bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P3-08-66: Metaplastic breast cancer in patients older than 65 years
Authors: Chahine Johnny , Thapa Bicky , Jia Xuefei , Haddad Abdo
Published: March 2020

Background: Metaplastic breast cancer (MBC) is a rare histologic subtype of breast cancer. It comprises less than 1% of all breast cancers. We evaluated the clinical characteristics and outcomes of MBC in geriatric patients older than age 65.

Methods: We reviewed the chart of the pathologically proven MBC cases from 2000-2017. Only patients with age more than 65 years were included in the study for analysis.

Results: A total of 48 MBC patients were included in the study. Thirty-six (76%) were white and 11 (23%) black. The number of patients in stages I, II, III, and IV were 12, 26, 6, and 4, respectively; 39 (81%) had nuclear grade III. Three (6%) had progesterone receptor positive, 3 (6%) were Her2 positive, and 4 (10%) were estrogen receptor positive. The most common distant metastases were lung (20%), followed by bone (12%). Fifty percent had a lumpectomy, 11% had hormonal therapy, and 60% had radiation therapy. Only 50% of patients received chemotherapy, out of which 46% received anthracycline. On univariable analysis, stage of the MBC and metastasis to the lung, bone, and brain were associated with worse overall survival (OS). There was no statistical significance in OS when stage II was compared with stage I MBC. Stage III had median OS of 18 months with HR of 3.25 (95% CI 0.85, 12.44) (p=0.086) and stage IV had 10 months median OS with HR of 11.17, (95% CI 2.37, 52.62) (p=0.002). Hormonal therapy, radiation therapy, and type of chemotherapy (anthracycline vs. non-anthracycline) did not show any statistical significance in regards to OS and progression-free survival.

Conclusion: In our study, MBC demonstrated overall poor survival and progression-free survival. Only stage of the MBC and metastasis to brain bone and lung proved to predict worse survival.

Citation Format: Johnny Chahine, Bicky Thapa, Xuefei Jia, Abdo Haddad. Metaplastic breast cancer in patients older than 65 years [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-66.
Abstract P3-08-71: Medication use to reduce mammographic breast density in premenopausal women: A systematic review
Authors: Salazar Ana S. , Rakhmankulova Malika , Simmon Laura E. , Toriola Adetunji
Published: March 2020

Background: Mammographic breast density (MBD) is a strong modifiable risk factor for breast cancer, especially in premenopausal women. It is estimated that up to 39% of breast cancer cases in premenopausal women could potentially be prevented by reducing dense breasts to non-dense breasts. Therefore, reducing breast density through targeted interventions is an excellent opportunity to substantially reduce breast cancer incidence in premenopausal women. We performed a critical evaluation of the literature to determine the associations of chemoprevention agents use with MBD. This will guide the management of premenopausal women at risk for breast cancer. Methods: Eleven databases were searched on July 2019. We included interventional, cross-sectional, longitudinal or observational studies in Englishreporting the associations of medication with mammographic breast density in premenopausal womenwith no history of breast cancer. Two researchers extracted the data and assessed the quality of the studies. Supplements not otherwise specified were excluded. Results: After de-duplication process, 1,464 citations were screened for eligibility. Seven studies met our inclusion criteria: two observational, four randomized controlled, and one non-randomized controlled trials (RCT). There were two categories of medications: dietary supplements (i.e. vitamin D, calcium, isoflavone) and drugs (non-steroidal anti-inflammatory drugs [NSAIDs], selective estrogen receptor modulators (SERMs) goserelin, and GnRHA deslorelin acetate). In observational studies, calcium use was associated with a significant reduction in MBD, while vitamin D and NSAIDs showed no reduction6. Likewise, Isoflavone and vitamin D in doses of 1000, 2000 or 3,000IU/day were not associated with a reduction in MBD in two different RCT. Groselin, GnRHA, deslorein acetate, statins were not associated with MBD reduction in an RCT’s. SERMs (tamoxifene and raloxifene) were the only drugs associated with reductions in MBD in RCTs. Conclusions: Only a very limited number of medications (SERMs) are associated with reductions in MBD. In view of their low uptake and adherence, identifying other medications that can reduce MBD is crucial, as these could have utility in breast cancer prevention.

Citation Format: Ana S. Salazar, Malika Rakhmankulova, Laura E. Simmon, Adetunji Toriola. Medication use to reduce mammographic breast density in premenopausal women: A systematic review [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-71.
Abstract P3-09-18: Immunization of breast cancer patients in combination with standard-of-care chemotherapy: Results of a phase Ib clinical trial
Authors: Makhoul Issam , Jousheghany Fariba , Mohammed Saddam , Siegel Eric , Pennisi Angela , Beck J Thaddeus , Hutchins Laura , Kieber-Emmons Thomas , Monzavi-Karbassi Behjatolah
Published: March 2020

We have developed a peptide mimotope-based cancer vaccine, P10s-PADRE, targeting tumor associated carbohydrate antigens (TACAs). We have previously shown safety, feasibility and induction of immune response in a phase I clinical trial in stage IV breast cancer patients. In the current clinical trial, immunization with P10s-PADRE vaccine is combined with the standard-of-care chemotherapy in neo-adjuvant setting in subjects diagnosed with early stage ER-positive breast cancer. Various schedules (timing of vaccination doses relative to chemo) for combination therapy were tested. Immunological endpoint variable include antibody response and activation of natural killer (NK) cells as tested in peripheral blood mononuclear cells. Tumor size before treatment and after surgery was measured for each subject. The secondary endpoint was pathologic complete response (pCR). We observed induction of antibody response and activation of NK cells independent of each other. Vaccination affected the expression of several NK markers including CD94 and NKp46 as we observed a significant upregulation of NKp46 (median = 1.79, P<0.0001), and CD94 (median = 1.50, P<0.0001) in response to immunization. The data indicate a significant increase in serum IFN-γ (Median=1.74, P=0.0016) upon vaccination. Increase in IFN-γ was positively correlated with increase in both CD69 (r = 0.46, P=0.0321) and NKp46 (r = 0.39, P=0.0763) on CD56-dim NK cells. Tumor shrinkage was associated with an increase in NK cells, upregulation of NKp46 and CD94 molecules, and increase in frequency of NKp46-positive and CD94-positive CD56-dim NK cells. Among 25 subjects enrolled in 5 different immunization schedules, 5 experienced complete eradication of their primary tumors that was associated with vaccine induced increase in the frequency of CD94-positive CD56-dim NK cells (p= 0.0473). The results are intriguing and warrant expansion of the immunologically effective combination schedule to further establish the clinical efficacy along with potential biomarkers of response.

Citation Format: Issam Makhoul, Fariba Jousheghany, Saddam Mohammed, Eric Siegel, Angela Pennisi, J Thaddeus Beck, Laura Hutchins, Thomas Kieber-Emmons, Behjatolah Monzavi-Karbassi. Immunization of breast cancer patients in combination with standard-of-care chemotherapy: Results of a phase Ib clinical trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-09-18.
Abstract P3-10-09: Gene deletion of IRS1 inhibited IGF-I, insulin and estradiol stimulated MCF-7L breast cancer cell growth
Authors: Zhang Xihong , Yee Douglas
Published: March 2020

Targeting of the type I insulin-like growth factor receptor (IGF-IR) has not been successful in breast cancer. Data suggest the highly homologous insulin receptor (IR) may be an alternate growth stimulatory pathway used by cancer cells. Since both receptors phosphorylate the insulin receptor substrate-1 (IRS-1) protein as an immediate consequence of ligand binding, disruption of both receptors could be accomplished by suppression of IRS-1. To test this hypothesis, we created a doxycycline-inducible IRS-1 shRNA lentiviral construct to infect hormone dependent MCF-7 breast cancer cells. IRS-1 shRNA downregulation resulted in decreased responses to IGF-I, insulin, and estradiol in monolayer and anchorage independent growth assays. Decreased IRS-1 levels also suppressed estradiol stimulated gene expression and estrogen receptor binding to DNA. Xenograft growth was also inhibited by induction of IRS-1 shRNA. These data show IRS-1 is a critical regulator of endocrine responsive breast cancer. To further study the critical effects of IRS1 in ER positive breast cancer biology, CRISPR technology was used to delete IRS1 from MCF-7L cells. We analyzed 5 CRISPR IRS1 gene edited clones. Two different commercial available IRS1 antibodies were used to examine IRS1 protein expression. Clones #16, #20 did not show any IRS1 expression, while clones #22, #33 and #38 showed truncated IRS1 expression. IGFIRβ and Insulin R levels were comparable to the parent MCF-7L cells in all the clones, while IRS2 and ERα levels were significantly lower in clone #16. IRS phosphorylation, detected by PY20 antibody, was significantly lower in clone #16. The downstream signaling measured by pAKT and pErk1,2 did not change in all clones compared to those in MCF-7L. In all the clones, ERα ser118 phosphorylation by estradiol stimulation (10 nM) and ERα downregulation by fulvestrant treatment (100 nM) were not affected by IRS1 knockout. IGF-I (5 nM), insulin (10 nM) and estradiol (10 nM) stimulated monolayer cell growth in clone #16 was completely inhibited, while other clones were partially inhibited. In contrast, growth in clone #22 was not inhibited due to extremely high IRS2 expression and compensation. In conclusion, when the IRS1 gene was deleted, multiple growth stimulatory ligands (IGF-I, insulin and estradiol) were inhibited in breast cancer cells. However, IRS-2 compensated for IRS-1 gene deletion in one of the clones we studied. Thus, targeting the IRS proteins may inhibit multiple ligands that cause growth stimulation in ER positive breast cancer therapy.

Citation Format: Xihong Zhang, Douglas Yee. Gene deletion of IRS1 inhibited IGF-I, insulin and estradiol stimulated MCF-7L breast cancer cell growth [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-10-09.
Abstract P3-10-17: CREBBP alterations lead to CDK4/6 inhibitor sensitivity in triple negative breast cancer
Authors: Natrajan Rachael
Published: March 2020

Fundamental to the effective clinical use of new therapeutic agents for cancer is the identification of genetic biomarkers of sensitivity as well as the identification of additional patient populations who would benefit from treatment. Here, through an unbiased functional genomics approach in a model of aggressive disease using cancer cell line spheroid cultures, we have uncovered a role for the histone acetyltransferase CREBBP as a tumour suppressor in aggressive hard to treat triple-negative breast cancers (TNBCs). We find that CREBBP protein expression is altered in a substantial proportion of TNBCs, as well as other solid tumours, including lung and lymphoma where CREBBP inactivating mutations are common. We found CREBBP alterations are associated with higher genomic heterogeneity and poorer patient survival in TNBCs and resulted in upregulation of the FOXM1 transcriptional network. Strikingly, treatment with clinical CDK4/6 inhibitors (CDK4/6i), that indirectly target FOXM1 activity, selectively impaired growth in spheroids, cell line xenografts and patient derived models from multiple tumour types with CREBBP alterations. Here we provide the pre-clinical and mechanistic rationale for assessing CREBBP alterations as a biomarker of single-agent CDK4/6 inhibitor response in a new patient population. This represents a novel synthetic lethal approach to targeting triple negative breast cancers with limited therapeutic options.

Citation Format: Rachael Natrajan. CREBBP alterations lead to CDK4/6 inhibitor sensitivity in triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-10-17.
Abstract P3-10-20: Targeting the tyrosine phosphatase SHP2 is efficacious against HER2-positive breast cancer
Authors: Agazie Yehenew , Hartman Zachary
Published: March 2020

Accumulating evidence suggests that the Src homology phosphotyrosyl phosphatase 2 (SHP2) is a bona fide oncogene. These conclusions are primarily based on the positive role of SHP2 in receptor tyrosine kinase (RTK) signaling in multiple systems. Because overexpression of the human epidermal growth factor receptor 2 (HER2) is one of the primary causes of BC, we investigated the potential of SHP2 targeting in this subtype of BC. We have used our recently patented SHP2 inhibitor called WGMDY (US 9,932,288) for targeting SHP2 under cell culture and in vivo conditions. We have also used the recently reported allosteric SHP2 inhibitor called SHP099 particularly in the cell culture studies. We found that HER2-positive BC cells are highly sensitive to SHP2 inhibition with WGMDY as determined by loss of viability in 2D, transformation in soft agar, and cancer stem cell properties in suspension cultures. Similar results were obtained with SHP099 albeit at a reduced rate. Analysis of protein and RNA extracts showed inhibition of the Ras-ERK and the PI3K-Akt signaling pathways by WGMDY, but SHP099 tend to activate Akt signaling. In addition, WGMDY blocked overexpression of the HER2 protein in HER2-positive BC cells. As such, we focused on WGMDY for the in vivo efficacy studies. The results showed that WGMDY induces regression of preformed tumors in a concentration dependent manner. Histopathology analyses of tumors showed induction of necrosis in treated samples. Hence, WGMDY has a promising anti-cancer effects in HER2-positive BC.

Citation Format: Yehenew Agazie, Zachary Hartman. Targeting the tyrosine phosphatase SHP2 is efficacious against HER2-positive breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-10-20.
Abstract P3-11-18: Partial RALBP1 loss depletes DNA repair pathway genes
Authors: Awasthi Sanjay , Bose Chhanda , Jones Catherine , Rahman Rakhshanda , Singhal Sharad S. , Singh Sharda P.
Published: March 2020

TP53 (p53) functions as a stress-responsive, genome protective, tumor suppressor whose functions are lost or altered a majority of breast cancers. TP53 homozygous null mice uniformly die of spontaneous malignancy. The human RALBP1 gene (18p11.22) encodes is a stress-protective, anti-apoptotic mercapturic acid pathway transporter protein (RLIP76 or Rlip) regulated by the Ral/Rac/Rho pathways. In stark contrast to TP53 null mice, RALBP1-null mice are highly cancer resistant, even to the most potent known chemical carcinogens benzo[a]pyrene or dimethylbenzanthracene. We recently reported that pharmacologically or chemically induced haploinsufficiency of Rlip switches off spontaneous carcinogenesis in p53-null mice (Proc. Natl. Acad Sci USA, 2018; 115:3918), indicating an existential role of Rlip in p53-deficient cancer cells and suggesting the possibility that DNA-repair deficient cells could be particularly susceptible to Rlip depletion. Results of present studies demonstrated that RALBP1 depletion by antisense inhibited the growth of the MDA-MB231 cell line in-vitro and in xenografts. Remarkably, Rlip depletion with antisense or upon treatment with an orange-derived flavanone (2-hydroxyflavanone) depleted the expression of PALB2 as well as BRCA1 and BRCA2 in triple negative breast cancer cell lines, and synergistically increased the efficacy of PARP inhibition. These findings suggest that drugs that inhibit or deplete Rlip could be useful in sensitizing DNA-repair sufficient triple negative breast cancer to PARP inhibitors.

Citation Format: Sanjay Awasthi, Chhanda Bose, Catherine Jones, Rakhshanda Rahman, Sharad S. Singhal, Sharda P. Singh. Partial RALBP1 loss depletes DNA repair pathway genes [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-11-18.
Abstract P3-11-23: GDC-0077 is a selective PI3K alpha inhibitor with robust efficacy in PIK3CA mutant hormone-positive breast cancer models
Authors: Edgar Kyle , Hong Rebecca , Song Kyung , Schmidt Steven , Hafner Marc , Arrazate Alfonso , Williams Erin , Cruz Cecile De La , Oeh Jason , Sampath Deepak , Staben Steve , Friedman Lori
Published: March 2020

The phosphatidylinositol 3kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway is a major regulator of tumor cell growth, proliferation and survival. Hotspot mutations of PIK3CA are common in all subtypes of breast cancer with a prevalence of approximately 30%. GDC-0077 is a potent ATP-competitive inhibitor of PI3K alpha (IC50 = 0.038 ± 0.003 nM), thereby inhibiting the phosphorylation of membranebound PIP2 to PIP3. Biochemically, GDC-0077 is more than 300fold selective over the other Class I PI3K isoforms, beta, delta, and gamma, and more than 2000-fold more selective over PI3K class II and III family members. Importantly, GDC-0077 is more selective for mutant versus wild-type PI3K alpha in cell-based assays. Mechanism of action studies indicate that GDC-0077 treatment leads to degradation of the mutant PI3K alpha protein in a proteasome dependent fashion, without changing WT PI3K alpha levels. Drug treatment results in sustained reduction of PI3K pathway biomarkers pAkt and pPRAS40, inhibition of cell proliferation, and increased apoptosis in human PIK3CA mutant breast cancer cell lines, to a greater extent than other non-degrading inhibitors such as alpelisib. Combination studies of GDC-0077 with the CDK4/6 inhibitor palbociclib demonstrate a stronger effect in estrogen-depleted HR+ PIK3CA mutant breast cell lines, compared to cells grown in the presence of estrogen. Daily dosing of GDC-0077 in PIK3CA mutant breast cancer patient derived xenograft (PDX) models (n=4) resulted in tumor regressions, induction of apoptosis and a reduction of pAkt, pPRAS40, and pS6RP in a dose-dependent fashion. In vivo combination efficacy studies of GDC-0077 with fulvestrant and palbociclib also indicate the triple combination results in the greatest efficacy. Collectively, our preclinical data support evaluation of GDC-0077 in a triple combination with endocrine therapy and CDK4/6 inhibition in the clinic, in patients with locally advanced or metastatic hormone receptor positive breast cancer whose tumors harbor mutant PIK3CA.

Citation Format: Kyle Edgar, Rebecca Hong, Kyung Song, Steven Schmidt, Marc Hafner, Alfonso Arrazate, Erin Williams, Cecile De La Cruz, Jason Oeh, Deepak Sampath, Steve Staben, Lori Friedman. GDC-0077 is a selective PI3K alpha inhibitor with robust efficacy in PIK3CA mutant hormone-positive breast cancer models [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-11-23.
Abstract P3-12-02: Anlotinib in pre-treated metastatic HER2-negative breast cancer: A phase II, single-arm clinical study
Authors: Hu Nanlin , Luo Yang , Wang Jiayu , Li Qing , Zhang Pin , Ma Fei , Xu Binghe , yuan Peng
Published: March 2020

Background: There is no standard treatment strategy for patients with locally advanced or metastatic breast cancer suffering progression after one prior chemotherapy with metastasis setting. Anlotinib is a novel multitarget tyrosine kinase inhibitor for tumor angiogenesis and proliferative signaling. This study is performed to assessed the efficacy and safety of anlotinib in patients with HER2 negative locally advanced or metastatic breast cancer for whom at least one lines of prior chemotherapy had failed.

Method: This open-label, single arm study enrolled patients with HER2-negative breast cancer, pretreated with anthracycline, taxanes, and who failed in the metastatic setting at least 1 prior chemotherapy regimens and at least one endocrine drug for hormone receptor-positive patients. Anlotinib was administered 12mg d1-d14 for a 21-day cycle. The primary end point of this study was progression free survival (PFS). Secondary end points included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and toxicity. The treatment duration is until disease progression or intolerability of anlotinib.

Results: From July 12th in 2018 to July 1st in 2019, 18 eligible patients were enrolled in this, open-label, single arm study and received anlotinib with a median age of 56 years old(range 32 to 74 years). Median follow-up time was 2.8 months(range 1.0 to 9.9 months). Median 18 patients were eligible for efficacy analysis. Median PFS was 4.43 months (95% confidence interval (CI), 3.15m - 5.71 m). ORR was 22.2% (4/18). DCR was 55.6% (10/18). Only 2/18(11.1%) patients was reported dead, so median OS was not reached for now. The most common grade 3/4 treatment-related AEs were hypertension (3/18,16.7%), and the blood pressure got back to grade 1/2 as soon as the antihypertensive drugs were offerd. No other grade 3/4 adverse events were observed. No patients had dose reduction because of adverse events.

Conclusion: Anlotinib exhibited objective efficacy in heavily pretreated, metastatic HER2-negative breast cancer with mild toxicity. Multi-center prospective studies enrolling more patients are needed.

TRIAL REGISTRATION:

ClinicalTrials.gov: NCT04002284

Citation Format: Nanlin Hu, Yang Luo, Jiayu Wang, Qing Li, Pin Zhang, Fei Ma, Binghe Xu, Peng yuan. Anlotinib in pre-treated metastatic HER2-negative breast cancer: A phase II, single-arm clinical study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-12-02.
Abstract P4-01-02: Circulating tumor cells detected after neoadjuvant therapy for inflammatory breast cancer are associated with early relapse despite pCR
Authors: Hall Carolyn , Meas Salyna , Narendran Boomadevi , Sarli Vanessa , Upshaw Joshua , Ueno Naoto , Lim Bora , Valero Vicente , Lucci Anthony
Published: March 2020

Background: IBC is a rare and aggressive subtype of breast cancer. A significant number of IBC patients who achieve pathologic complete response (no residual tumor in breast and axillary nodes, pCR), still relapse after neoadjuvant chemotherapy (NAC). We hypothesized that circulating tumor cells (CTCs) identified in blood after NAC would add additional relapse risk information beyond just PCR alone.

Methods: Blood was assessed for CTCs after NAC in 128 stage III IBC patients as part of an IRB approved study, (LAB04-0698) using the Cell Search® System (Menarini Silicon Biosystems). The presence of ≥ 1 CTC meeting morphological criteria for malignancy was considered a positive result. Fisher exact test was used to evaluate associations between CTC detection and clinicopathologic characteristics, and log-rank test was used to analyze associations between CTC detection after NAC, pCR, and relapse free survival.

Results: Median follow-up was 2.4 years and mean patient age was 53 years. One or more CTC was identified after NAC in 36/128 (28%) of patients. Thirty-six patients (28%) had pCR following NAC. CTC detection was not associated with body mass index, estrogen, progesterone, or human epithelial growth factor receptor-2 (HER2) status, or Ki-67 staining (P= NS). Participants were grouped according to their post NAC CTC and pCR statuses as follows: CTC- and pCR (n = 28), CTC- and no pCR (n = 48), ≥1 CTC and pCR (n = 5) and ≥1 CTC and no pCR (n =18). Difference in recurrence free survival were identified in these groups, with worse relapse-free survival at 2 years identified in those with ≥1 CTCs and no pCR (log-rank p-value = <0.0001).

Conclusions: CTC detection after NAC identified non-metastatic IBC patients who achieved pCR, but remained at risk for relapse. This study warrants larger studies combining both PCR and CTC information in IBC patients to improve risk stratification and to identify patients who could derive benefit from additional adjuvant therapies to reduce their risk for relapse.

Citation Format: Carolyn Hall, Salyna Meas, Boomadevi Narendran, Vanessa Sarli, Joshua Upshaw, Naoto Ueno, Bora Lim, Vicente Valero, Anthony Lucci. Circulating tumor cells detected after neoadjuvant therapy for inflammatory breast cancer are associated with early relapse despite pCR [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-01-02.
Abstract P4-01-17: Viable circulating ensembles of tumor associated cells persist in patients with no radiologically detectable disease after treatment in breast cancer
Authors: Srinivasan Ajay , Akolkar Dadasaheb , Patil Darshana , Crook Timothy , Sims Cynthe , Patil Revati , Datta Vineet , Ranade Anantbhushan , Fulmali Pradip , Devhare Pradip , Fulmali Pooja , Patel Shoeb , Ainwale Akshay , Puranik Sneha , Datar Rajan
Published: March 2020

Oncological orthodoxy holds that (metastatic) breast cancer is an incurable disease. Response evaluation in metastatic breast cancer is determined by clinical, biochemical and radiological parameters, FDG PET CT being the imaging modality of choice for most types of breast cancer. However, even in cases where FDG PET CT and/or normalisation of serum tumour markers imply complete response to systemic therapy, durable disease-free survival is uncommon. To explore the mechanistic basis underlying persistent disease in spite of apparently effective systemic therapy, we hypothesized that Circulating Metastatic Disease (CMD) in the form of viable tumor cells or clusters might be a feature of persisting breast cancer. To address this, we obtained 15ml of peripheral blood from 927 known and previously treated cases of breast cancers immediately prior to FDG PET CT restaging. Peripheral blood mononuclear cells (PBMCs) were harvested by centrifugation. Circulating Ensembles of Tumor Associated Cells (C-ETACs), which are clusters of heterotypic apoptosis resistant cells of tumorigenic origin were enriched by a novel process using a combination of commercially available stabilizing agents. C-ETACs were characterized by immunostaining for EpCAM, pan-CK and CD45 as well as GCDFP-15 or GATA3. 927 patients underwent FDG PET CT of whom 731 (78.9%) had evidence of FDG avid residual disease. 196 patients (21.1%) had no metabolically active disease, among whom C-ETACs were detected in 171/196 cases (87.2%). The presence of CMD in a high proportion of cases in patients with no evidence of metabolically active disease implies that the majority of patients in whom conventional parameters of disease are negative have residual disease and are not biologically cured.

Citation Format: Ajay Srinivasan, Dadasaheb Akolkar, Darshana Patil, Timothy Crook, Cynthe Sims, Revati Patil, Vineet Datta, Anantbhushan Ranade, Pradip Fulmali, Pradip Devhare, Pooja Fulmali, Shoeb Patel, Akshay Ainwale, Sneha Puranik, Rajan Datar. Viable circulating ensembles of tumor associated cells persist in patients with no radiologically detectable disease after treatment in breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-01-17.
Abstract P4-02-07: Validity of omission of axillary lymph node dissection after neoadjuvant chemotherapy for node-positive primary breast cancer
Authors: Matsumoto Akiko , Umemoto Yasuko , Tsukahara Daisuke , Jinno Hiromitsu
Published: March 2020

Background: Anthracycline and taxane-based neoadjuvant chemotherapy (NAC) has been shown to downstage axillary lymph nodes in approximately 40% of patients. However, the feasibility of sentinel lymph node biopsy (SLNB) following NAC for initially node-positive patients is unclear because of high false-negative rates reported in previous trials. The aim of this study was to evaluate whether axillary lymph node dissection (ALND) could be safely omitted for patients with clinically node-positive breast cancer treated with NAC. Patients and methods: We identified 128 patients with clinically node-positive breast cancer who received NAC from March 2006 to March 2017. A correlation between axillary pathologic response and clinicopathological factors was analyzed. Preoperative clinical assessment of lymph-node status was performed by palpation and diagnostic imaging such as ultrasound and MRI. Lymphatic mapping was performed using a combined method of blue dye and radioisotope. Results: The median age was 56.5 (range: 29-79) years and the mean tumor size was 3.6 ± 2.37cm. Of 128 patients, 72 (56.2%) patients had luminal, 32 (31.3%) had HER2-positive, and 24 (18.8%) had triple-negative disease. Sequential anthracycline and taxane were administered for 115 (89.8%) patients, and 25 (78.1%) patients with HER2-positive disease received concomitant trastuzumab preoperatively. Overall, 53 (41.4%) patients achieved axillary pathologic complete response (ypN0). The ypN0 status was significantly correlated with clinical complete response (cCR) in breast (67.9%, p=0.004), ER-negative disease (59.5%, p=0.004) and HER2-positive disease (56.3%, p=0.049). Multivariate analysis demonstrated that cCR in breast (p=0.015) and ER negativity (p=0.006) were significant predictive factors for ypN0. In 14 ER-negative patients achieving cCR in breast, ypN0 was found in 12 (85.7%) patients. Among 85 patients who converted to clinically node-negative, ALND was omitted in 16 patients (18.8%) after SLNB. Of these 16 patients, irradiation to whole-breast and axilla was performed in 14 (87.5%) and 5 (31.3%) patients, respectively. After a median follow-up of 53.2 months, no axillary recurrence was observed in entire patients and 5-year disease-free survival was not significantly different between patients with or without ALND (85.5% vs. 87.5%, p=0.965). Conclusions: As ER-negativity and cCR were correlated with high eradication rate of initially positive lymph nodes, these patients might be good candidates of omission of ALND after NAC.

Citation Format: Akiko Matsumoto, Yasuko Umemoto, Daisuke Tsukahara, Hiromitsu Jinno. Validity of omission of axillary lymph node dissection after neoadjuvant chemotherapy for node-positive primary breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-02-07.
Abstract P4-02-08: What happened to clinically node positive breast cancer patients who showed conversion into pN0 after neoadjuvant chemotherapy?: Single center for 10 years
Authors: Kwak Joo Hwa , Jo Heein , Lee Eun-Gyeong , Song Eun Jin , Han Jai Hong , Jung So-Youn , Kang Han-Sung , Lee Eun Sook , Lee Seeyoun
Published: March 2020

Objective: This study aimed to evaluate the outcomes between sentinel lymph node biopsy (SLNB) and axillar lymph node dissection (ALND) on recurrence and survival in clinically node positive breast cancer patients who showed conversion into pN0 after neoadjuvant chemotherapy (NAC) from 10 years cohort in single center.

Materials & Method: This study enrolled total 225 patients, from January 2006 to December 2015 who underwent breast cancer surgery and axillar lymph node approach in clinically axillar lymph node metastasis with conversion into node negative after neoadjuvant chemotherapy. One hundred patients had only SLNB and 125 patients had ALND finally.

Results: The median follow-up time was 58 months (range, 12-147 months) in only SLNB group and 103 months (range 9-174 months) in ALND group and the median number of retrieved SLNs was 2 (range, 1-6) and 11 (2-31).

The 5 years overall survival rate of SLNB and ALND group is 94%, 95.7% (P=0.786), disease free survival rate 91.9%, 91.6%, (p=0.753) which was not statistically significant. Three patients (3%) and 6 patients (4.8%) showed loco-regional recurrence respectively. All they showed ipsilateral axillary lymph node recurrence. Seven patients (7%) and 6 patients (4.8%) in SLNB group and ALND group showed distant metastasis. However, there were more complications in the ALND group than in the SLNB group. Among them, ALND group showed the higher rate of shoulder stiffness than SLNB group (7% vs 10.4%, p=0.384, respectively). Especially, the incidence of lymphedema was 6 times higher in ALND group. (4 patients (4%) vs 29 patients (23.2%), p=0.271)

Conclusion: We found the SLNB only group did not increase the recurrence or metastatic rate from the patients, but reduced the incidence of complications such as lymphedema from the 10 years single center cohort. Therefore, we suggest SLNB can be considered as a reliable as an alternative to ALND when the complete response is achieved by re-staging with imaging study after neoadjuvant chemotherapy.

Keyword: neoadjuvant chemotherapy, sentinel lymph node biopsy, axillar lymph node dissection

Citation Format: Joo Hwa Kwak, Heein Jo, Eun-Gyeong Lee, Eun Jin Song, Jai Hong Han, So-Youn Jung, Han-Sung Kang, Eun Sook Lee, Seeyoun Lee. What happened to clinically node positive breast cancer patients who showed conversion into pN0 after neoadjuvant chemotherapy?: Single center for 10 years [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-02-08.
Abstract P4-02-19: First reported use of the Faxitron LOCalizer™ Radiofrequency Identification (RFID) system in the axilla- A pilot trial in targeted axillary dissection (TAD)
Authors: Malter Wolfram , Eichler Christian , Puppe Julian , Thangarajah Fabishy , Mallmann Peter , Krug Barbara , Warm Mathias , Holtschmidt Johannes
Published: March 2020

Introduction: Adequately marking suspicious lymph nodes before neoadjuvant chemotherapy in breast cancer patients is commonly done by introducing a titanium clip followed by stereotactic hook wire location. However, clip dislocation and/or wire dislocation are common problems. Furthermore, locating a clip within the axilla is problematic since stereotactic location may be anatomically challenging. An ideal solution would be a clip which can be easily found without the use of a stereotactic intervention. This pilot trial proves the concept of using radiofrequency identification devices (RFID) in targeted axillary dissection (TAD).Methods: This pilot trial represents a single center, consecutively recruited, evaluation (n=10) for targeted axillary dissection using the Faxitron LOCalizer™ radiofrequency identification chip system. Patients were given the choice between wire guided TAD vs. LOCalizer™ TAD. Primary endpoints were: percentage of successful location /failure to locate. Secondary endpoints were major and minor complication rates as well as surgeon evaluated outcome.Results: Primary endpoints showed a 100% location rate of the suspicious lymph nodes at a 0% major complication (revision surgery) rate. Additional guided wire marking was not necessary for lymph node location. Surgeons evaluated the new system as being safe to use and only slightly more difficult to place than a standard clip or a wire system.Conclusion: This pilot trial proved the concept of TAD via a RFID system. When using this system, preoperative stereotactic lymph node marking is no longer required, thus patients may be spared additional x-ray exposure. Using the LOCalizer™ system should therefore be considered for any TAD.

Citation Format: Wolfram Malter, Christian Eichler, Julian Puppe, Fabishy Thangarajah, Peter Mallmann, Barbara Krug, Mathias Warm, Johannes Holtschmidt. First reported use of the Faxitron LOCalizer™ Radiofrequency Identification (RFID) system in the axilla- A pilot trial in targeted axillary dissection (TAD) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-02-19.
Abstract P4-03-04: Stereotactic vaccum-assisted breast biopsy: A cost effective diagnostic method for suspicious calcifications investigation in Brazil
Authors: Amorim Andressa , Ramos Marcellus N. M. , Sawada Maria Isabela B. A. C. , Mattar André , Shida Jorge Y. , Gebrim Luiz H.
Published: March 2020

Background: Mammographic screening carried out in Brazil's Public Health System (SUS) is opportunistic and restricted to large cities mainly in the South and Southeast regions. However, only 30% of the suspicious calcifications are confirmed to be malignancy after the biopsy. The surgical procedure to investigate is still the routine in most centers in Brazil. A vacuum assisted stereotactic biopsy (VASB) is expensive and it is not available in most centers in the developing countries. Objective: To estimate saved values in SUS by performing VASB instead of performing classic surgical procedure in the investigation of suspicious calcifications. Methods: We’ve performed a retrospective and descriptive study from July, 2012 to June, 2019, in which 1,809 patients diagnosed with suspicious calcifications on mammography (BIRADS 4 and 5) had VASB performed at Hospital Estadual Pérola Byington. The device used was Surus Pearl (Hologic, Malbolrough, Massachusetts, USA) with probe gauge 9. The biopsy`s costs were calculated and estimated in terms of American Dollars (US$) in 2019. No direct medical and nonmedical or indirect costs have been evaluated. Results: the histopathological study of the lesions revealed benign alterations in 1,179 (65.1%) The findings were positive for malignancy in 533 (29.5%) and the precursor lesions were diagnosed in 97 (5.4%) VASB is an outpatient procedure; a single biopsy has an average cost of US$ 36. Instead, the classic surgical procedure is a procedure that requires hospitalization and general anesthesia with estimated cost of US$ 97 for every single procedure. The saved values in that time by SUS were US$ 29,077. Conclusion: we found a high economic impact of VASB in the SUS scenario. Lower costs than surgical procedures and being an outpatient procedure may indirectly increase hospital beds` supply for cancer treatment. Studies focusing on other direct and indirect costs are desirable, especially in developing countries.

Keywords: calcifications; vacuum-assisted stereotactic biopsy; breast cancer.

Citation Format: Andressa Amorim, Marcellus N. M. Ramos, Maria Isabela B. A. C. Sawada, André Mattar, Jorge Y. Shida, Luiz H. Gebrim. Stereotactic vaccum-assisted breast biopsy: A cost effective diagnostic method for suspicious calcifications investigation in Brazil [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-03-04.
Abstract P4-04-09: The acquired resistance of mammary cancer cells to CDK4/6 inhibitors drives a DNA methylation reprogramming of genes encoding for BCL2 family members that confers a phenotype of high apopto-sensitivity induced by a BH3-mimetic drug
Authors: FRENEL Jean-Sebastien , Voisin Deborah , Nadaradjane Arulraj , Bougras-Catron Gwenola , Campone Mario , Serandour Aurelien , Cartron Pierre-Francois
Published: March 2020

Introduction. Due to the aberrant deregulation of the CDK4/6-INK4-RB pathway in breast cancer, CDK4/6 inhibitors are now a cornerstone of first line treatment of metastatic breast cancer showing an increase of progression free survival and overall survival. However, resistance to treatment eventually occur. We aimed at deciphering the molecular mechanisms of resistance to CDK4-6 inhibitors and at evaluating associations of therapies that could restore the sensitivity to the treatment. Methods. To identify potential DNA methylation signatures associated with the acquired resistance to CDK4/6 inhibitors, we established a MCF7 model, resistant to CDK4/6 inhibitors that we also used in Swiss nude mice via xenograft experiments. qMSRE were used to analyze the methylation status of genes encoding for BCL2 family members in cells, but also on circulating tumor DNA (ctDNA) in our in vivo model. Results. Using acquired resistant MCF7 cells to CDK4/6 inhibitors, our work demonstrate that these cells harbor a phenotype of high apopto-sensitivity induced by a BH3-mimetic drug. We next discern that DNMT3A and TET2 are the molecular determinants of this phenomenon via the epigenetic modulation of DNA methylation profile of genes encoding for BCL2 family. Using in vivo model, we noted that the ctDNA dynamic of the DNA methylation level of genes encoding for BCL2 family members is associated with the emergence of the resistance to CDK4/6 inhibitor demonstrated by the absence of tumor growth inhibition. Our experiments also indicated that the administration of a BH3-minetic drug at this time point restores the inhibition of tumor growth. Conclusion. This work provides the evidence that epigenetic modulation (methylation level) of key genes detected in ctDNA is associated with resistance to CDK4-6 inhibitors. The BH3-mimetic drugs are seem really appealing in that context.

Citation Format: Jean-Sebastien FRENEL, Deborah Voisin, Arulraj Nadaradjane, Gwenola Bougras-Catron, Mario Campone, Aurelien Serandour, Pierre-Francois Cartron. The acquired resistance of mammary cancer cells to CDK4/6 inhibitors drives a DNA methylation reprogramming of genes encoding for BCL2 family members that confers a phenotype of high apopto-sensitivity induced by a BH3-mimetic drug [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-04-09.
Abstract P4-06-12: Understanding how precancerous lesions progress to breast cancer using mouse models
Authors: Bu Wen , Jiang Weiyu , Li Yi
Published: March 2020

There are distinct cell subpopulations in normal epithelial tissue, including stem cells, progenitor cells, and more differentiated cells, all of which have been extensively studied for their susceptibility to tumorigenesis and intertumoral heterogeneity. However, normal cells usually have to progress through a precancerous lesion state before becoming a full-blown tumor. Precancerous early lesions are heterogeneous too. It remains unclear whether distinct subsets of precancerous cells contribute to the eventual cancer and intertumoral heterogeneity. By using mouse models of breast cancer that are tailored to address this question, we demonstrated that both precancerous stem cells (PcSCs) and more differentiated cells in the precancerous lesion can be induced to form cancer readily upon introduction of constitutively active versions of either HRAS or BRAF. However, the resulting tumors were dramatically different in protein profiles and histopathology: PcSCs gave rise to adenocarcinoma while more differentiated precancerous cells yielded metaplastic carcinoma with severe squamous differentiation and more robust activation of MEK/ERK signaling. In contrast, constitutively activated PIK3CA caused both PcSCs and more differentiated precancerous cells to progress into adenocarcinoma. Therefore, both cell types in precancerous lesions and the genetic mutations that these cells suffer contribute to the characteristics of the resulting cancer. This work identifies previously unknown players in cancer heterogeneity and suggests that cancer prevention should target precancerous cells broadly and not be limited to PcSC.

Citation Format: Wen Bu, Weiyu Jiang, Yi Li. Understanding how precancerous lesions progress to breast cancer using mouse models [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-06-12.
Abstract P4-07-09: Identification and functional analysis of interleukin-1 (IL-1) induced gene expression pattern in breast cancer (BCa) and prostate cancer (PCa) cells
Authors: Nawas Afshan Fathima , Kanchwala Mohammed , Thomas-Jardin Shayna , Dahl Haley , Roos Nicole , Bautista Monica , Wong Ally , Xing Chao , Delk Nikki
Published: March 2020

Breast cancer (BCa) and prostate cancer (PCa) are both hormone receptor (HR) driven cancers with similar etiology, where tumor microenvironment inflammation promotes both BCa and PCa progression. Interleukin-1 (IL-1) is an inflammatory cytokine present in the tumor microenvironment, is elevated in BCa and PCa patient tumor tissue, correlates with poor prognosis, and inversely correlates with HR expression in tumor tissue. We have shown that IL-1 represses the BCa and PCa therapeutic targets, Estrogen Receptor Alpha (ERα) and Androgen Receptor (AR), respectively, in PCa and BCa cell lines; yet the cells remain viable. Thus, we hypothesize that IL-1 induces similar molecular responses in BCa and PCa cells that promote HR independence and subsequent treatment resistance. To address our hypothesis, we performed RNA sequencing of HR positive (HR+) BCa and PCa cell lines treated with IL-1 and compared IL-1-modulated gene expression patterns with the basal gene expression of HR negative (HR-) BCa and PCa cell lines. Our bioinformatics analysis revealed a suite of 350 genes that, based on ontology, promote inflammation response, angiogenesis, oxidative stress response, and cell motility. We chose two IL-1-induced genes from the genes list, p62 and SOX9, for functional analysis. p62 is an antioxidant and autophagy-related scaffold protein and SOX9 is an embryonic transcription factor. We performed p62 and SOX9 siRNA and found that loss of p62 or SOX9 reduce cell viability in HR- cell lines. We also found that the FDA approved p62-targeting drug, verteporfin, reduces cell viability in HR- cells line. Thus, our 350 genes list revealed alternative therapeutic targets for HR-independent cells, including BCa or PCa patients that might evolve HR-independence due to inflammation.

Citation Format: Afshan Fathima Nawas, Mohammed Kanchwala, Shayna Thomas-Jardin, Haley Dahl, Nicole Roos, Monica Bautista, Ally Wong, Chao Xing, Nikki Delk. Identification and functional analysis of interleukin-1 (IL-1) induced gene expression pattern in breast cancer (BCa) and prostate cancer (PCa) cells [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-07-09.