Gary Unzeitig

Whole Genome Analysis Informs Breast Cancer Response to Aromatase Inhibition

To correlate the variable clinical features of oestrogen-receptor-positive breast cancer with somatic alterations, we studied pretreatment tumour biopsies accrued from patients in two studies of neoadjuvant aromatase inhibitor therapy by massively parallel sequencing and analysis. Eighteen significantly mutated genes were identified, including five genes (RUNX1, CBFB, MYH9, MLL3 and SF3B1) previously linked to haematopoietic disorders. Mutant MAP3K1 was associated with luminal A status, low-grade histology and low proliferation rates, whereas mutant TP53 was associated with the opposite pattern. Moreover, mutant GATA3 correlated with suppression of proliferation upon aromatase inhibitor treatment. Pathway analysis demonstrated that mutations in MAP2K4, a MAP3K1 substrate, produced similar perturbations as MAP3K1 loss. Distinct phenotypes in oestrogen-receptor-positive breast cancer are associated with specific patterns of somatic mutations that map into cellular pathways linked to tumour biology, but most recurrent mutations are relatively infrequent. Prospective clinical trials based on these findings will require comprehensive genome sequencing.

Randomized Phase II Neoadjuvant Comparison Between Letrozole, Anastrozole, and Exemestane for Postmenopausal Women With Estrogen Receptor–Rich Stage 2 to 3 Breast Cancer: Clinical and Biomarker Outcomes and Predictive Value of the Baseline PAM50-Based Intrinsic Subtype—ACOSOG Z1031

PURPOSE Preoperative aromatase inhibitor (AI) treatment promotes breast-conserving surgery (BCS) for estrogen receptor (ER)-positive breast cancer. To study this treatment option, responses to three AIs were compared in a randomized phase II neoadjuvant trial designed to select agents for phase III investigations. PATIENTS AND METHODS Three hundred seventy-seven postmenopausal women with clinical stage II to III ER-positive (Allred score 6-8) breast cancer were randomly assigned to receive neoadjuvant exemestane, letrozole, or anastrozole. The primary end point was clinical response. Secondary end points included BCS, Ki67 proliferation marker changes, the Preoperative Endocrine Prognostic Index (PEPI), and PAM50-based intrinsic subtype analysis. RESULTS On the basis of clinical response rates, letrozole and anastrozole were selected for further investigation; however, no other differences in surgical outcome, PEPI score, or Ki67 suppression were detected. The BCS rate for mastectomy-only patients at presentation was 51%. PAM50 analysis identified AI-unresponsive nonluminal subtypes (human epidermal growth factor receptor 2 enriched or basal-like) in 3.3% of patients. Clinical response and surgical outcomes were similar in luminal A (LumA) versus luminal B tumors; however, a PEPI of 0 (best prognostic group) was highest in the LumA subset (27.1% v 10.7%; P = .004). CONCLUSION Neoadjuvant AI treatment markedly improved surgical outcomes. Ki67 and PEPI data demonstrated that the three agents tested are biologically equivalent and therefore likely to have similar adjuvant activities. LumA tumors were more likely to have favorable biomarker characteristics after treatment; however, occasional paradoxical increases in Ki67 (12% of tumors with > 5% increase after therapy) suggest treatment-resistant cells, present in some LumA tumors, can be detected by post-treatment profiling.

Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab as neoadjuvant treatment for patients with HER2-positive breast cancer (Z1041): a randomised, controlled, phase 3 trial

BACKGROUND Neoadjuvant chemotherapy with trastuzumab for patients with HER2-positive breast cancer can produce a pathological complete response in the breast in 30-65% of patients. We investigated the effect of the timing of trastuzumab administration with anthracycline and taxane neoadjuvant chemotherapy. METHODS This randomised trial was done at 36 centres in the USA and Puerto Rico. Women with operable HER2-positive invasive breast cancer were randomly assigned (1:1) with a biased coin minimisation algorithm, stratified for age, tumour size, and hormone receptor status. Neither patients nor investigators (except for a cardiac safety review panel) were masked to treatment assignment. Patients randomly assigned to sequential treatment received fluorouracil 500 mg/m(2), epirubicin 75 mg/m(2), and cyclophosphamide 500 mg/m(2) (FEC-75) on day 1 of a 21-day cycle for four cycles followed by paclitaxel 80 mg/m(2) and trastuzumab 2 mg/kg (after a 4 mg/kg loading dose) once per week for 12 weeks, while those randomly assigned to the concurrent treatment group received paclitaxel and trastuzumab once per week for 12 weeks followed by four cycles of FEC-75 (on day 1 of each 21-day cycle) and once-weekly trastuzumab, in the same doses as the sequential group. Surgery, including evaluation of the axilla, was done within 6 weeks of completion of neoadjuvant treatment. The primary outcome was the percentage of patients who had a pathological complete response in the intention-to-treat population. The study is registered with ClinicalTrials.gov, number NCT00513292. FINDINGS From Sept 15, 2007, to Dec 15, 2011, 282 women were enrolled (140 in the sequential group, 142 in the concurrent group). Two patients in the sequential group withdrew consent before starting treatment. 78 of 138 (56·5%, 95% CI 47·8-64·9) patients who received sequential treatment had a pathological complete response in the breast versus 77 of 142 (54·2%, 95% CI 45·7-62·6) who received concurrent treatment (difference 2·3%, 95% CI -9·3 to 13·9). No treatment-related deaths occurred. The most common severe toxic effects were neutropenia (35 [25·3%] of 138 patients in the sequential group vs 45 [31·7%] of 142 patients in the concurrent group) and fatigue (six [4·3%] vs 12 [8·5%]). Left ventricular ejection fraction dropped below the institutional lower limit of normal at week 12 in one (0·8%) of 130 patients who received sequential treatment and four (2·9%) of 137 patients who received concurrent treatment; by week 24, it had dropped below this limit in nine (7·1%) of 126 patients and in six (4·6%) of 130 patients, respectively. INTERPRETATION Concurrent administration of trastuzumab with anthracyclines offers no additional benefit and is not warranted. FUNDING US National Cancer Institute.

Prevalence and Type of BRCA Mutations in Hispanics Undergoing Genetic Cancer Risk Assessment in the Southwestern United States: A Report From the Clinical Cancer Genetics Community Research Network

PURPOSE To determine the prevalence and type of BRCA1 and BRCA2 (BRCA) mutations among Hispanics in the Southwestern United States and their potential impact on genetic cancer risk assessment (GCRA). PATIENTS AND METHODS Hispanics (n = 746) with a personal or family history of breast and/or ovarian cancer were enrolled in an institutional review board-approved registry and received GCRA and BRCA testing within a consortium of 14 clinics. Population-based Hispanic breast cancer cases (n = 492) enrolled in the Northern California Breast Cancer Family Registry, negative by sequencing for BRCA mutations, were analyzed for the presence of the BRCA1 ex9-12del large rearrangement. RESULTS Deleterious BRCA mutations were detected in 189 (25%) of 746 familial clinic patients (124 BRCA1, 65 BRCA2); 21 (11%) of 189 were large rearrangement mutations, of which 62% (13 of 21) were BRCA1 ex9-12del. Nine recurrent mutations accounted for 53% of the total. Among these, BRCA1 ex9-12del seems to be a Mexican founder mutation and represents 10% to 12% of all BRCA1 mutations in clinic- and population-based cohorts in the United States. CONCLUSION BRCA mutations were prevalent in the largest study of Hispanic breast and/or ovarian cancer families in the United States to date, and a significant proportion were large rearrangement mutations. The high frequency of large rearrangement mutations warrants screening in every case. We document the first Mexican founder mutation (BRCA1 ex9-12del), which, along with other recurrent mutations, suggests the potential for a cost-effective panel approach to ancestry-informed GCRA.

Ki67 proliferation index as a tool for chemotherapy decisions during and after neoadjuvant aromatase inhibitor treatment of breast cancer: Results from the American college of surgeons oncology group Z1031 trial (alliance)

Purpose To determine the pathologic complete response (pCR) rate in estrogen receptor (ER) –positive primary breast cancer triaged to chemotherapy when the protein encoded by the MKI67 gene (Ki67) level was > 10% after 2 to 4 weeks of neoadjuvant aromatase inhibitor (AI) therapy. A second objective was to examine risk of relapse using the Ki67-based Preoperative Endocrine Prognostic Index (PEPI). Methods The American College of Surgeons Oncology Group (ACOSOG) Z1031A trial enrolled postmenopausal women with stage II or III ER-positive (Allred score, 6 to 8) breast cancer whose treatment was randomly assigned to neoadjuvant AI therapy with anastrozole, exemestane, or letrozole. For the trial ACOSOG Z1031B, the protocol was amended to include a tumor Ki67 determination after 2 to 4 weeks of AI. If the Ki67 was > 10%, patients were switched to neoadjuvant chemotherapy. A pCR rate of > 20% was the predefined efficacy threshold. In patients who completed neoadjuvant AI, stratified Cox modeling was used to assess whether time to recurrence differed by PEPI = 0 score (T1 or T2, N0, Ki67 < 2.7%, ER Allred > 2) versus PEPI > 0 disease. Results Only two of the 35 patients in ACOSOG Z1031B who were switched to neoadjuvant chemotherapy experienced a pCR (5.7%; 95% CI, 0.7% to 19.1%). After 5.5 years of median follow-up, four (3.7%) of the 109 patients with a PEPI = 0 score relapsed versus 49 (14.4%) of 341 of patients with PEPI > 0 (recurrence hazard ratio [PEPI = 0 v PEPI > 0], 0.27; P = .014; 95% CI, 0.092 to 0.764). Conclusion Chemotherapy efficacy was lower than expected in ER-positive tumors exhibiting AI-resistant proliferation. The optimal therapy for these patients should be further investigated. For patients with PEPI = 0 disease, the relapse risk over 5 years was only 3.6% without chemotherapy, supporting the study of adjuvant endocrine monotherapy in this group. These Ki67 and PEPI triage approaches are being definitively studied in the ALTERNATE trial (Alternate Approaches for Clinical Stage II or III Estrogen Receptor Positive Breast Cancer Neoadjuvant Treatment in Postmenopausal Women: A Phase III Study; clinical trial information: NCT01953588).

Abstract PD07-01: Z1031B Neoadjuvant Aromatase Inhibitor Trial: A Phase 2 study of Triage to Chemotherapy Based on 2 to 4 week Ki67 level > 10%.

Background: Neoadjuvant aromatase inhibitor (AI) therapy would become a more acceptable alternative to chemotherapy if there was a way to identify AI-resistant cases early for triage to alternate systemic treatment. We therefore conducted a Phase 2 trial of post-menopausal patients with clinical stage 2 or 3 ER+ (Allred Score 6 to 8) breast cancer who were re-biopsied 2 to 4 weeks after initiating neoadjuvant AI therapy. If the tumor Ki67 level was > 10% (AI resistant) the patient was triaged to either chemotherapy or immediate surgery and if Results: 51 patients (21%) had 2 to 4 week Ki67>10%, of these 36 received chemotherapy per protocol (27) anthracycline (A) and taxane (T)-based, 7 T-based, 1 A-only based and 1 other (non-NCCN) regimen but only 2 patients had a pCR (5.5%). 194 patients (79%) had a Ki67 Conclusion. A Ki67 value >10% at 2 to 4 weeks strongly enriches for high-risk molecular subtypes (mainly LumB) however standard neoadjuvant chemotherapy did not meet pre-assigned criteria for adequate Phase 2 activity in this group. Novel neoadjuvant approaches for AI resistant-disease defined by high on treatment Ki67 are therefore a high priority. Management of patients with excellent response to neoadjuvant endocrine therapy (PEPI-0) without adjuvant chemotherapy is feasible. The ALTERNATE trial will enroll over 2000 patients to establish a new standard of care for neoadjuvant treatment of ER+ HER2− disease based on these principles. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD07-01.

Disease-Free and Overall Survival Among Patients With Operable HER2-Positive Breast Cancer Treated With Sequential vs Concurrent Chemotherapy: The ACOSOG Z1041 (Alliance) Randomized Clinical Trial

Importance Pathologic complete response rate (pCR), the primary end point of the ACOSOG (American College of Surgeons Oncology Group) Z1041 (Alliance) trial, and disease-free survival (DFS) and overall survival (OS) in women with operable HER2-positive breast cancer are similar between treatment regimens. Objective To assess DFS and OS for patients treated with sequential vs concurrent anthracycline plus trastuzumab. Design, Setting, and Participants Phase 3 randomized clinical trial conducted at 36 centers in the continental United States and Puerto Rico. Women 18 years or older with invasive operable HER2-positive breast cancer were enrolled from September 15, 2007, to December 15, 2011, and randomized to 1 of 2 treatment arms. The analysis data set was locked on October 15, 2017, and analysis was completed on December 15, 2017. Interventions Patients randomized to arm 1 received 500 mg/m2 of fluorouracil, 75 mg/m2 of epirubicin, and 500 mg/m2 of cyclophosphamide (FEC) every 3 weeks for 12 weeks followed by the combination of 80 mg/m2 of paclitaxel and 2 mg/kg (except initial dose of 4 mg/kg) of trastuzumab weekly for 12 weeks. Patients randomized to arm 2 received the same combination of paclitaxel with trastuzumab weekly for 12 weeks followed by FEC every 3 weeks with weekly trastuzumab for 12 weeks. Women with hormone receptor–positive disease received endocrine therapy, and radiotherapy was delivered at physician discretion. Main Outcomes and Measures The primary outcomes were DFS and OS and pCR in the breast and nodes. Results Two hundred eighty-two women with HER2-positive breast cancer were enrolled in the trial, and 2 withdrew consent before treatment. Among the remaining 280 women, the median age was 50 years (range, 28-76 years), 232 (82.9%) were white, 29 (10.3%) were black, 8 (2.9%) were Asian, 4 (1.4%) were American Indian or Alaskan Native, and 7 (2.5%) did not report race/ethnicity. There were 22 disease events in arm 1 and 27 in arm 2. Disease-free survival rates did not differ with respect to treatment arm (stratified log-rank P = .96; stratified hazard ratio [HR] [arm 2 to arm 1], 1.02; 95% CI, 0.56-1.83). Overall survival did not differ with respect to treatment arm (stratified log-rank P = .73; stratified HR [arm 2 to arm 1], 1.17; 95% CI, 0.48-2.88). Conclusions and Relevance Across a median follow-up of 5.1 years (range, 26 days to 6.2 years), pCR, DFS, and OS did not differ with respect to sequential or concurrent administration of FEC with trastuzumab. Trial Registration ClinicalTrials.gov identifier: NCT00513292

Abstract PD6-02: The genomics of response to neoadjuvant trastuzumab and chemotherapy in HER2-positive breast cancer – Results from the ACOSOG Z1041 (Alliance) trial

Support: Alliance U10CA180821; Alliance Statistical Center grant U10CA180882; ACOSOG grant U10CA76001 HER2 gene amplification and its corresponding overexpression are present in approximately 12% of invasive breast cancers. While HER2-targeted agents (e.g. trastuzumab, pertuzumab, and lapatinib) are effective treatments, resistance remains a major cause of death from HER2-positive breast cancer. Mechanisms of resistance are poorly understood. Without a molecular understanding of these mechanisms, therapeutic advances will be delayed. We have generated molecular profiles of primary HER2-positive breast cancers treated on a neoadjuvant clinical trial, and compared features associated with response to treatment. The American College of Surgeons Oncology Group (ACOSOG) Z1041 trial in HER2-positive breast cancer was designed to compare the pathologic complete response (pCR) rate of a regimen of paclitaxel and trastuzumab, followed by trastuzumab administered with fluorouracil, epirubicin, and cyclophosphamide (FEC-75) to a regimen of FEC-75 alone followed by paclitaxel and trastuzumab. The trial identified no difference in pCR rates between the regimens (Buzdar et al., The Lancet Oncology 2013). In supplement to the tissues obtained from 37 of the patients enrolled in the Z1041 trial, an additional 11 cases were obtained from a single institution study (201101961) of patients treated with neoadjuvant trastuzumab that had pre-treatment core biopsies suitable for genomic studies. We have extracted genomic DNA from both pretreatment tumor biopsies and blood samples of these 48 patients and performed whole genome (WGS) and exome sequencing. Coincident with these efforts, we have extracted high quality RNA from 42 of the 48 biopsies, and have processed RNA-seq profiles of the tumors. Among patients in this cohort, 24 (50%) achieved a pCR. Because no difference was observed between arms of the Z1041 trial, patients with or without a pCR were directly compared without adjusting for treatment regimen. On average, each tumor and normal sample pair were sequenced to a depth of 49.4x and 32.5x by WGS respectively. In total, 15,027 candidate somatic variants were identified in known genes, including 11,606 missense, 860 nonsense, and 418 frameshift insertions or deletions. Preliminary results identified mutations in HER2 that were associated with the failure to achieve pCR in several cases. Furthermore, tumors assigned to the HER2-enriched subtype by RNA-seq analysis were more likely to achieve a pCR (19 compared to 8) than tumors with genomic features indicative of either the luminal or basal-like subtypes (3 compared to 12); a significant difference in the proportion of cases that achieve pCR (Fisher9s exact test p-value = 0.0032). The identification of these features suggests that it may be possible to predict, at the time of diagnosis, those patients who will not respond to the current standard of care for HER2-positive breast cancer. Citation Format: Lesurf R, Griffith O, Griffith M, Watson MA, Hoog J, Ellis MJ, Ota D, Suman VJ, Meric-Bernstam F, Leitch AM, Boughey JC, Unzeitig G, Buzdar AU, Hunt KK, Mardis ER. The genomics of response to neoadjuvant trastuzumab and chemotherapy in HER2-positive breast cancer – Results from the ACOSOG Z1041 (Alliance) trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD6-02.

Abstract OT2-1-04: Alliance A011106: ALTernate approaches for clinical stage II or III Estrogen Receptor positive breast cancer NeoAdjuvant TrEatment (ALTERNATE) in postmenopausal women: A phase III study

Neoadjuvant endocrine therapy (ET) in patients (pts) with locally advanced estrogen receptor positive (ER+) breast cancer (BC) improves breast conservation rate, and importantly offers an opportunity for individualized assessment of tumor responsiveness to ET to guide subsequent treatment. Previous neoadjuvant ET trials demonstrated that pathologic tumor size (pT), axillary lymph node status (N), and tumor Ki67 value at surgery predicted risk of relapse. Preoperative endocrine prognostic index (PEPI) was therefore developed to assign risk scores based on these factors. Modified PEPI 0, defined by pT1-2 N0 Ki67 ALTERNATE trial is a three-arm phase III neoadjuvant/adjuvant ET trial designed to achieve two primary objectives. The first is to prospectively validate that modified PEPI 0 predicts > 95% relapse-free survival (RFS). The second is to determine whether fulvestrant (F), or fulvestrant (F) plus anastrozole (A), is superior to A in inducing a higher rate of modified PEPI 0. Secondary objectives include assessing RFS for pts with endocrine resistant tumor, defined by Ki67 > 10% at 4 or 12 wk, disease progression, or modified PEPI non-0, and pathologic responses of resistant tumors to neoadjuvant chemotherapy. Correlative studies include degrees of Ki67 suppression and ER level post treatment. In addition, ongoing research sequencing studies of DNA and RNA will be performed to contrast sensitive vs resistant tumors. During the first phase of the trial, 1200 pts are randomized 1:1:1 to the F, A or F/A. This provides an 82% chance, 1-sided alpha 0.025 chi-square test to detect at least 10% difference in modified PEPI 0 rate comparing F or F/A with A. While waiting for result of analysis, the A arm will continue for the 2 nd phase enrollment. Only the F-containing arm(s) superior over A will be continued to the 2 nd phase. During the 2 nd phase, an additional 540 pts in each arm is estimated to obtain 317 pts with PEPI score 0. This will have a 90% chance, with a one-sided alpha=0.025 nonparametric Brookmeyer-Crowley type one sample survival test, rejecting that 5 year RFS rate is 95%. The maximum sample size is 2820 pts. Eligible pts include postmenopausal women with newly diagnosed clinical stage II or III ER+ (Allred score 6-8) HER2- BC. Tumor biopsy is required at baseline, 4 wk, and surgery for central Ki67 analysis. Treatment decision is individualized based on 4 wk Ki67 and modified PEPI score. Pts with Ki67 > 10% at 4 wk are switched to chemotherapy. Pts with a modified PEPI score of 0 are recommended not to receive chemotherapy, but continue the assigned ET for 1.5 years followed by 3 years of A. This trial is currently accruing pts through CTSU. This research is supported in part by NCI BIQSFP, and grants from Breast Cancer Research Foundation, Genentech, and the Investigator-Sponsored Study Program of AstraZeneca. The Clinical Trials.gov Identifier: NCT01953588. Citation Format: Cynthia X Ma, Vera Suman, A Marilyn Leitch, Souzan Sanati, Katherine DeSchryver, Gary W Unzeitig, Paul Haluska, Mark Watson, Olwen Hahn, Jo Anne Zujewski, Kelly Hunt, Eric P Winer, Cliff A Hudis, Matthew J Ellis. Alliance A011106: ALTernate approaches for clinical stage II or III Estrogen Receptor positive breast cancer NeoAdjuvant TrEatment (ALTERNATE) in postmenopausal women: A phase III 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 OT2-1-04.

Abstract 2759: Possible later age of breast cancer onset for Hispanic BRCA1 carriers with the protective rs140068132-G allele

Hispanic women in the U.S. have lower incidence of breast cancer compared to Non-Hispanic Whites (NHW). A genome-wide association study (GWAS) of breast cancer in Hispanics reported a relatively strong protective variant near the ESR1 gene, only observed among women with Indigenous American ancestry (rs140068132-A/G). The study also reported lower mammographic density among women who were homozygous for the Indigenous American variant (G) and a stronger protective effect for estrogen receptor negative (ER-) breast cancer. In the present study, we assessed if this variant had an effect on age at breast cancer diagnosis among Hispanic BRCA1 carriers, who commonly present with ER- disease. We combined data from four studies of Hispanic BRCA1 mutation carriers with breast cancer: the Clinical Cancer Genetics Community Research Network (CCGCRN; N = 152), Northern California Breast Cancer Family Registry (NC-BCFR, N = 27), and two studies in Latin America, one from Colombia (N = 33) and one from Chile (N = 27). We genotyped the rs140068132 variant using a Taqman assay following the recommended protocol. We used a non-parametric Kruskal-Wallis equality-of-populations rank test to evaluate if the age of breast cancer diagnosis was associated with the rs140068132 polymorphism among BRCA1 carriers. We conducted separate analyses of Hispanic women from California and women from Colombia and Chile. For the California studies, we also had information on ovarian cancer status and were able to conduct stratified analyses. Among 239 BRCA1 carriers, we observed 201 homozygous AA, 36 heterozygous AG, and 2 missing genotypes, with an overall allele frequency of the G allele of 7.6%. We did not find a statistically significant effect of rs140068132 on age at diagnosis among Hispanic BRCA1 carriers overall. However, we found a suggestion of later age at diagnosis, with median age at diagnosis of 39.8 years (33-46 years) in AA homozygous compared to 44 years (34-50 years) in heterozygous (p value = 0.1) women from California. Among women without ovarian cancer either before or after the breast cancer diagnosis, the difference in age at breast cancer diagnosis by genotype was slightly stronger (p value 0.06). We did not observe an association among the patients from Colombia and Chile. Studies of BRCA mutation carriers are often limited by selection for breast cancer cases, thus there may be a bias against enrollment of BRCA carriers with the protective allele in the present analysis. The observed suggestion of a difference in age at diagnosis in the samples from California, similar to genome-wide identified variants that have been shown to have an effect among BRCA1 and BRCA2 carriers, warrants further investigation. Citation Format: Laura Fejerman, Jeffrey N. Weitzel, Esther M. John, Cynthia Villarreal, Gary Unzeitig, Darling Horcasitas, Charite Ricker, Adrian Daneri, Kayla Castaneda, Alexander Miron, Ana Marie Tuazon, Magdalena Echeverry, Pilar Carvallo, Carolina Alvarez, Teresa Tapia, Columbus Consortium, Luis Carvajal-Carmona, Susan Neuhausen, Elad Ziv. Possible later age of breast cancer onset for Hispanic BRCA1 carriers with the protective rs140068132-G allele. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2759. doi:10.1158/1538-7445.AM2015-2759