kg IV every three weeks (after Paclitaxel when given concurrently) for a total of 17 doses over 51 weeks. Beginning 2-3 weeks after the last dose of Paclitaxel, patients receive Doxorubicin hydrochloride 60 mg/m\^2 IV over 5-10 minutes and Cyclophosphamide 600 mg/m\^2 IV infusion over 30-60 minutes every 2 weeks for 8 weeks. arm 6: Patients with ER-positive, HER2-negative disease may receive neoadjuvant endocrine therapy (NET) with an aromatase inhibitor: (either Anastrozole 1 mg po daily; Letrozole 2.5 mg po daily, Exemestane 25 mg po daily or Tamoxifen 20 mg po daily) for 4-6 months prior to surgery (or longer if clinically indicated). Anastrozole for 6 months is the preferred regimen for NET.
Interventions: intervention 1: Cyclophosphamide intervention 2: Cytology Specimen Collection Procedure intervention 3: Doxorubicin Hydrochloride intervention 4: Laboratory Biomarker Analysis intervention 5: Paclitaxel intervention 6: Trastuzumab intervention 7: Endocrine therapy
Intervention descriptions: intervention 1: Given IV intervention 2: Correlative studies intervention 3: Given IV intervention 4: Correlative studies intervention 5: Given IV intervention 6: Given IV intervention 7: Patients with ER-positive, HER2-negative disease may receive neoadjuvant endocrine therapy (NET) with an aromatase inhibitor: (either Anastrozole 1 mg po daily; Letrozole 2.5 mg po daily, Exemestane 25 mg po daily or Tamoxifen 20 mg po daily) for 4-6 months prior to surgery (or longer if clinically indicated). Anastrozole for 6 months is the preferred regimen for NET.

Protocol documents:
Prot_SAP_000.pdf: 
Title: Chemotherapy Before Surgery and Tissue Sample 
Collection in Patients with Stage IIA-IIIC Breast Cancer
IRB ID:  13-02-079
NCT01897441
IRB Approval Date:  05/11/2021


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Title: Prospective tissue collection in breast cancer patients receiving preoperative systemic therapy
Coordinating Center:
Albert Einstein Cancer Center Clinical Trials Office (CTO)
Montefiore Medical Center-Weiler Division
1825 Eastchester Rd., 2South, Rm 60, Bronx, NY 10461
Project Coordinator: Karen Fehn, RN, Phone 718-405-8446, 718-Fax 405-8230 
Email: kfehn@montefiore.org
Principal Investigator:
Jesus Anampa-Mesias, MD
Montefiore Medical Center-Einstein Campus
  
Department of Medical Oncology, 2nd floor
1695 Eastchester Road, Bronx, New York 10461
Phone 718-405-8404; Email: janampa@montefiore.org
Co-principal Investigators: 
Della Makower, MD
Montefiore Medical Center-Einstein Campus
  
Department of Medical Oncology, 2nd floor
1695 Eastchester Road, Bronx, New York 10461
Phone 718-405-8404; Email: dmakower@montefiore.org
Sun Young Oh, MD
Montefiore Medical Center-Einstein Campus
  
Department of Medical Oncology, 2nd floor
1695 Eastchester Road, Bronx, New York 10461
Phone 718-405-8404; Email: suyoung@montefiore.org
Susan Fineberg, MD, 
Montefiore Medical Center- Moses Division
Department of Pathology
111 East 210th Street, Central 313,  Bronx, NY 10467
Phone 718-920-4976; Email: sfineber@montefiore.org
Kathleen Whitney, MD
Montefiore Medical Center-Einstein Campus
  
Department of Pathology
1825 Eastchester Road, Bronx, New York 10461
Phone 718.904.2947; Email: kwhitney@montefiore.org
Maja Oktay, MD, PhD
Montefiore Medical Center- Moses Division
Department of Pathology
111 East 210th Street, Central 313, Bronx, NY 10467
Phone 718-920-6091; Email: moktay@montefiore.org
                                                  
Cristina Montagna, PhD
                                                  
Albert Einstein College of Medicine
                                                
Department of Genetics and Pathology R401
                                                      
1301 Morris Park Ave., Bronx, NY 10461
                                                      
Phone: 718 678 1158; Email: cristina.montagna@einstein.yu.edu
Protocol statistician:                   Nan Xue, PhD
                                                      Albert Einstein College of Medicine
                                                      Division of Biostatistics
                                                      Phone: 718-430-2431; Email: xiaonan.xue@einstein.yu.edu
Summary of Protocol Changes :
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
Amendement 1 (Version 4.1 1/9/17) : (1) Cover page: removed Dr. Montgomery, Koenigsberg, 
McDaid and co-investigators; (2) Schema and section 4.1: eliminate pre-randomization, all patients receive 
sequential pacitaxel-AC (unless physician chooses AC-paclitaxel sequence), (3) Schema and section 4: 
trastuzumab (+/- pertuzumab) plus carboplatin/docetaxel or paclitaxel added as a treatment option for 
HER2-positive disease to reflect a new standard of care option, additional stratum added (stratum III) to 
include neaodjuvant endocrine therapy (4) Schema and section 5.1 : prior version allowed FNA or FNA 
followed by core biopsy, which was more made more explicitly clear in current protocol version and 
consent,  and reduced optional core biopsies from 5 to 3, (5) consolidated background section and study 
objectives, (6) statistical section and accrual goal modified, (6) deleted Appendix A (RCB staging) and B 
(AJCC staging), as these are considered part of standard care 
 
TABLE OF CONTENTS
SCHEMA....................................................................................................................................................4
1.
HYPOTHESIS & OBJECTIVES .....................................................................................................5
2.  BACKGROUND...................................................................................................................................5
3.
PATIENT SELECTION....................................................................................................................9
4.
MANAGEMENT PLAN..................................................................................................................10
5.
SPECIMEN COLLECTION AND BIOPSY PROCEDURES.....................................................12
6. 
CORRELATIVE STUDIES............................................................................................................14
7.
STUDY CALENDAR.......................................................................................................................17
8.
MEASUREMENT OF EFFECT.....................................................................................................18
9.
REGULATORY AND REPORTING REQUIREMENTS...........................................................18
10. DATA SAFETY AND MONITORING BOARDS .........................................................................19
11. STATISTICAL CONSIDERATIONS............................................................................................19
12. REFERENCES: .................................................................................................................................22
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SCHEMA
 
 
Breast Cancer

Eligible for neoadjuvant chemotherapy or endocrine treatment.

Meet protocol eligibility criteria

Provide written informed consent
Stratum I:
HER2-Negative Tumor
Chemotherapy Indicated

Blood sample - pretreatment

Fine needle aspiration of tumor -  before treatment and 2-3 weeks after treatment begins

Core needle biopsy (optional) - before treatment and 2-3 weeks after treatment begins
Surgery After Completion of Neoadjuvant Chemotherapy or Endocrine Therapy
 Tissue collection and banking
Standard post protocol care
Stratum II:
HER2-Positive Tumor
Chemotherapy Indicated
Stratum III:
ER-Pos, HER2-Neg Tumor
Endocrine Therapy Indicated
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1.
HYPOTHESIS & OBJECTIVES
We hypothesize that the chemotherapy combinations/agents that are commonly used to treat breast cancer 
(including doxorubicin/cyclophosphamide, paclitaxel trastuzumab, pertuzumab, carboplatin/docetaxel) 
will have different biological outcomes on breast cancer cell fate; specifically cell death versus senescence. 
Accelerated senescence is a potent tumor suppressive response that halts the proliferation of cancer cells 
following treatment with cytotoxic chemotherapy. Our hypothesis predicts that persistent senescent cells 
and or / senescent reverted cells drive disease progression, and/or epithelial to mesenchymal transition 
(EMT). This is mediated via the pro-inflammatory activity of the senescence-associated secretory 
phenotype (SASP), a unique property of senescent cells and their resistant counterparts. Thus, the presence 
of these cells within a tumor mass likely contributes to disease progression, drug resistance and metastasis, 
ultimately leading to death. 
We propose to evaluate the effects of commonly used standard chemotherapy regimens on the 
propensity for senescence, and as a consequence EMT; and to create a biorepository for future studies. 
Objectives: 
(1) To evaluate the effects of preoperative neoadjuvant chemotherapy (+/- anti-HER2 therapy) on 
invasive Mena isoforms (ie Menainv, MenaCalc), TMEM score, and cancer stem cells
(2) To create a biospecimen repository for future studies derived from patients with breast cancer 
receiving standard neoadjuvant chemotherapy. 
2.  BACKGROUND
a) Preoperative Neoadjuvant Chemotherapy 
A metanalysis of 9 randomized trials including 3496 patients with operable breast cancer has 
shown comparable survival rates whether chemotherapy was given preoperatively (neoadjuvant) or 
postoperatively (adjuvant)1.  Patients with operable breast cancer typically undergo surgery first followed 
by adjuvant chemotherapy, but neoadjuvant chemotherapy may be indicated in certain clinical scenarios, 
including: (1) locally advanced inoperable breast cancer (eg, inflammatory disease, large primary tumor, 
bulky adenopathy) in which breast conservation is not an option without therapeutic downstaging induced 
by systemic therapy, (2) operable disease in which downstaging with systemic therapy may facilitate beast 
conservation when it would otherwise might not have been feasible.2-4 The goal of neoadjuvant 
chemotherapy is to induce a pathologic complete response (pCR) in the breast or breast and lymph nodes, 
which has been shown to be a short-term surrogate indicative of long-term cure. 2-4 In fact, the U.S. Food 
and Drug Administration has recently issued draft guidance recognized the value of pCR in the breast and 
lymph nodes after neoadjuvant chemotherapy as an acceptable endpoint in clinical trials supporting 
accelerated drug approval of a new agent/regimen. 5  
b) Type and Sequence of Preoperative Chemotherapy Regimens
 As previously stated, the goal of neoadjuvant chemotherapy is to induce a pCR. Approximately 
10% of patients with operable breast cancer achieve breast pCR  after 4 cycles of neoadjuvant AC 
(doxorubicin 60 mg/m2, cyclophosphamide 600 mg/m2) given every 3 weeks.6 A subsequent trial (B27) 
that compared preoperative sequential AC x 4 followed by docetaxel (100 mg/m2 every 3 weeks x 4) to 
AC alone x 4 demonstrated a significant improvement in pCR from 14% to 26%. 7  Other studies have 
shown that weekly paclitaxel therapy (80 mg/m2 weekly x 12) to be associated with a higher pCR rate in 
the breast and lymph  nodes compared with paclitaxel given every 3 weeks (225 mg/m2 x 4)  sequentially 
with an anthracycline-cyclophosphamide combination 8, including all  patients treated (28.2% 15.7%; P = 
.02), and patients with both ER-negative disease (48% vs. 23%) and ER-positive disease (22% vs. 11%).  
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The addition of HER2-directed therapy (ie, trastuzumab) to chemotherapy has been shown to further 
improve pCR rate.9 Sequential AC-taxane therapy (plus trastuzumab for HER2-positive disease) has 
therefore become an accepted standard of care for patients who are candidates for both postoperative 
adjuvant chemotherapy and preoperative neoadjuvant chemotherapy.
Evidence suggests that the paclitaxel-AC sequence of drug administration may be more effective 
than the standard sequence of AC-taxane therapy. Antiangiogenic therapy improves blood flow in tumors 
that exhibit disordered vascular beds, thereby improving drug delivery of cytotoxic agents.10 Taxanes have 
potent angiogenic effects11, and may also improve tumor blood flow by reducing tumor-associated vascular 
compression.12  Preoperative paclitaxel more effectively reduced interstitial fluid pressure (IFP) in primary 
breast cancers than AC in a study which included 54 patients with breast cancer treated with neoadjuvant 
AC or weekly paclitaxel.13 Weekly paclitaxel, when administered first, decreased the mean IFP by 36% (P 
= .02) and improved the tumor pO(2) by almost 100% (P = .003). In contrast, doxorubicin did not have a 
significant effect as measured by ultrasound. These changes were independent of the tumor response to 
both drugs as evaluated by ultrasound, and the study was not powered to demonstrate a significant 
difference in clinical outcome based on the sequencing of drugs.  Recent studies in mouse models suggested 
that doxorubicin downregulates the surface programmed cell death 1 ligand 1 (PD-L1) in certain breast 
cancer cell types, which is a co-inhibitory molecule for cytotoxic T cells. Thus, it is hypothesized that this 
that might at least partially increased immunogenic apoptotic death.14 In contrast, in MDA-MB-468 breast 
cancer cell culture models, paclitaxel promotes PD-L1 mediated T cell apoptosis. These findings reveal a 
potential link between taxane chemotherapy and immunoresistance.15 Although it remains unknown 
whether the efficacy of anthracycline and paclitaxel combinations is affected by their sequence of 
administration, one phase III trial demonstrated a significantly higher pCR rate when the taxane followed 
by an anthracycline/cyclophosphamide-containing regimen was compared with the reverse sequence (20% 
vs. 15%, p=0.03), suggesting that the reverse sequence (taxane AC) may be somewhat more effective 
than the standard AC  taxane sequence. 8 In addition, a neoadjuvant randomized phase III trial (Neo-
tAnGo) in women with high-risk early breast cancer demonstrated a significant advantage in pCR (20% 
vs15%) with the sequence of paclitaxel+/-gemcitabine compared with the more conventional anthracycline  
first sequencing.16 Of note, the benefit was higher for the ER positive group. Moreover, a recent  
restrospective analysis  of the clinical outcome 
of the two sequences  in a large number of 
patients treated with neoadjuvant therapy 
reported that the sequence of  paclitaxel-
anthracycline compared to the antracycline-
paclitaxel is associated with lower risk of 
relapse.17 
Therefore, 
although 
either 
sequence of drug administration, (AC  
taxane sequence, or taxane AC sequence), 
are considered acceptable regimens for 
neoadjuvant chemotherapy treatment, there 
is tentative evidence that supports superior 
‘biological’ and clinical activity for taxane 
AC regimen.
c) TMEM as a measure of Cancer 
Cell 
Invasion 
and 
Interaction 
with 
Microenvironment
Highly invasive and motile cells are capable of 
metastasizing, 
non-proliferating 
and 
chemotherapy resistant. A multidisciplinary 
team of scientists from the Condeelis 
laboratory at Einstein and clinicians at 
 Figure 1: Migration of discohesive tumor cells leads to 
intravasation in mammary tumors. Tumor cell migration 
is believed to involve the tumor microenvironment-
initiated decreased expression of the epithelial isoform of 
Mena, Mena11a, and increased expression of MenaINV 
which promotes discohesion of the tumor and paracrine-
dependent tumor cell migration (bracket), as well as 
TMEM assembly leading to intravasation (box).
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Montefiore have shown that only a subset of tumor cells is capable of metastasizing and that these cells 
show reduced response to chemotherapy and express a distinct set of genes and their splice variants.18 Using 
multiphoton-based intra-vital imaging in mouse and rat mammary tumors the team identified a 
subpopulation of cancer cells that is discohesive and migratory (shown in bracket in Figure 1) and 
demonstrated that these discohesive, migratory tumor cells intravasate when associated with peri-vascular 
macrophages. 19-22. In addition, an in vivo invasion assay developed by Condeelis and Goswami has 
facilitated collection of invasive tumor cells from mammary tumors of rats, mice, and humans for 
expression profiling 23,24Many of the epigenetic changes in these cells are clustered in the motility pathways 
that control actin polymerization, directional cell movement toward EGF, and invadopodium formation 
25,26. The Mena family of actin binding proteins functions at the convergence of these motility pathways 
implying that Mena expression levels reflects the activity of motility pathways involved in the 
migratory/metastatic potential of cancer cells. Thus, Mena expression level is used as a summary marker 
for the motility pathways 24,26-28. Mena promotes actin polymerization by enhancing the activation of cofilin 
via increasing the sensitivity of the EGFR to EGF, interfering with the activity of inhibitory capping 
proteins and increasing actin filament elongation rates 26,29. This activity is essential for sustained directional 
cell movement in response to growth factors like EGF. Mena knockout mice crossbred with PyMT-
oncogene carrying mice develop dramatically less metastatic mammary tumors 30. Furthermore, the survival 
of these animals was prolonged due to the almost complete absence of hematogenous dissemination of 
tumor cells from the primary tumor 30. Breast carcinoma cells express three Mena isoforms: Menaclassic, 
MenaINV and Mena11a. Menaclassic contains only the constitutive exons, while the two splice variants 
MenaINV or Mena 11a contain the alternately-included exons INV or 11a, respectively. Mena is up regulated 
in rat, mouse and human mammary tumors 19. The Condeelis laboratory discovered that the observed 
increase of Mena expression in invasive and disseminating tumor cells reflects increased expression of both 
Menaclassic and MenaINV, and correlates with decreased Mena 11a expression relative to non-invasive, non-
intravasating tumor cells within the primary mammary tumor 19. They demonstrated that expression of 
MenaINV helps increase invasiveness of tumor cells in vitro and in vivo, and metastatic activity in mammary 
tumors in vivo by increasing the sensitivity of the EGFR to EGF by 50 fold which increases paracrine 
signaling between macrophages and tumor cells (Fig. 1, bracket) 29,31. It is believed that Menaclassic co-
oligomerizes with MenaINV to form a Menaclassic/MenaINV hetero-tetramer so that they are co-localized and 
function together 19,26,32. On the other hand, Mena 11a is associated with epithelial growth 33 and epithelial 
integrity 34 in breast tumors. Thus cancer cells overexpressing Menaclassic/MenaINV hetero-tetramer may be 
essential for intravasation step of metastasis. 
Dr. Oktay  has identified the discohesive migratory, MenaINV expressing cell population shown in 
the bracket in Figure 1 in fine needle aspirate (FNA) samples from human invasive ductal carcinomas of 
the breast and shown that the level of MenaINV expression correlates with the number of macrophage 
assisted cancer cell intravasation sites called TMEM (“tumor microenvironment of metastasis”, box in 
Figure 1) 35. As mentioned above, TMEM intravsation sites have been identified in mouse by intravital 
imaging. They have been also identified in humans by triple immunostain using anti CD-31 antibodies for 
endothelial cells, anti-CD68 for macrophages and anti-Mena for cancer cells. Furthermore, TMEM score 
has been shown to correlate with the development of distant metastases in humans independent of other 
clinicopathologic features 36. Interestingly, the induction of cell death by cytotoxic agents such as 
doxorubicin is much lower in invasive migratory cell population than in the cells isolated from the whole 
tumor profiling 23,24, suggesting that Mena isoform expression and TMEM status can identify patients 
who are not good candidate for chemotherapy because they have high proportion of invasive, metastatic 
chemoresistant cells. Immunohistochemical (TMEM score) and cytological (Mena isoform expression) 
assays developed by Drs. Condeelis, Oktay and Goswami  can be easily incorporated into current clinical 
practice and used to identify patients with high risk of metastasis. 
d) Rationale for amdendment 1 (1/9/17): The protocol was modified to eliminate 
prerandomization for drug sequence (paclitaxel – AC vs. AC – paclitaxel) for patients with HER2-negative 
disease, as paclitaxel –AC sequence is an accepted standard, and to reflect changing standard of care for 
HER2-positive disease (TCH-P).  Based on preliminary data generated from the first 14 patients enrolled 
indicating that chemotherapy induces expression of invasive Mena isoforms (comparing pre-treatment 
FNA/biopsy with during treatment FNA/biopsy) and TMEM score (comparing pre-treatment biopsy and 
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post-treatment residual cancer), we now have focused the aims of this protocol on obtaining additional 
information regarding the effect of chemotherapy on invasive Mena isoforms, TMEM score, and cancer 
stem cells, and to clarify that patients who agree to only FNA (but decline core biopsy) are eligible.  
3.
PATIENT SELECTION
3.1
Eligibility Criteria
3.1.1    Patients must have histologically confirmed adenocarcinoma of the breast associated 
with the following clinical stage: IIA, IIB, IIIA, IIIB, or IIIC (see AJCC staging 
criteria, 7h Edition). Patients with stage IV disease are also eligible if there is an 
intention to perform breast surgery after neoadjuvant therapy is completed, or in 
patients participating in clinical trials where surgery after neoadjuvant therapy may be 
an option. 
3.1.2    ER, PR, and HER2/neu status documented by core needle biopsy of the primary tumor 
and/or regional lymph node must be known prior to beginning systemic therapy. 
3.1.3    Patients must have had a bilateral diagnostic mammogram within 6 months of 
registration, and may also have a targeted sonography of the breast and/or ipsilateral 
axilla and MRI if clinically indicated. 
3.1.4     Patients with clinically suspicious axillary lymph node involvement must have either 
aspiration cytology or biopsy prior to beginning therapy. 
3.1.5     It is strongly encouraged that all patients have metallic clips placed in the tumor prior 
to neoadjuvant therapy in order to facilitate evaluation for microscopic disease at the 
time of surgery; placement of clips is particularly encouraged for patients being 
considered for breast conserving surgery. 
3.1.6     No prior chemotherapy, irradiation, or definitive therapeutic surgery (eg, mastectomy 
or lumpectomy or axillary dissection) for this malignancy. Patients who have had a 
prior sentinel lymph node biopsy for this malignancy are eligible. 
3.1.7     Patients who received tamoxifen or another selective estrogen receptor modulator 
(SERM) for prevention or for other indications (e.g., osteoporosis, prior DCIS) are 
eligible. Tamoxifen therapy or other SERMs should be discontinued at least 1 week 
before the patient is enrolled on this study. 
3.1.8     Age >18 years.  Because breast carcinoma is a disease of adults that rarely occurs in 
children, children are excluded from this study. 
3.1.9     The patient is medically suitable candidate for preoperative chemotherapy and surgery 
in the judgment of the treating physicians.  
3.1.10 Ability to understand and the willingness to sign a written informed consent document, 
and to willing to provide blood samples before and during preoperative therapy. 
Patients are also asked but not required to have research biopsies performed before and 
after therapy.  
4.
MANAGEMENT PLAN
4.1
Treatment 
Note:..All drugs doses are based on actual body weight, and are regarded as standard of care. See 
section 5.2 for criteria for dose modification/delay. 
4.1.1 Paclitaxel alone (Stratum I) or plus Trastuzumab +/- Pertuzumab (Stratum II) 

Paclitaxel (Stratum I or II ): 80 mg/m2 IV infusion over 1 hour weekly x 12 consecutive 
weeks. Paclitaxel premedication: administer dexamethasone 10 mg IV prior to the first 
paclitaxel dose. If no reaction after the first dose administer dexamethasone 4 mg IV (or 
lower doses if well tolerated without reaction), diphenhydramine 25-50 mg IV, and an H2 
blocker (cimetidine 300 mg, ranitidine 20 mg, or an equivalent) approximately 30-60 
minutes prior to each paclitaxel dose. Proceed with each weekly dose of paclitaxel (+/- 
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trastuzumab +/- pertuzumab) if:

Absolute neutrophil count > 1000/uL and platelets > 50,000/uL

No grade 3-4 toxicity, or prohibitive grade 2 toxicity

No evidence of clinical cardiac dysfunction

Trastuzumab (+/- pertuzumab) plus paclitaxel (Stratum II- HER2-positive disease 
only): Trastuzumab 8 mg/kg IV loading dose over 90 minutes, then 6 mg/kg every 3 weeks 
(after paclitaxel when given concurrently) for a total of 17 doses (51 weeks) To be 
administered after paclitaxel.  Pertuzumab (840 mg IV loading dose cycle 1, then 420 mg 
every 3 weeks for 6 cycles prior to surgery) may also be used at the discretion of the treating 
physician.

TCH+P or TCH - docetaxel/carboplatin, trastuzumab +/-  pertuzumab (Stratum II: 
Docetaxel 75 mg/m2 and carboplatin AUC 6 (Calvert formula) every 3 weeks for 6 cycles, 
plus ,trastuzumab (8 mg/kg loading dose cycle 1, then 6 mg/kg every 3 weeks) for up to 17 
doses before and after surgery (51 weeks), and pertuzumab (840 mg IV loading dose cycle 
1, then 420 mg every 3 weeks for 6 cycles prior to surgery). Patients to receive standard 
antiemetic premedication, plus dexamethasone 8 mg PO BID x 3 days beginning 1 day 
prior to each cycle. Pertuzumab may be omitted at discretion of treating physician.  Repeat 
every 3 weeks if:

Absolute neutrophil count > 1000/uL and platelets > 50,000/uL

No grade 3-4 toxicity, or prohibitive grade 2 toxicity

No evidence of clinical cardiac dysfunction

Granulocyte colony stimulating factor (G-CSF; filgrastim): G-CSF should not be used 
during paclitaxel unless: (1) treatment with paclitaxel is delayed due to neutropenia, (2) the 
patient has a serious or life-threatening documented or suspected infection associated with 
neutropenia (absolute neutrophil count [ANC]< 1000/mm3), or (3) or another complication 
that in the judgment of the treating physician could derive potential benefit from G-CSF. 
The drug should be used at a dose/schedule specified in the package insert. Pegfilgrastim 
should not be used during paclitaxel therapy. Pegfilgrastim (6 mg) should be given after 
each AC dose if given on an every 2 week schedule, or after TCH+/-P at discretion of 
treating physicians. 
4.1.2
Doxorubicin and Cyclophosphamide (AC) – Stratum I or II

Doxorubicin 60 mg/m2 IV over 5-10 minutes, Cyclophosphamide 600 mg/m2 IV 
infusion over 30-60 minutes. To be given 3very 2 weeks x 4 cycles. When given 
after paclitaxel, the first cycle should be initiated 3 weeks after the last paclitaxel 
and trastuzumab dose, or 2 weeks after the last paclitaxel dose when used without 
trastuzumab.  For patients in stratum II, AC may be omitted at discretion of treating 
physician depending upon clinical response to therapy, toxicity, or other factors, 
in accordance with standard clinical practice. 

Premedication: Administer antiemetic therapy in accordance with NCCI guidelines.

Pegfilgrastim 6 mg SC on day 2 of each cycle

Repeat every 2 weeks x 4 cycles if: (a) absolute neutrophil count > 1500/uL, platelets 
> 100,000/uL, (b) recovered from non-hematologic toxicity to grade 1 or less (except 
alopecia)
4.13
Neoadjuvant Endocrine Therapy – Stratum III
Patients with ER-positive, HER2-negative disease may receive neoadjuvant endocrine 
therapy with an aromatase inhibitor (anastrozole 1 mg po daily, letrozole 2.5 mg daily, or 
exemestane 25 mg po daily) for 4-6 months prior to surgery (or longer if clinically indicated). 
4.1.4
Chemotherapy Dose Modifications (StrataI & II)

Proceed with each dose of chemotherapy if:

Absolute neutrophil count > 1000/uL and platelets > 50,000/uL (> 100,000/uL for AC)
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
No persistent grade 3-4 toxicity, or prohibitive grade 2 toxicity

No evidence of clinical cardiac dysfunction

Patients who experience the toxicities outlined below should have the chemotherapy dose 
modified according to the criteria outlined in the table below. 
Toxicity
Paclitaxel or AC
Grade 3 or 4 febrile neutropenia (fever > 38.5C 
and ANC < 1,000/mm3):
Reduce 1 dose level
Grade 3 or 4 non-hematologic toxicity 
Reduce 1 dose level
Grade 2 non-hematologic toxicity
Reduce 1 dose level if poorly tolerated and 
attributable to therapy
Dose Reduction
Paclitaxel 
Dose
AC Dose
Docetaxel 
Dose
Carboplatin 
Dose
Initial Dose
80 mg /m2
A-60 mg/m2; C-
600 mg/m2
75 mg/m2
AUC6
First Reduction
Reduce 25% - 
60 mg/m2
Reduce 25% 
(A45, C450 
mg/m2)
60 mg/m2
AUC4.5
Second Reduction
Reduce 50% - 
45 mg/m2
Reduce 50% 
(A30, C300 
mg/m2)
45 mg/m2
AUC3
 
4.1.5
Surgery 
Patients will be reassessed for surgery following completion of chemotherapy or endocrine 
therapy.  Primary surgery may consist of a modified radical mastectomy, radical 
mastectomy, segmental mastectomy or lumpectomy with an axillary lymph node 
dissection, or sentinel lymph node biopsy without further axillary dissection if the sentinel 
node biopsy is negative if deemed medically appropriate. The goal of surgery is to 
completely debulk the tumor and achieve tumor free margins. The local pathologist should 
carefully evaluate the specimen for microscopic residual disease, including searching for 
the prior biopsy tract and/or metallic clips placed preoperatively. The surgery should be 
performed about 4 weeks (range of 2-6 weeks) after the last chemotherapy dose  unless it 
needs to be delayed because of persistent adverse events or other medical problems. 
4.1.5
Post-Protocol Therapy 
The following portions of the treatment are recommended after surgery in accordance with 
the standard of care: 

Adjuvant chest wall/breast irradiation if standard indications met (eg, if tumor > 5 cm, 
inflammatory carcinoma, 4 or more positive axillary nodes, or 1-3 positive nodes with 
extranodal extension or large metastasis)

Adjuvant hormonal therapy for a minimum of 5 years (for patients with ER and/or PR-
positive disease)

Postoperative trastuzumab (for up to 51 weeks, or up to 17 doses of trastuzumab given 
before and after surgery (if HER2-positive). 
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5.
SPECIMEN COLLECTION AND BIOPSY PROCEDURES 
5.1. Tumor Fine Needle Aspiration +/- Core Biopsies 
Consented patients will undergo serial tumor sampling  and blood specimen collection at:

Baseline  (before treatment initiation)

2-3 weeks after the first chemotherapy dose
o
Stratum I: 2 weeks after the first chemotherapy dose, (ie, just before the 3rd planned 
paclitaxel dose) 
o
Stratum II: 2 weeks after first chemotherapy dose (ie, just before the 3rd planned paclitaxel 
dose if paclitaxel dose) or 3 weeks after first chemotherapy dose (if carboplatin/docetaxel 
used

At the time of definitive surgery (residual tumor/ tumor bed - section 7.0).
Biospecimens will be collected and the study conducted in accordance with the recommendations of 
the NCI-BIG Breast Cancer Intergroup37,38. 
Procedures for collection and processing specimens will be stipulated in detail in a Standard Operation 
Procedure Manual developed specifically for this protocol. A recent study evaluated the aliquots of fresh 
primary tumor tissue from 17 surgically resected invasive breast cancers were placed into RNA later at 
room temperature after tumor removal (baseline) and up to 3 hours thereafter or were snap frozen at baseline 
and 40 minutes thereafter.39 Although sample preservation in RNAlater was associated with improved RNA 
yield and quality, whereas cold ischemia increased RNA fragmentation as measured by the 3'/5' expression 
ratio of control genes, expression levels of single genes and multigene signatures that are of diagnostic 
relevance in breast cancer were mostly unaffected by sample preservation method, or prolonged cold 
ischemic duration. This indicates that for  
The following guidelines apply to sampling and specimen processing:

All patients will have fine needle biopsy (FNA) procedure), sonographically guided if necessary. 
Patients may elect to have: (1) FNA only, (2) FNA plus core biopsies

The procedure may be billed to the insurance company if performed to confirm/establish a 
diagnosis or biomarkers (e.g., ER, PR, HER2) at baseline, but not in other circumstances (e.g. 
during treatment biopsy). 

Five FNA passes (all patients) followed  3 core biopsies (if patient agrees) will be obtained with 
25 and 12 gauge needles respectively. The specimens should be processed a follows:
o
FNA: immediately placed in cytology solution
o
1st core biopsy (if done): 10% formalin (to confirm histologic presence of tumor) 
o
2rd core biopsy (if done): RNA Later (for gene expression studies in future). RNAlater® 
samples should be shipped on a cold pack. For more information on RNAlater, see 
http://www.ambion.com/techlib/tn/114/6.html 
o
3rd : Snap frozen 
5.2 Blood Specimens

Draw peripheral blood using vacutainer into two Acid Citrate Dextrose (ACD tubes (yellow 
top, draw volume 6 ml/tube), then gently invert tube 8-10 times at baseline (before treatment).

Label tube with patient ID number 

Place specimen on cool pack deliver specimen and form to Einstein Biorepository on same 
day. 

Samples will be processed in the Einstein biorepository for storage of peripheral blood 
mononuclear cells (PBMC’s) and plasma. 
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6. 
CORRELATIVE STUDIES
6.1 TMEM 
TMEM stain is a triple immunostain for predicting metastatic risk in which 3 antibodies are applied 
sequentially, and developed separately with different chromogens on a Bond Max Autostainer as described 
previously 36. TMEM is defined as the direct apposition of an endothelial cell, a perivascular macrophage, 
and a Mena expressing tumor cell. The antibodies used are CD31 (endothelial cell), CD68 (macrophage) 
and pan Mena (intravasation competent tumor cell) 36.  A pan-Mena mouse monoclonal (A351F7D9) will 
be used to identify Mena positive tumor cells. The assessment of TMEM scores will be performed using 
Adobe Photoshop on 10 contiguous 400x digital images of the most representative areas of the tumor. The 
total TMEM for each image will be tabulated, and the scores from all ten images will be summed to give a 
final TMEM density for each patient sample, expressed as the number of TMEM per 10 400x fields (total 
magnification). Two pathologists will score TMEM, including Dr. Oktay. TMEM score will be obtained 
on pre-treatment core biopsies and the post-treatment excision.
6.2 qRT-PCR for Mena isoform expression and Flow Cytometry for Cancer Stem Cells
PCR analyses will be performed using SyBR Green kit and ABI 7300 sequence detector. PCR primers used 
for the detection of Menaclassic, MenaINV and Mena 11a isoforms have been described by us previously 19. 
These primers do not recognize other Ena/VASP family members. Also, macrophages do not express Mena 
40. Therefore, PCR detects Mena levels in tumor cells only. PCR analysis will be performed on FNA 
samples obtained before treatment and on FNA samples obtained from surgical resections of chemoresistant 
tumors. The percentage of CD44high/CD24low breast cancer stem cells (BCSCs) by flow cytometry will be 
quantified. 
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7.
STUDY CALENDAR
Parameter
Specimen Collection Time Points
Correlative studies
Research Blood 
Samples 
o
Pretreatment 
 

Biospecimen banking
Research Tumor 
Samples
o
Pretreatment 
o
2-3 
weeks 
after 
first 
chemotherapy dose (section 
5.1) 

TMEM 
(from 
pretreatment 
diagnostic core biopsy, and week 2-
3 biopsy if done)

qPCR Mena isoform (FNA)

Cancer stem cells (FNA)
Tissue 
Collection 
at 
Surgery
 
o
At time of surgical procedure 

AJCC Y stage (routine pathlogy)

RCB Score (study pathologist)

TMEM, qPCR Mena isoform, and 
cancer stem cells in residual tumor if 
present 
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8.
MEASUREMENT OF EFFECT
Pathological Response
The pathologic response to treatment will be assessed by in all patients as follows:

 “y staging” denoting prior neoadjuvant chemotherapy using AJCC Y version 7.0, as 
described in the pathology synoptic report

 Residual Cancer Burden" will be assessed by one of the study pathologists as 
described 
(http://www3.mdanderson.org/app/medcalc/index.cfm?pagename=jsconvert3). 41 
9.
REGULATORY AND REPORTING REQUIREMENTS
9.1 Registration and Data Reporting 

All patients must be screened for eligibility and meet all eligibility criteria before being 
offered participation in the trial

Patients who meet eligibility criteria for stratum A  may be consented for participation if 
the eligibility criteria are met.

Patients who meet the eligibility criteria for stratum B or C (HER2-negative disease, 
candidate for preoperative chemotherapy) must be pre-randomized first with the Cancer 
Clinical Trials Office and receive a stratum assignment to stratum B or C. After pre-
randomization, patients must be offered the trial and consented. 

Data and specimen collection will be collected using study specific case report form. 
9.2 Adverse Event Reporting

Adverse events will be reported in accordance with guidelines established by the Institutional 
Review 
Board 
(.http://www.einstein.yu.edu/docs/administration/institutional-review-
board/policies/AE-internal.pdf). All of the treatment given as a component of this protocol is 
consistent with standard of care. Only the biopsies are considered research-related procedures 
and require adverse event reporting, including: 

DEATH: The following must be reported: (a) deaths that occur while subject is on study 
treatment, or (b) deaths that occur within thirty 30 days of conclusion of study intervention.  
All deaths, whether or not anticipated or related to the protocol, must be reported to the 
designated IRB within 48 hours of the PI’s knowledge of the death. Within 10 business 
days of informing the designated IRB, the Principal Investigator is required to submit a 
completed Adverse Event Report to the designated IRB.

SERIOUS EVENT: A serious event is defined as (a) an adverse event, whether or not 
anticipated, that has the potential to cause significant impairment of health or death; or (b) an 
adverse event that prompts the Principal Investigator to suspend the research protocol, 
(temporarily or permanently) even if the risk is explicitly identified in the Consent Form; or (c) 
events that occur with a frequency or degree of severity greater than anticipated. (Examples of 
Serious Events are: disability, inpatient hospitalization, prolongation of hospitalization, 
congenital anomaly, laboratory anomalies critical to safety evaluations, and serious adverse 
drug reactions.) The following must be reported: (a) serious events that occur while subject is 
on study treatment, or (b) serious events that occur within thirty (30) days of conclusion of 
study intervention All reportable serious events must be reported to the designated IRB 
within 48 hours by phone, e-mail, or fax. Within 10 business days of initial notification to 
the designated IRB the Principal Investigator is required to submit a completed Adverse 
Event Report. 

NON-SERIOUS UNANTICIPATED EVENT: A reportable non-serious unanticipated event 
is an adverse event that is not explicitly identified in the consent form and/or in the 
investigator's brochure, does not pose a serious impairment to a subject's health, and is not life-
threatening. Non-Serious Unanticipated Events must be reported to the designated IRB 
within 30 days via submission of a completed Adverse Event Report. 
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10. DATA SAFETY AND MONITORING BOARDS
All trials initiated by the Montefiore Medical Center are subject to oversight by the Albert Einstein 
Cancer Center Data Safety Monitoring Board (DSMB).  This board meets once a month with any 
additional meetings scheduled when needed.  The responsibilities are as follows:

Familiarize themselves with the research protocol (s)

Review interim analyses of outcome data and cumulative toxicity data summaries to 
determine whether the trial should continue as originally designed, should be changed, or 
should be terminated based on these data.  

The Albert Einstein Cancer Center DSMB reviews trial performance information such as 
accrual information.  

The Albert Einstein Cancer Center DSMB also determines whether and to whom 
outcome results should be released prior to the reporting of study results.

All adverse events are reviewed by the committee with assurances that these have been in 
fact sent for review to all pertinent IRBs.

Review of reports of related studies to determine whether the monitored study needs to be 
changed or terminated.

Review major proposed modifications to the study prior to their implementation (e.g., 
termination, dropping an arm based on toxicity results or other reported trial outcomes, 
increasing target sample size).
Following each Albert Einstein Cancer Center DSMB meeting, provide the study leadership with 
written information concerning findings for the trial as a whole related to cumulative toxicities 
observed and any relevant recommendations related to continuing, changing, or terminating the 
trial.  The study leadership will provide information on cumulative toxicities and relevant 
recommendations to the local principal investigators to be shared with their IRB’s.
11. STATISTICAL CONSIDERATIONS
The primary aim of the study is to examine the difference in change of the outcome variables (Mena 
isoforms, cancer stem cells, and TMEM score) before treatment and 2-3 weeks after chemotherapy 
treatment begins. Two-sampled t-test will be used for this comparison. Appropriate transformation may be 
used to improved normality of the outcome variable. With 46 patients in stratum I and II  (92 total), our 
study will have 80% power to detect a difference in change of 0.60SD of each outcome variable in each 
stratum, a moderate to large effect size42..As an exploratory analysis, we will also conduct multivariable 
linear regression model to examine the treatment difference in change in outcome variables while adjusting 
for other clinical and patient characteristics. We will also perform an exploratory analysis in 20 patients in 
stratum III. 
IRB NUMBER: 13-02-079
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12. REFERENCES 
1.
Mauri D, Pavlidis N, Ioannidis JP: Neoadjuvant versus adjuvant systemic treatment 
in breast cancer: a meta-analysis. J Natl Cancer Inst 97:188-94, 2005
2.
Kaufmann M, von Minckwitz G, Mamounas EP, et al: Recommendations from an 
international consensus conference on the current status and future of neoadjuvant systemic 
therapy in primary breast cancer. Ann Surg Oncol 19:1508-16
3.
Berruti A, Generali D, Kaufmann M, et al: International expert consensus on 
primary systemic therapy in the management of early breast cancer: highlights of the Fourth 
Symposium on Primary Systemic Therapy in the Management of Operable Breast Cancer, 
Cremona, Italy (2010). J Natl Cancer Inst Monogr 2011:147-51
4.
Kaufmann M, Morrow M, von Minckwitz G, et al: Locoregional treatment of 
primary breast cancer: consensus recommendations from an International Expert Panel. Cancer 
116:1184-91
5.
Prowell TM, Pazdur R: Pathological Complete Response and Accelerated Drug 
Approval in Early Breast Cancer. N Engl J Med 
6.
Wolmark N, Wang J, Mamounas E, et al: Preoperative chemotherapy in patients 
with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel 
Project B-18. J Natl Cancer Inst Monogr:96-102, 2001
7.
Bear HD, Anderson S, Brown A, et al: The effect on tumor response of adding 
sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary 
results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 
21:4165-74, 2003
8.
Green MC, Buzdar AU, Smith T, et al: Weekly paclitaxel improves pathologic 
complete remission in operable breast cancer when compared with paclitaxel once every 3 weeks. 
J Clin Oncol 23:5983-92, 2005
9.
Buzdar AU, Valero V, Ibrahim NK, et al: Neoadjuvant therapy with paclitaxel 
followed by 5-fluorouracil, epirubicin, and cyclophosphamide chemotherapy and concurrent 
trastuzumab in human epidermal growth factor receptor 2-positive operable breast cancer: an 
update of the initial randomized study population and data of additional patients treated with the 
same regimen. Clin Cancer Res 13:228-33, 2007
10.
Hansen-Algenstaedt N, Stoll BR, Padera TP, et al: Tumor oxygenation in hormone-
dependent tumors during vascular endothelial growth factor receptor-2 blockade, hormone 
ablation, and chemotherapy. Cancer Res 60:4556-60, 2000
11.
Hotchkiss KA, Ashton AW, Mahmood R, et al: Inhibition of endothelial cell 
function in vitro and angiogenesis in vivo by docetaxel (Taxotere): association with impaired 
repositioning of the microtubule organizing center. Mol Cancer Ther 1:1191-200, 2002
12.
Padera TP, Stoll BR, Tooredman JB, et al: Pathology: cancer cells compress 
intratumour vessels. Nature 427:695, 2004
13.
Taghian AG, Abi-Raad R, Assaad SI, et al: Paclitaxel decreases the interstitial fluid 
pressure and improves oxygenation in breast cancers in patients treated with neoadjuvant 
chemotherapy: clinical implications. J Clin Oncol 23:1951-61, 2005
14.
Ghebeh H, Lehe C, Barhoush E, et al: Doxorubicin downregulates cell surface B7-
H1 expression and upregulates its nuclear expression in breast cancer cells: role of B7-H1 as an 
anti-apoptotic molecule. Breast Cancer Res 12:R48, 2010
15.
Zhang P, Su DM, Liang M, et al: Chemopreventive agents induce programmed 
death-1-ligand 1 (PD-L1) surface expression in breast cancer cells and promote PD-L1-mediated 
T cell apoptosis. Mol Immunol 45:1470-6, 2008
16.
Earl H.M VL, Hiller N et al: Neo-tAnGo: A neoadjuvant randomized phase III trial 
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of epirubicin/cyclophosphamide and paclitaxel ± gemcitabine in the treatment of women with 
high-risk early breast cancer (EBC): First report of the primary endpoint, pathological complete 
response (pCR). J Clin Oncol 27:(suppl; abstr 522), 2009
17.
Alvarez RH BG, Hsu L, Cristofanilli M, Esteva FJ, Pusztai L, Buzdar AU, 
Hortobagyi GN, Valero V: Clinical Outcome of Two Sequences of Administering Paclitaxel (P) 
and Anthracyclines (A) as Primary Systemic Therapy (PST) and Adjuvant Chemotherapy (ACT) 
in Breast Cancer (BC) Patients: A Retrospective Analysis from the M. D. Anderson Cancer Center 
(MDACC).
. J Clin Oncol  28:(suppl; abstr 548), 2010
18.
Roussos ET, Goswami S, Balsamo M, et al: Mena invasive (Mena(INV)) and 
Mena11a isoforms play distinct roles in breast cancer cell cohesion and association with TMEM. 
Clin Exp Metastasis 28:515-27
19.
Goswami S, Philippar U, Sun D, et al: Identification of invasion specific splice 
variants of the cytoskeletal protein Mena present in mammary tumor cells during invasion in vivo. 
Clin Exp Metastasis 26:153-9, 2009
20.
Kedrin D, Gligorijevic B, Wyckoff J, et al: Intravital imaging of metastatic behavior 
through a mammary imaging window. Nat Methods 5:1019-21, 2008
21.
Kedrin D, Wyckoff J, Sahai E, et al: Imaging tumor cell movement in vivo. Curr 
Protoc Cell Biol Chapter 19:Unit 19 7 2007
22.
Roussos ET, Keckesova Z, Haley JD, et al: AACR special conference on epithelial-
mesenchymal transition and cancer progression and treatment. Cancer Res 70:7360-4, 2010
23.
Goswami S, Sahai E, Wyckoff JB, et al: Macrophages promote the invasion of 
breast carcinoma cells via a colony-stimulating factor-1/epidermal growth factor paracrine loop. 
Cancer Res 65:5278-83, 2005
24.
Wang W, Goswami S, Lapidus K, et al: Identification and testing of a gene 
expression signature of invasive carcinoma cells within primary mammary tumors. Cancer Res 
64:8585-94, 2004
25.
Condeelis J, Singer RH, Segall JE: The great escape: when cancer cells hijack the 
genes for chemotaxis and motility. Annu Rev Cell Dev Biol 21:695-718, 2005
26.
Gertler F, Condeelis J: Metastasis: tumor cells becoming MENAcing. Trends Cell 
Biol 21:81-90, 2011
27.
Wang W, Wyckoff JB, Goswami S, et al: Coordinated regulation of pathways for 
enhanced cell motility and chemotaxis is conserved in rat and mouse mammary tumors. Cancer 
Res 67:3505-11, 2007
28.
Roussos ET, Condeelis JS, Patsialou A: Chemotaxis in cancer. Nat Rev Cancer 
11:573-87, 2011
29.
Philippar U, Roussos ET, Oser M, et al: A Mena invasion isoform potentiates EGF-
induced carcinoma cell invasion and metastasis. Dev Cell 15:813-28, 2008
30.
Roussos ET, Wang Y, Wyckoff JB, et al: Mena deficiency delays tumor 
progression and decreases metastasis in polyoma middle-T transgenic mouse mammary tumors. 
Breast Cancer Res 12:R101, 2010
31.
Roussos ET, Balsamo M, Alford SK, et al: Mena invasive (MenaINV) promotes 
multicellular streaming motility and transendothelial migration in a mouse model of breast cancer. 
J Cell Sci 124:2120-31, 2011
32.
Bear JE, Svitkina TM, Krause M, et al: Antagonism between Ena/VASP proteins 
and actin filament capping regulates fibroblast motility. Cell 109:509-21, 2002
33.
Shapiro IM, Cheng AW, Flytzanis NC, et al: An EMT-driven alternative splicing 
program occurs in human breast cancer and modulates cellular phenotype. PLoS Genet 
7:e1002218, 2011
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Version 4.2   26 April 2021 
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34.
Roussos ET, Goswami S, Balsamo M, et al: Mena invasive (Mena(INV)) and 
Mena11a isoforms play distinct roles in breast cancer cell cohesion and association with TMEM. 
Clin Exp Metastasis 28:515-27, 2011
35.
Oktay MH, Gertler FB, Liu YF, et al: Correlated immunohistochemical and 
cytological assays for the prediction of hematogenous dissemination of breast cancer. J Histochem 
Cytochem 60:168-73
36.
Robinson BD, Sica GL, Liu YF, et al: Tumor microenvironment of metastasis in 
human breast carcinoma: a potential prognostic marker linked to hematogenous dissemination. 
Clin Cancer Res 15:2433-41, 2009
37.
Loi S, Symmans WF, Bartlett JM, et al: Proposals for uniform collection of 
biospecimens from neoadjuvant breast cancer clinical trials: timing and specimen types. Lancet 
Oncol 12:1162-8, 2011
38.
Fumagalli D, Bedard PL, Nahleh Z, et al: A common language in neoadjuvant 
breast cancer clinical trials: proposals for standard definitions and endpoints. Lancet Oncol 
13:e240-8, 2012
39.
Hatzis C, Sun H, Yao H, et al: Effects of tissue handling on RNA integrity and 
microarray measurements from resected breast cancers. J Natl Cancer Inst 103:1871-83
40.
Krause M, Dent EW, Bear JE, et al: Ena/VASP proteins: regulators of the actin 
cytoskeleton and cell migration. Annu Rev Cell Dev Biol 19:541-64, 2003
41.
Symmans WF, Peintinger F, Hatzis C, et al: Measurement of residual breast cancer 
burden to predict survival after neoadjuvant chemotherapy. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology 25:4414-22, 2007
42.
Cohen j: Statistical Power Analysis for the Behavioral Sciences. 2nd ed.Hillsdale, 
New Jersey: Erlbaum
, 1988
IRB NUMBER: 13-02-079
IRB APPROVAL DATE: 05/11/2021
IRB NUMBER: 13-02-079
IRB APPROVAL DATE: 05/11/2021

ICF_001.pdf: 
 Version 4.2 April 7th, 2023, 
1
Montefiore Medical Center
Albert Einstein College of Medicine of Yeshiva University
Individual's Informed Consent to Participate as a Subject in Clinical Research
You are being asked to join this research study.  
The title of the study is:   Prospective tissue collection in breast cancer patients receiving 
preoperative systemic therapy. 
The study is being done under the supervision of: 
Principal Investigator (Researcher Study Doctor): Jesus Anampa-Mesias, MD
Office Address: 1695 Eastchester Road 2nd Floor, Bronx, NY 10461
Telephone #: 718-405-8404
IRB Protocol #:  13-02-079
DO I HAVE TO TAKE PART IN THIS RESEARCH STUDY? 

Your participation is voluntary.  This means that you decide whether you want to join the
study after speaking with the researcher, or other members of the research team.

If you decide to take part, you will be asked to sign this consent form. Your signature
means that you agree to be a subject in this research.

After reading this form and discussing what it says, you should ask all the questions you
want to ask.  You should take as much time as you need to decide.

If you do not understand some of the terms used in this form, ask the person who is
discussing the study with you to give any additional information that may make this
easier to understand.

You do not have to consent to participate in the study immediately, or ever. Take time to
decide whether you wish to join.  You may take home a copy of this consent form to
think about it or discuss the information with family or friends before you decide.

If you decide not to participate the care providers at this facility will give you all the
standard care that is appropriate for you.

You will be given a copy of this form whether you agree to participate in this study.  Do
not sign the form unless you have had all your questions answered and understand
exactly what is involved.

If you decide to take part, you are still free to withdraw at any time without giving a
reason.  This will not affect your care and you will continue to be treated at this facility.

If you decide to withdraw after receiving the study drug, you should talk with the
research study doctor to see how best to complete the withdrawal process.

The form discusses:
WHAT THE RESEARCHERS WILL LEARN FROM THE RESEARCH
WHAT WILL HAPPEN TO YOU DURING THE RESEARCH
WHAT RISKS AND/OR DISCOMFORTS YOU MIGHT EXPECT/EXPERIENCE AS
A RESEARCH SUBJECT
IF YOU CAN EXPECT ANY BENEFITS AND ARE THERE ANY ALTERNATIVES
TO THIS RESEARCH FOR YOUR CONDITION.
IRB NUMBER: 13-02-079
IRB APPROVAL DATE: 10/25/2023
IRB EXPIRATION DATE: 10/24/2024


 Version 4.2 April 7th, 2023, 
2
WHY HAVE I BEEN ASKED TO TAKE PART IN THIS RESEARCH STUDY? 

You are being asked to take part in this study because you have breast cancer that has a
high chance of having spread to other organs if treated by surgery alone.
WHY IS THIS RESEARCH STUDY BEING DONE? 
This study involves blood and/or tissue collection during treatment with standard chemotherapy 
for the treatment of breast cancer.
The purpose of this study is to obtain blood and/or tumor samples before treatment, 2-3 weeks 
after treatment begins and before surgery to find tests that may lead to a better understanding of 
how the chemotherapy is working and might predict which patients will or will not respond to 
chemotherapy. This may help to develop better treatments in the future.
HOW MANY PEOPLE WILL TAKE PART IN THE RESEARCH STUDY?
With reopening of the study, a total of 92 patients will take part in this study, all at Montefiore 
Medical Center. 
WHAT WILL HAPPEN IF I TAKE PART IN THIS RESEARCH STUDY? 
You will be treated with the same standard chemotherapy combinations used most commonly for 
patients who are not participating in a research study. The combination of chemotherapies will 
depend on the type of breast cancer that you have.
If the breast cancer is HER2 negative (about 75% all cancers), then you will be treated with 
paclitaxel (+/- carboplatin) given weekly for 12 weeks followed by doxorubicin and 
cyclophosphamide given every 2 -3 weeks for 4 treatments, or you will be treated with the same 
drugs in the reverse sequence if your doctor feels that is a better tolerated sequence in your case. 
Both sequences are considered standard ways to administer this treatment. Other standard of care 
chemotherapy regimens can be used as per your physician decision such as docetaxel plus 
cyclophosphamide, or docetaxel plus carboplatin. Pembrolizumab can be used in patients who 
have HER negative/ER negative disease.  If your tumor is estrogen-receptor (ER) positive and 
your doctor feels you are a good candidate for hormonal therapy, you will have a 4-6 month or 
longer course of hormonal therapy prior to surgery.
You will receive tests and examinations that are routinely used for the treatment of breast cancer.
The study procedures are summarized below: 

Before treatment:  Blood specimens (3-5 tubes, about 3-5 tablespoons). Fine needle
aspiration (FNA) of the breast tumor (5 passes using a thin needle) is recommended, but
is optional. A sample from the biopsy that was done to diagnose breast cancer will be
collected.

After 2-3 weeks on study: Blood specimens (3-5 tubes, about 3-5 tablespoons). Fine
needle aspiration (FNA) of the breast tumor (5 passes using a thin needle) is
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recommended but is optional.

At the time of Surgery: Blood specimens (3-5 tubes, about 3-5 tablespoons). A sample
of breast tumor removed at time of surgery will be collected.
WILL THIS STUDY INVOLVE GENETIC RESEARCH and/or TESTING?
Genetic means having to do with information that is passed on in families from parents to their 
children through genes. 
No, this study will not involve genetic research and/ or testing.
In the future, before the extract from your tissue or blood samples can be used for research, the 
people doing the research must get a specific approval from the Institutional Review Board 
(IRB) of Montefiore/Einstein. The IRB is a committee made up of doctors, researchers and 
members of the community. The IRB is responsible for protecting the participants involved in 
research studies and making sure all research is done in a safe and ethical manner. All research 
done at Montefiore/Einstein, including research involving your tissue and blood samples from 
this bank must first be approved by the IRB. Portions of the extracts from the tumor specimens 
and blood samples may be shared with investigators outside Montefiore/Einstein in order to 
perform studies on the tissue that are not readily available at this institution. 
Treatment (explained in detail in the next several paragraphs):
You will not need to be hospitalized to take part in this study. 
The standard of care treatment, not related to this study, will include excision of your tumor 
that may require hospitalization and standard chemotherapy, Your doctor may choose one of 
the following standard treatment options that he/she thinks is the best option for you based on 
its effectiveness and side effect profile:
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Stratum I (HER negative, chemotherapy indicated)
Patients in Stratum I can be treated with the following regimens:
If hormone positive:

Paclitaxel weekly x12 consecutive weeks followed by AC every 2 weeks for 4
cycles, OR

Docetaxel plus cyclophosphamide IV every 3 weeks for 4-6 cycles, OR
If hormone negative:

Paclitaxel weekly x12 weeks (+/- carboplatin) followed by AC every 2-3 weeks
x4 cycles, OR 

Docetaxel plus cyclophosphamide IV every 3 weeks for 4-6 cycles, OR

Docetaxel plus carboplatin IV every 3 weeks for 4-6 cycles.

If there is no contraindication to immunotherapy, ER- patients will receive
pembrolizumab every 3 weeks for 6-8 doses along with neoadjuvant 
chemotherapy. 
Stratum II (Hormone positive, Her2 negative, Endocrine therapy indicated)
Patients in Stratum II can be treated with the following regimens:

Anastrozole 1 mg po daily for 4-6 months.

Letrozole 2.5 mg po daily for 4-6 months.

Exemestane 25 mg po daily for 4-6 months.

Tamoxifen 20 mg po daily for 4-6 months.
When I am finished taking the standard chemotherapy

You will undergo breast surgery. The surgery may include a mastectomy or
lumpectomy, whichever procedure your research study doctor feels is the best 
procedure to remove the breast tumor. Most patients with locally advanced breast 
cancer require mastectomy in order to assure that all the tumor cells have been 
removed. The surgery will usually also include removal of the axillary lymph nodes 
(lymph nodes in the arm pit). Your research study doctor will ask you to sign a 
separate hospital consent form for the surgery. Potential complications from the 
surgery include pain, bleeding, and infection.

Your surgical and blood specimen will be collected for mandatory research studies.

You will follow up in 3-4 weeks with the study doctor.

If you developed side effects, shown either by physical exam or laboratory
abnormalities, your doctor will continue to follow you until resolution of these issues.

Standard post-operative care will continue. After completing the protocol-specified 
therapy indicated above, your research study doctor may advise additional treatment 
that is part of routine standard care. These possible treatments include radiation 
therapy, hormonal therapy, and continued trastuzumab therapy. These are considered 
standard treatments and are not part of this research study.  If radiation therapy is 
given, it typically begins within about 4 weeks of completion of chemotherapy. You 
will be evaluated by a radiation oncologist who will discuss the potential benefits and 
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risks of radiation, and who will prescribe and monitor the radiation. It is usually given 
as a single dose to the breast, chest wall, and nearby lymph nodes five days per week 
for 6 weeks. 

If your tumor is estrogen-receptor (ER) positive, your research study doctor will also
recommend hormonal therapy (e.g., tamoxifen or an aromatase inhibitor [such as
anastrozole, letrozole, or exemestane]) for a period of at least 5 years, or possibly
longer.

If you received pembrolizumab prior to surgery, you will be treated with the same
drug for up to 27 weeks after surgery. 

If your disease still remains after surgery, you will be treated with capecitabine.

If you have germline BRACA1/2 mutation and HER2 negative tumors who meet
standard of care guidelines, you will be given PARP inhibitors after surgery.

If you have high-risk HR+/HER2 breast cancer which meets standard of care
guideline, you will be given abemaciclib. 
Study Plan
Another way to find out what will happen to you during the study is to read the chart 
below.  Start reading at the top and read down the list, following the lines and arrows. 
 

Blood sample – before treatment, 2-3 weeks after treatment begins, and before surgery.

Fine needle aspiration of tumor (optional) - before treatment and 2-3 weeks after
treatment begins.

Core needle biopsy (optional) - before treatment and 2-3 weeks after treatment begins.
Surgery after completion of neoadjuvant systemic therapies.
 Tissue collection and banking.
Breast Cancer

Eligible for neoadjuvant therapy.
Meet protocol eligibility criteria.

Provide written informed consent.
Stratum I:
HER2-Negative Tumor
Chemotherapy Indicated
Standard of care adjuvant therapies.
Stratum III:
ER-Pos, HER2-Negative Tumor
Endocrine Therapy 
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WHAT ELSE DO I HAVE TO DO?

You must tell the research study doctor about any past and present diseases or allergies
you are aware of and about all medications you are taking including over-the-counter
remedies and nutritional supplements or herbs.

If you do not feel well at any time, call your doctor or the research study doctor
immediately.

Drugs may cause a reaction that, if not treated promptly, could be life-threatening. It is
important that you report all symptoms, reactions and other complaints to the research 
study doctor.

If you think you have become pregnant, contact your research study doctor immediately.

If any other doctor recommends that you take any medicine, please inform him/her that
you are taking part in a research study. You should give the other doctor the research 
study doctor’s name and phone number. 

You may carry out all your normal daily activities that are suitable to you.
HOW LONG WILL I BE IN THE STUDY?
You will be asked to take standard pre-operative chemotherapy treatment for 18-24 weeks. 
 Treatment may be stopped if:

your tumor progresses (grows) despite the treatment.

you develop severe side effects.

scientific developments occur that indicate the treatment is not in your best
interest or

you elect to withdraw from the research protocol for any reason.
 After you are finished taking pre-operative treatment, you will undergo surgery. Following the 
surgery, the study doctor will ask you to visit the office for follow-up exams every 6 months for 
the first 5 years and yearly for the next 5 years. We would like to keep track of your medical 
condition for the rest of your life.  We would like to do this by calling you on the telephone once 
a year to see how you are doing.  Keeping in touch with you and checking on your condition 
every year helps us look at the long-term effects of the study.
WHAT ARE THE POSSIBLE SIDE EFFECTS, DISCOMFORTS, RISKS OR 
INCONVENIENCES I CAN EXPECT FROM BEING IN THIS RESEARCH STUDY? 
Blood Drawing:  This may cause temporary bruising and pain at the puncture site. There is also 
the possibility you may experience bleeding into the tissue around where the blood was drawn, 
and an infection may occur.
Fine Needle Aspiration (FNA): Having an FNA biopsy performed may cause mild pain (very 
common), bruising (occasional), bleeding (rare), redness (rare), swelling (rare), and/or infection 
(extremely rare) at the site of the biopsies. Mild pain is usually controlled with over-the-counter 
pain relievers. Most side-effects go away within a few days. 
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If infection occurs with either of the procedures, it will be treated accordingly with the standard 
of care antibiotics. 
Everyone taking part in the study will be watched carefully for any side effects. However, 
doctors don’t know all the side effects that may happen. You should talk to your study doctor 
about any side effects that you have while taking part in the study. Your health care team may 
give you medicines to help lessen side effects. Many side effects go away soon after you stop 
taking the standard treatment. Death as result of FNA or blood draw is very rare.
PREGNANCY AND IMPREGNATION DURING THIS STUDY

The drug(s) used to treat breast cancer are not part of the study. You should discuss with
your medical oncologist about the implications of pregnancy in the treatment of breast 
cancer.

For more information about risks and side effects, ask your research study doctor.
ARE THERE LIKELY TO BE ANY BENEFITS TO TAKING PART IN THIS 
RESEARCH STUDY? 
If you take part in this study, there will be no medical benefit to you.  We hope the information 
learned from this study will benefit other breast cancer patients in the future.
WHAT OTHER CHOICES DO I HAVE IF I DO NOT TAKE PART IN THIS 
RESEARCH STUDY? 
Before agreeing to join the study and before signing this consent form your personal doctor 
should have discussed with you what, and if, standard treatments are available and/or other 
research protocols.  Your other choices may include:

Getting similar treatment or care for your cancer without being in a research study.

You may choose not take part in this study and take part in another study.
Talk to your research study doctor about your choices before you decide if you will take part in 
this study.
WILL I BE PAID FOR BEING IN THE STUDY?  
You will not be paid for taking part in this research study.
WHO MAY SEE MY RECORDS? 

The research records will be kept private, and your name will not be used in any written or
verbal reports.  

Your research records and medical records may be inspected by members of the research
team and designated employees of Montefiore Medical Center.
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
As this research involves a drug, the U.S. Food and Drug Administration (FDA), the agency
for regulating the drugs, may inspect your research records and medical records.

The research study doctor and research staff will review your medical records and will keep
the information private.

All laboratory specimens, reports, and other records will be identified only by a number
known only to the research study doctor.  The research records will be kept in a secured
manner and computer records will be password protected.

The people who reviewed this research study as members of the Institutional Review Board
of The Albert Einstein College of Medicine may also review your research and medical 
records.

The Office for Human Research Protections (OHRP) may also review your research study
records.

All of these groups have been requested to keep your name private.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov. This Web 
site will not include information that can identify you. At most, the Web site will include a 
summary of study results.  You can search this Web site at any time.
WILL THERE BE ANY COSTS TO ME? 
You and/or your health plan/ insurance company will need to pay for some or all of the costs of 
treating your cancer in this study.  Some health plans will not pay these costs for people taking 
part in studies. Check with your health plan or insurance company to find out what they will pay 
for.  Taking part in this study would not cost your insurance company more than the cost of 
getting regular cancer treatment. All treatment agents are commercially available and all tests 
(with the exception of the tumor biopsy and research blood specimens) are considered standard 
of care for your condition.
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute's Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage .    You 
can print a copy of the "Clinical Trials and Insurance Coverage" information from this Web site.
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy.
WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THIS RESEARCH 
STUDY? 
If there is a physical injury as a result of this research, only immediate, essential, short-term 
medical treatment as determined by the participating hospital, will be available for the injury 
without charge to you personally. 

No monetary compensation will be offered.

You are not waiving any of your legal rights by signing this informed consent document.

If additional treatment is required as a result of a physical injury related to the research,
necessary medical treatment will be provided to you and billed to your insurance 
company or to you as part of your medical expenses. 
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Immediately report any discomforts, problems or injuries you experience during the course of 
your participation in the study to Dr. Jesus Anampa at 718-405-8404.
WHO CAN ANSWER MY QUESTIONS ABOUT THE STUDY?  
Researcher’s Name:  Dr. Jesus Anampa
Office Address:         Montefiore Einstein Cancer Center1695 Eastchester 
Rd, Bronx, NY 10461
Office Phone:
718-405-8404

If any questions arise related to this research project, or you believe you have any injury
related to this study, you can call the researcher above. 

You may also call Anastasia Abdul -Wahab at 718-405-8505.

If you have questions regarding your rights as a research subject, you may also call the
Administrator of The Albert Einstein College of Medicine Institutional Review Board 
(IRB) at (718) 798-0406, Monday through Friday between 9 AM and 5 PM.  
WHERE CAN I GET MORE INFORMATION?
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the 
Web site will include a summary of the results.  You can search this Web site at any time.
You will get a copy of this form. If you want more information about this study, ask your study 
doctor. 
WILL ANY OF THE SAMPLES (BLOOD, TISSUE, DNA) TAKEN FROM ME BE USED 
FOR FUTURE RESEARCH STUDIES?
In addition to the research you are consenting to under this research study, Dr. Jesus Anampa or 
other researchers at this or other institutions may wish to study the samples in future research, 
which unlikely may include genetic analysis. These samples, taken from your body, would NOT 
be linked back to you. No one will know your name or protected health information. 
At this time, the researcher does not know what the future studies will be. Your specimens may 
also be submitted to a tissue/cell/DNA bank. The specimens may be kept for a long time and 
may be more than 50 years. 
In some research using human blood or tissue, the specimens and their parts may enable 
researchers to develop medical tests or treatments that have commercial value. You will not 
receive any money that may result from any such commercial tests or treatments.
Your specimens may be used for future research, even though the purpose of the future research 
is not known at this time. 
PARTICIPANT: 
PLEASE INDICATE YOUR CHOICE BY INITIALING ONE (1) OF THE FOLLOWING 
OPTIONS 
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___ I consent to have my specimens used for future research studies. 
___ I consent to have my specimens used for future research studies only for the study of 
_____________________________________. 
___ I do NOT consent to have my specimens used for future research studies. (The specimens 
will be destroyed at the end of the study.)
CAN I BE ASKED TO STOP PARTICIPATING IN THIS STUDY BEFORE THE 
STUDY IS FINISHED? 
Sometimes the company sponsoring the research may stop your part in the study for the 
following reasons:

You fail to follow instructions given to you by the research study doctor.

New information about important medical risks and benefits become available.

If you are a female and become pregnant while on the study, you will be taken off of
protocol treatment. 
WHAT IF NEW INFORMATION BECOMES AVAILABLE?

If the research study doctor obtains new information that might lead you to change your
mind about continuing in this study, the research study doctor will tell you about it. 

If you decide to withdraw, the research study doctor and your personal doctor will make
arrangements for your care to continue. 
MAY I STOP THE STUDY AT ANY TIME? 

Your participation in this study is voluntary, and you may withdraw from the study at any
time without giving a reason. 

It is important to tell the study doctor if you are thinking about stopping so any risks from
the treatment or biopsies can be evaluated by your doctor.  

If you agree to participate and withdraw at a later time, some of your information may 
have already been entered into the study and that will not be removed. 

In addition, you may be asked to return to the research study doctor again for any final
tests in order to close the record and tests or monitoring that are necessary for your health 
as a result of your participation. These results may be recorded. 

Your treatment by doctors and staff at the institution(s) involved in this study, now and in
the future, will not be affected in any way if you agree to participate and withdraw later. 
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WHAT ARE MY RIGHTS IF I TAKE PART IN THIS RESEARCH STUDY? 

Your participation in this study is voluntary.

You do not waive any of your legal rights by participating in this research study.

Your treatment by doctors and staff at the institution(s) involved in this study, now and in
the future, will not be affected in any way if you refuse to participate or if you enter the
study and withdraw later.
Informed Consent Signature Page 
The following is a list of items that have been discussed with you about this research study.  If 
you have any questions about any of these items, please ask the person who is discussing the 
study with you for more information before agreeing to participate. 

What the study is about.

What I must do when I am in the study.

The possible risks and benefits to me.

Who to contact if I have questions or if there is a research related injury.

Any costs and payments.

I can discontinue participating in the study at any time without penalty.

Other choices.

My name will not appear on interview or other data collection forms.

All written and published information will be reported as group data with no reference to
my name. 

If there is a schedule explaining how the study medicines are to be taken, I will be given
the time schedule. 

I have been given the name of the researcher and others to contact.

I have the right to ask any questions.
Optional Procedure
Patient 
Initials
Date

I consent to have a Fine Needle Aspiration of the tumor for
research before therapy (initial and date if yes)

I consent to have a Fine Needle Aspiration of the tumor for
research after 2-3 weeks after therapy begins (initial and date if 
yes)
Printed Name of Participant
Signature of Participant
Time
Printed Name of Person 
Conducting the Informed 
Consent Process
Signature of Person 
Conducting the Informed 
Consent Process
Date
Time
IRB NUMBER: 13-02-079
IRB APPROVAL DATE: 10/25/2023
IRB EXPIRATION DATE: 10/24/2024