Citations

Abstract Disruption of the MDM2/p53 pathway is an oncogenic driver alteration observed in the vast majority of GBM. This study evaluated the efficacy of the small molecule, human-specific, MDM2 inhibitor SAR405838 across a panel of GBM xenografts with distinct alterations within the MDM2/p53 pathway. Through screening a panel of 56 GBM xenografts with a combination of array CGH and MDM2-specific PCR amplification, five xenograft models were identified with high-level MDM2 amplification (GBM 5, 102, 108, 122, and 143). MDM2 transcript expression was elevated in all of these lines except GBM102, which had expression levels similar to non-amplified lines. The effects of SAR405838 were studied in 2 of the MDM2 amplified lines (GBM102, GBM108), and non-amplified lines with wild-type p53 (GBM10) or mutant p53 (GBM12). Using a combination of neurosphere and Cyquant assays to assess in vitro sensitivity, 100 nM SAR405838 completely inhibited growth of GBM108 (6% +/- 1% absorbance relative to control), partially inhibited GBM102 neurosphere formation (34 +/- 17% relative to control), and had nominal impact on relative neurosphere formation in GBM10 (51% +/- 4% relative to control) or GBM12 (96% +/- 4% relative to control). Twenty-four hours after treatment with 100 nM SAR405838, transcript expression of p53 target genes p21 and PUMA were elevated by 14 and 12 fold relative to control in GBM108, while more limited changes in expression were observed in GBM102 (4 and 2.5 fold increase, respectively). Similarly, analysis of apoptosis after 72h by Annexin-V staining demonstrated a 5-fold increase in apoptotic fraction from control in GBM108 compared to no increase in GBM102. A more striking difference in efficacy was observed in flank tumor xenograft studies where the time to reach a median tumor volume of 1000 mm3 was marginally extended in GBM102 (36 days for placebo vs. 44 days for SAR405838). In contrast, GBM108 placebo-treated mice grew to a median volume of 1000 mm3 in 53 days while treatment with SAR405838 resulted in complete tumor regression at 70 days. SAR405838 is a known substrate for the P-glycoprotein efflux pump that functions in the blood brain barrier to exclude xenobiotics from the central nervous system. Consistent with limited penetration of SAR405838 into the brain, a parallel study in an intracranial xenograft model for GBM108 demonstrated no significant survival benefit with SAR405838 treatment compared to placebo. Thus, although SAR405838 provides marked efficacy in vitro and in a flank tumor model of an MDM2 amplified tumor line, the lack of efficacy in an orthotopic model of this study suggests that more prudent investigation is needed before advancing the development of this specific drug in human tumors growing in the brain. Citation Format: Ann C. Mladek, Isabelle Meaux, Katrina Bakken, Pascal Pannier, Cedric Barriere, James W. Watters, Laurent R.J. Debussche, Jann N. Sarkaria. Targeted murine double minute 2 (MDM2) inhibition results in dramatic tumor regression in an MDM2-amplified glioblastoma multiforme (GBM) xenograft model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1799. doi:10.1158/1538-7445.AM2014-1799

Abstract Background: We have previously shown in animal models that combination anti-HER2 therapy leads to complete tumor regression of HER2+ breast cancer (BC). We translated these findings in a neoadjuvant trial of 12 weeks (wks) of L+T (TBCRC006) that demonstrated a meaningful pathologic complete response (pCR) and near pCR (in ER+ tumors) in patients with locally advanced HER2+ BC. In the present trial, we sought to determine whether longer treatment would lead to a higher rate of pCR without the use of chemotherapy by converting near pCR to pCR especially in the ER+ subset. Methods: TBCRC023 (NCT00999804) is a randomized phase II trial combining a Simon Phase 2 design in the experimental arm with a pick-the-winner design, not powered for direct comparison. Women with HER2+ BC measuring 2 cm or larger were eligible and were randomized in a 1:2 ratio to 12 vs. 24 wks of L+T. Letrozole (along with ovarian suppression if premenopausal) was also administered in patients whose tumors were also ER+. Serial tumor biopsies were obtained at baseline, wk 1, wk 12, and at the time of surgery. All evaluable patients were assessed for pCR, defined as no residual invasive carcinoma in the breast. Patients did not undergo surgery, withdrew consent, or received additional neoadjuvant therapy were counted as non-responders. Results: Ninety-seven patients were enrolled (33 in 12-wk arm and 64 in 24-wk arm), of whom 95 were evaluable. Seventy seven percent of patients were white and 18% were black. Twenty percent were of Hispanic ethnicity. Median age was 51 and 55% were postmenopausal. Median tumor size was 5 cm and 65% were ER+. Study treatment was well tolerated with grade 1-2 diarrhea (24% in 12-wk arm, 31% in 24-wk arm) and grade 1-2 acneform rash (12% in 12-wk arm, 19% in 24-wk arm) being the most common toxicities. Grade 3 toxicities were uncommon and were mostly in the 24-wk arm (elevated liver function test: 9%, diarrhea 2%, mucositis 2%), while the 12-wk arm had one grade 3 anemia and the study’s only serious adverse event (acute kidney injury). There were no grade 4 toxicities. The experimental arm completed stage 2 accrual and pCR rate was numerically superior to control, entirely due to better results in ER+ (Table 1), but lower than the expected pCR rate of 36% needed in the planned analysis to conclude in favor of enhanced efficacy with extended therapy. pCR rates were also lower in the control arm than in the previous study. Table 1. pCR rates 12-week arm % (n)24-week arm % (n)ER-positive8.7% (2/23)33.2% (13/39)ER-negative20% (2/10)8.7% (2/23)Overall pCR12.2% (4/33)24.2% (15/62) Conclusions: Treatment with L+T (with endocrine therapy in ER+ tumors) for 24 weeks leads to doubling of the pCR rate in women with HER2+ breast cancer without using cytotoxic chemotherapy. This approach is effective and well tolerated and warrants study as part of a de-escalation strategy that may spare some patients the cost and toxicity of chemotherapy. Tissue obtained on this trial will provide a valuable resource to validate correlative findings from our prior studies and discover new biomarkers to help guide proper patient selection for treatment. Citation Format: Mothaffar F Rimawi, Polly A Niravath, Tao Wang, Brent Rexer, Andres Forero, Antonio C Wolff, Rita Nanda, Anna M Storniolo, Ian Krop, Matthew P Goetz, Julie R Nangia, Sao Jiralerspong, Anne C Pavlick, Carolina Gutierrez, Rachel Schiff, Susan G Hilsenbeck, C Kent Osborne. TBCRC023: A randomized multicenter phase II neoadjuvant trial of lapatinib plus trastuzumab, with endcorine therapy and without chemotherapy, for 12 vs. 24 weeks in patients with HER2 overexpressing breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S6-02.

Abstract Background Cancer genomic investigations have identified recurrent genomic aberrations critical for cancer initiation, progression, and metastases. However, these investigations are typically performed in isolation, and the effects of treatment on the clonal selection of tumor cells are mostly unknown. We hypothesized that molecular profiling of residual tumors after neoadjuvant chemotherapy (NAC) would identify new drug targets/pathways in patients at high risk for disease recurrence. To better identify clonal populations of resistant breast cancer cells, we utilized DNA content-based flow sorting of nuclei to identify and isolate clonal populations for aCGH and next generation sequencing (NGS) both before and after NAC. Methods The Breast Cancer Genome Guided Therapy Study (BEAUTY) (NCT 02022202) is a prospective study of patients with high-risk breast cancer treated with neoadjuvant 12 weekly paclitaxel (T) +/- trastuzumab followed by 4 cycles of anthracycline based chemotherapy. Tumor tissue from baseline, residual disease from surgery, distant metastases, and patient derived xenografts (PDX) are obtained for cell sorting by DNA ploidy, aCGH, RNA and exome sequencing. Results: 140 patients have been enrolled, 104 have completed surgery and 30 unique PDX have been established corresponding to 26 patients prior to chemotherapy and 4 from residual disease at surgery. Baseline exome and RNA sequencing is complete in 140. Currently, genomic analyses of flow sorted matched baseline, surgical, PDX, and distant disease samples are available in 6 patients. Substantial genomic variation was observed in the surgical sample compared to the primary tumor including gain of oncogenic drivers (EGFR) and loss of negative regulators (ATG5) (Table). The PDX recapitulated these events with excellent fidelity compared to the corresponding human tumor. In patients with TNBC, RNA seq obained from matched samples demonstrated changes in immune related pathways. Evaluation of drug targets/pathways identified in the resistant tumors are ongoing using the PDX and sequencing of the remaining matched baseline/surgical disease will be reported. Clonal changes occurring over time in patients with residual disease or disease recurrence after NACTumor SubtypeResidual Cancer BurdenDisease StatusClonal Aberration Changes (baseline and post NAC)TNBC (AR subtype)3Contralateral lymph node recurrence at 150 days2p25.2 - p25.1 amplicon lost at recurrence; 6p21.32 -p21.31 amplicon lost at recurrenceTNBC (BL 1)3Bone/liver/lymph node recurrence at 135 days5q11.2 amplicon gained at surgery; 12p13.33 - p13.2 amplicon gained at surgeryTNBC (BL 1)3Disease-free at day 1506q21 amplicon lost at sugeryTNBC (BL 2)0Brain recurrence at 390 daysChr 2 chromothripsis at surgeryLuminal B3Progression during chemotherapy7p12.1 - p11.2 amplicon gained at surgeryLuminal HER23Disease-free at day 3609q33.2 amplicon lost at surgery; 15q13.1 - q13.3 amplicon lost at surgery; 15q22.2 - q24.1 amplicon lost at surgery Conclusions: We observed substantial evolutionary changes in residual breast tumors remaining after NAC. Our findings suggest that a comprehensive assessment of the mutational landscape that has evolved during NAC can inform drug development in high risk breast cancer patients. Citation Format: Matthew P Goetz, Michael T Barrett, Krishna R Kalari, Vera J Suman, Sarah A McLaughlin, Alvaro Moreno-Aspitia, Ann M Moyer, Donald W Northfelt, Richard J Gray, Jason Sinnwell, Douglas Mahoney, Poulami Barman, Peter Vedell, Xiaojia Tang, Kevin Thompson, Travis Dockter, Katie Jones, Sara J Felten, Amy Conners, Jeanette Eckel-Passow, Hughes Sicotte, Steven N Hart, Jia Yu, Daniel W Visscher, Eric D Wieben, Cloann Schultz, Minetta C Liu, James N Ingle, Liewei Wang, Richard W Weinshilboum, Judy C Boughey. Impact of neoadjuvant chemotherapy on the clonal composition of breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PD3-3.

Abstract Background: The ECOG E5194 study was a prospective trial designed to evaluate surgical excision (lumpectomy) without radiation for selected women with ductal carcinoma in situ (DCIS) of the breast with low risk clinical and pathologic features. Methods: Eligible patients were enrolled on two study cohorts (not randomized): (1) low or intermediate grade DCIS, tumor size < 2.5 cm; or (2) high grade DCIS, tumor size < 1.0 cm. Cohort assignment was based on pathology assessment from the treating institution. Protocol specifications included surgical excision of the DCIS tumor with a minimum negative margin width of at least 3 mm or no tumor on re-excision. Radiation treatment was not allowed. From April 1997 to October 2002, 665 evaluable patients were enrolled through ECOG or NCCTG (561 in Cohort 1; 104 in Cohort 2). Tamoxifen was optional (not randomized) beginning in May 2000, and was given to 30% of the patients. The primary study endpoint was the rate of developing an ipsilateral breast event (IBE), defined as local recurrence of DCIS or invasive carcinoma in the treated breast. The median follow-up was 12.3 years. We have previously reported 7-year results (L. Hughes, J Clin Oncol 27:5319, 2009; median follow-up 6.3 years; 66 IBE’s), and we herein provide 12-year results. Results: Median patient age was 60 years and 58 years for Cohort 1 and Cohort 2, respectively. Tumor size was < 10 mm for 79% and 80% of patients, respectively. The minimum negative margin width was > 5 mm for 64% and 69% of patients, respectively. There were 99 IBE’s, of which 51 (52%) were an invasive IBE. The IBE and invasive IBE rates increased over time in both cohorts (see Table). The 12-year rates of an IBE were 14.4% for Cohort 1 and 24.6% for Cohort 2 (p = 0.003), and for an invasive IBE, 7.5% and 13.4%, respectively (p = 0.08). No difference was seen for the 12-year rates of overall survival (84.0% vs 82.8%; p = .96) or contralateral breast events (6.7% vs 12.0%; p = 0.16). On multivariate analysis, study cohort (hazard ratio = 1.81; p = 0.01) and tumor size (p = 0.01) were statistically significant for an IBE, and study cohort was borderline statistically significant for an invasive IBE (p = 0.08). On central pathology review (75% of cases), neither grade nor comedo necrosis was associated with the risk of an IBE or invasive IBE (all p > 0.15). Salvage treatment at the time of an IBE included mastectomy for 42% (31/74) and 64% (16/25) of the patients, respectively. Conclusions: For these selected patients with favorable DCIS based on clinical and pathologic characteristics treated with surgical excision without radiation, the rates of an IBE and an invasive IBE continued to increase through at least 12 years of follow-up. IBE Rates According To Study Cohort. Cohort 1 (Low or Intermediate Grade)Cohort 2 (High Grade)TimeIBEInvasive IBEIBEInvasive IBEAt 5 years6.0% (4.0%, 8.1%)2.7% (1.3%, 4.1%)15.0% (7.7%, 21.7%)5.3% (0.8%, 9.7%)At 7 years9.5% (7.0%, 12.0%)4.8% (2.9%, 6.6%)18.2% (10.6%, 25.8%)7.6% (2.2%, 13.0%)At 10 years12.5% (9.5%, 15.4%)6.4% (4.2%, 8.6%)24.6% (15.7%, 33.4%)13.4% (5.9%, 20.9%)At 12 years14.4% (11.2%, 17.6%)7.5% (5.1%, 10.0%)24.6% (15.7%, 33.4%)13.4% (5.9%, 20.9%) Citation Format: Lawrence J Solin, Robert Gray, Lorie L Hughes, William C Wood, Mary Ann Lowen, Sunil Badve, Frederick L Baehner, James N Ingle, Edith A Perez, Abram Recht, Joseph Sparano, Kathy Miller, Nancy E Davidson. Local excision without radiation for ductal carcinoma in situ: 12-year results from the ECOG E5194 study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-13-01.

Abstract Background: Statins are the most widely prescribed cholesterol-lowering drugs in the United States, with approximately 25% of US adults using statins by 2008. The anti-carcinogenic effect of statins may reduce the metastatic potential of cancer cells leading to ‘stage migration’ with statin users more likely diagnosed with early rather than late stage cancer. We evaluated the effects of statins on breast cancer stage migration and breast cancer-specific mortality in the Women’s Health Initiative (WHI) Clinical Trial and Observational Study. Methods: The study population included 128,675 postmenopausal women aged 50 to 79 years, with 7,883 newly-diagnosed pathologically-confirmed cases of in situ (19%), local stage (61%), regional stage (19%) and distant stage (1%) breast cancer and 401 deaths due to breast cancer after an average of 11.5 (SD=3.7) years of follow-up. To reduce the possibility of detection bias, we excluded women who did not report a mammogram within 5 years of study entry, and who had no health insurance or medical care provider (n=28,237). Stage was coded using criteria implemented in the Surveillance, Epidemiology and End Results Program and stratified into early stage (in situ and local) vs. late stage (regional and distant). Information on statin use prior to breast cancer diagnosis was collected at baseline and years one, three, six, and nine years post-baseline. Self- and interviewer-administered questionnaires were used to collect risk factor information. Cause of death was based on medical record review by physician adjudicators. Cox proportional hazards regression models were used to calculate hazard ratios (HR) with 95% confidence intervals (CI) to evaluate the relationship between statin use as a time-dependent exposure and diagnosis of late stage breast cancer and breast cancer-specific mortality adjusting for important confounders. For these models, participants who had early stage breast cancer or who died during follow-up were censored at time of diagnosis or death, respectively. We also evaluated the effect of statins stratified by estrogen receptor (ER) status. Statistical tests were two-sided. Results: Statins were used by 10,474 women (8%) at baseline. In the multivariable-adjusted time-dependent model, statin use was associated with a marginal reduction in risk of late stage breast cancer (HR 0.84, 95% CI: 0.70-1.02, p=0.082) and a reduction in risk of late stage estrogen receptor positive breast cancer (HR 0.79, 95% CI: 0.63-0.99, p=0.044). Statin use was also associated with a marginal reduction in breast cancer-specific mortality although it did not reach statistical significance (HR 0.59, 95% CI: 0.32-1.06, p=0.075). Conclusions: In the WHI, statin use was associated with a modest reduction in risk of late stage estrogen positive breast cancer and a non-significant decrease in breast cancer mortality. We are currently performing sensitivity analyses on these models. Studies using other large data sets with longer follow-up and information on cancer-directed therapy are needed to further evaluate this possible association. Citation Format: Monica P Arun, Pinkal Desai, Amy Lehman, Marilyn L Kwan, JoAnn E Manson, Sayeh Lavasani, Sylvia Wasswertheil-Smoller, Gloria E Sarto, Meryl S LeBoff, Jane Cauley, Michele L Cote, Jennifer Beebe-Dimmer, Allison Jay, Rowan T Chlebowski, Michael S Simon. Statins and breast cancer stage and mortality in the Women's Health Initiative cohort [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-10-04.

Abstract Background: While the biological functions and clinical importance of ERα are well understood in breast cancer, much less is known about its most closely related family member, ERβ, particularly in the setting of triple negative disease. Additionally, the ability to therapeutically target ERβ in triple negative breast cancer (TNBC) has not been fully explored. Methods: Expression of ERβ protein was determined using a well characterized and validated ERβ specific monoclonal antibody that only recognizes the full-length form of this receptor (PPG5/10) in a cohort of 71 TNBCs. To further define the biological functions of ERβ in TNBC, novel ERβ expressing triple negative cell lines (MDA-MB-231 and Hs578T) were developed and comprehensively characterized at the level of global gene expression profiling, modulation of important biological pathways, cellular proliferation and response to targeted therapies. Results: In TNBCs from 71 patients, nuclear and cytoplasmic ERβ was detected at moderate to high levels in 24% and 32% of cases respectively. This moderate to high expression of both nuclear and cytoplasmic ERβ was associated with higher levels of Ki67. Of the 17 tumors expressing ERβ, 13 (76%) were negative for androgen receptor expression. In the triple negative MDA-MB-231-ERβ and Hs578T-ERβ cell lines, expression of ERβ led to inhibition of proliferation in response to both estrogen and multiple ERβ specific agonists. Microarray analysis and RT-PCR profiling of these cells revealed that estrogen and ERβ agonists highly induced the expression of multiple cystatins, a family of small secreted cysteine protease inhibitors, while suppressing the expression of many interleukins. Conditioned media isolated from estrogen or ERβ agonist treated MDA-MB-231-ERβ cells inhibited the proliferation rates and blocked TGFβ signaling in non-ERβ expressing TNBC cells, effects that were completely reversed following depletion of cystatins from the conditioned media. Conclusions: ERβ is expressed in a substantial proportion of TNBCs, and most do not express the androgen receptor. In TNBC, where targeted therapies are lacking, our data suggest that estrogen or ERβ specific agonists would be expected to elicit anti-tumor effects when ERβ is expressed. These tumor suppressive effects of ERβ appear to be mediated in part through the actions of cystatins, and their inhibition of TGFβ signaling, suggesting that this family of secreted proteins may represent novel biomarkers for monitoring ERβ specific drug responsiveness and/or patient outcomes. Citation Format: Jordan M Reese, Malayannan Subramaniam, Vera J Suman, Xianglin Wu, Vivian Negron, Anne Gingery, Kevin S Pitel, Sejal S Shah, Heather E Cunliffe, Ann E McCullough, Barbara A Pockaj, Thomas C Spelsberg, Matthew P Goetz, James N Ingle, John R Hawse. Therapeutic targeting of ERβ in triple negative breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-03-06.

Abstract Background: In CALGB-49907 (NEJM 2009;360:2055), older patients (pts) with ESBC were randomized to standard adjuvant chemo (AC or CMF versus capecitabine). The objective of this secondary QoL analysis is to assess if pts’ BL chemo preference (CP, defined as high or low), is associated with the following during and after completion of chemo: self and professional-reported toxicity, changes in mental health, function, QoL, recurrence-free (RFS) and overall (OS) survival. Patients and Methods: Of 633 trial pts 350 participated in the QoL substudy; 145/350 pts completed the BL assessment regarding CP. CP was measured by asking the amount of benefit women would require to choose adjuvant chemo in a hypothetical situation, irrespective of chemo agents. Women who chose chemo for an increase in OS of ≤12 months (mo) were designated as high chemo preference (HCP) and those who chose >12 mo were designated low chemo preference (LCP). CP associations were evaluated with: BL perception of self-health and perceived QoL on chemo; patient reported outcomes (PROs), changes in function and QoL (based on EORTC-QLQ-C30); anxiety and depression (Hospital Anxiety and Depression Scale); observed grade 3-5 adverse events (AEs) by NCI common toxicity criteria (CTC v2.0). Pts were assessed at midtreatment and at 1, 12, 18 and 24 mo post-treatment. Chi-square tests, t-tests, and Cox models were used for categorical, continuous, and time-to-event variables, respectively. Results: The demographic and tumor characteristics of women (median age 71) who provided CP at BL were not different from women in the QoL subset or from non-QoL pts. 68/145 (47%) women had a HCP. CP groups did not differ based on age, surgery type, tumor and nodal stage, hormone receptor status, performance status, chemo assignment, education, marital or employment status except the LCP group had a higher proportion of white women (95% vs. 78%, p=0.004). At BL, there were no differences in perception of self-health based on CP but women with LCP predicted QoL on chemo to be worse than women with HCP (p=0.006) and reported greater nausea/vomiting. Mid-treatment, LCP pts reported worse nausea/vomiting, financial worries, and cancer symptoms. Post-treatment, LCP pts had worse constipation (at 1 mo) and financial worries (at 24 mo). There were no differences based on CP for dyspnea, pain, fatigue, insomnia, anxiety or depression at any timepoint. Mid-treatment, LCP women reported lower QoL and worse social, emotional and physical function compared to HCP women. These scores were not significantly different after treatment completion. LCP women had significantly higher rates of grade 3-5 AEs (53 vs. 34%, p=0.02) during treatment but these did not persist post-therapy. CP was not significantly associated with OS (HR =0.75, p=0.36) or RFS (HR=0.94, p=0.84). Conclusions: LCP at BL was associated with lower QoL, worse physical symptoms, AEs and function mid-therapy, but not mental health. Mid-therapy declines in women with LCP largely reversed post-therapy. This information may be useful for oncology professionals to counsel older ESBC pts with LCP receiving adjuvant chemo. Citation Format: Ajeet Gajra, Linda McCall, Hyman B Muss, Harvey J Cohen, Aminah Jatoi, Karla V Ballman, Ann H Partridge, Linda Sutton, Barbara A Parker, Gustav Magrinat, Jaqueline M Lafky, Arti Hurria. Association of patient preference for adjuvant chemotherapy (chemo) at baseline (BL) with toxicity, mental health, function, quality of life (QoL) and survival in older women with early stage breast cancer (ESBC) [CALGB 49907 Alliance] [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-15-07.

Abstract Background: The development of novel chemotherapeutic agents has significantly improved the prognosis and survival of patients with breast cancer. ER positive or luminal tumors represent around two thirds of all breast cancers and these cancers are comprised of different histologies including differing gene expression and mutational profiles. This study examined biomarkers involved in immune evasion including PD-L1 and its association with other biological pathways as potential treatment options for luminal breast cancer patients. Methods: We analyzed 1311 breast samples using a multiplatform approach including whole genome mRNA expression (HumanHT-12 v4 BeadChip Illumina Inc., San Diego, CA), protein expression (immunohistochemistry), gene copy number changes (in situ hybridization) and gene sequencing and an additional 304 breast samples were tested for PD-1 and PD-L1 by IHC. The mRNA expression data was based on whole tumor and represents cell type heterogeneity. Heat map analysis was done to look at differential gene expression between the PD-L1 high vs low luminal breast cancers. Results: Based on expression of ER, PR and HER2 by IHC, we subdivided the data into sub- cohorts. Elevated mRNA expression of immune markers including PD-L1, CTLA4, B7H-3, and IDO1 was noted in the ER+HER2- luminal population including ER+ PR- and ER+PR+ cohort. Positive correlation was found between PD-L1 and other immune regulators including CTLA-4, B7-H3 and IDO1 (Spearman correlations of 0.49, 0.36 and 0.46). Protein expression of PD-L1 was found to be specific to the HER2 negative cohort with no expression in the HER2 positive cohort regardless of ER status. Within the ER+HER2- cohort, PD-L1 expression was 5% {ER+PR+ was 5% (4/81) and the ER+PR- was 6% (2/34)}. In contrast, PD-L1 expression was higher in the triple negative cohort, 17% (13/75). The expression of PD-1 on the other hand was present throughout the different cohorts. PD-1 expression ranged from 43% in the ER+HER2- cohort {41% (14/34) in ER+PR-HER2-; 43% (35/81) in ER+PR+HER2-} to 33% in the ER+HER2+ cohort {44% (4/9) in ER+PR-Her2+; and 17% (1/6) in ER+PR+HER2+}. In the ER-HER2+ cohort PD-L1 expression was 75%{6/8 in ER-PR-HER2+ and 0/0 in ER-PR+HER+} and 63%(47/75) in the triple negative cohort. Pathway analysis of the PD-L1 negative vs positive luminal population identified 127 genes involved in various cancer pathways including EGFR and VEGF signaling network (P=7.47e-09). Conclusions: The expression of immune regulatory targets in the breast cancer population suggests that immune- targeted therapies with anti PD-1/PD-L1, CTLA4, B7-H3 and IDO1 may be effective especially in the luminal cohort. Our study further shows that ER+HER2- breast cancer patients may be better candidates for immunotherapy with checkpoint inhibitors as compared to ER+HER2+ due to lack of PD-L1 expression in the HER2 positive cohort. Further validation of our findings is ongoing. Citation Format: Gargi D Basu, Anatole Ghazalpour, Randal Vader, Sandeep Reddy, Karen Anderson, Ann McCullough, Barbara Pockaj. Expression of novel immunotherapeutic targets in luminal breast cancer patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-04-08.

Abstract BACKGROUND: Flat epithelial atypia (FEA) is a recently described breast lesion that may coexist with cancer or atypical ductal hyperplasia (ADH). Currently, there is no consensus on whether to surgically excise FEA diagnosed by core needle biopsy. Our aim was to perform a systematic review and meta-analysis of pertinent studies to determine the frequency of upgrade to cancer or ADH at surgical excision of "pure" FEA (no other high risk lesion on core biopsy). METHODS: A retrospective search was performed using MEDLINE, Embase, Scopus and Web of Science databases from 1/2003- 4/2014 to capture studies on core biopsy diagnosed FEA followed by surgical excision. Search terms were: FEA, flat epithelial atypia, DIN1A, columnar cell, breast diseases, core needle biopsy. Inclusion criteria were: 1) manuscript with original data on FEA diagnosed on core needle biopsy, 2) data included outcome of cancer at surgical excision, 3) English Language. RESULTS: Of 224 articles, 30 met inclusion criteria. StudyTotal Pure FEA cases%N excisedN upgraded to cancer% upgradedLim, 2006862.55120Kunju 20071485.712325Martel 20076338.124938Piubello, 20093360.62000Chivukula, 20093989.735514Senneta,20094187.83600Hayes, 200981008113Davashian, 20091210012217Tamasino, 20095444.424313Noske, 20104369.83027Lee, 20101546.77114Ingegnoli, 20101883.315320Noel, 20106232.32000Flegg, 2010NANA5240Sohn, 20113666.72428Lavoue, 20116010060813Rakha, 20112410024521Soloranzo,20113384.828414Verschuur-Maes, 20116934.824938Peres, 201212879.71021010Uzoaru, 201214565.69533Bianchi, 2012190100190189Biggar, 2012511005136Yamaguchi, 20121747.18113Polom, 20122010020210Khoumais, 201310490.4941011Villa, 201314285.212176Becker, 201330378.9239104Ceugnart, 20136382.55236Uzan, 2013351003500 Across 1420 patients with pure FEA in 30 studies, observed proportions with upgrade to cancer varied from 0-40% with a pooled estimate of 11% (95% CI: 8-15%) using a random effects model. Test for heterogeneity was statistically significant (p < 0.0001, I2 statistic=58%). After excluding 7 studies with <50% (or unreported %) of all FEA cases excised, heterogeneity decreased (p=0.07, I2=32%) and the pooled estimate of cancer upgrade was 9% (95% CI: 7-12%). For upgrade to ADH, 693 subjects with pure FEA were analyzed from 21 studies. The percent upgraded to ADH ranged from 0-60% with significant heterogeneity (p < 0.0001, I2 = 64%). Excluding 4 studies with <50% of FEA cases excised did not improve heterogeneity (p < 0.0001 and I2 = 66%). The random effects model pooled estimate of upgrade to ADH was 16% (95% CI: 11-23%) for the 21 studies and 17% (95% CI: 12-25%) for the subset of 17 studies. CONCLUSION: The pooled upgrade rate of FEA to cancer was 9-11% and upgrade to ADH was 16-17%. For patients with FEA on core needle biopsy, surgical excision should be strongly considered. Citation Format: Anatoliy V Rudin, Hoskin L Tanya, Ann M Farrell, Amy C Degnim. Flat epithelial atypia on core biopsy and upgrade to cancer: A systematic review and meta-analysis [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-13-06.

Abstract Background: There is an increasing recognition that many young women with breast cancer will have favorable outcomes without chemotherapy. We sought to characterize decision-making surrounding adjuvant chemotherapy treatment (CT) in this population for whom chemotherapy has historically been a standard of care. Methods: As part of an ongoing, multi-center, prospective cohort of young women diagnosed with breast cancer at age 40 and younger, we identified 657 women with Stage I-III breast cancer. Participants were asked to complete surveys by mail that included questions about socio-demographics, decision-making, and treatment history within the first year following diagnosis. Tumor characteristics were ascertained via pathology and medical record review. We used Chi-square tests to compare: decisional involvement (patient-driven vs. shared vs. physician-driven), degree of confidence, and feeling informed about the CT decision (the latter two measured on a 0-10 scale, categorized as follows: 0-5=low; moderate=6-8; 9-10=high) between women who did and did not receive CT. To explore clinical appropriateness of the CT decision, we used logistic regression to assess the relationship between tumor characteristics and non-receipt of CT among women with Stage I/II disease. Results: Among women with Stage I (n=250), II (n=312), and III (n=95), disease, 66%, 95%, and 100%, received CT, respectively. A greater proportion of women who had CT were highly confident with their decision compared with women who did not have CT (80% vs. 60%, p<0.0001); women who did not have CT were more likely to report a low level of feeling informed about the CT decision compared to women who received CT (20% vs. 5%, p<0.0001). Women who did not have CT were also more likely to report the final CT decision as made by their doctor (49% vs. 28%) and less likely to report a shared decision (33% vs. 59%, p<0.0001). Non-receipt of CT in women with Stage I/II disease (n=546) was associated within having node negative disease, T1 (vs. T2 or larger), Her2- negative, and hormone receptor positive tumors. Conclusion: Although non-receipt of CT would be expected to be viewed favorably by patients and doctors, we found that women who received CT felt more confident and better informed than those who received no CT. Given that women who did not have CT were also less likely to perceive the CT decision as shared, improved communication together with better decisional support may be beneficial, especially for women who do not receive adjuvant chemotherapy. Citation Format: Shoshana M Rosenberg, Karen Sepucha, Kathryn J Ruddy, Lidia Schapira, Steven Come, Virginia Borges, Evan Morgan, Nancy U Lin, Shari Gelber, Rulla M Tamimi, Ann H Partridge. Decision-making surrounding adjuvant chemotherapy in young women with early stage breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-10-03.