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Background BRCA1 and BRCA2 (BRCA) mutation carriers face a high lifetime risk of developing ovarian cancer. Oral contraceptives are protective in this population; however, the impact of other types of contraception (e.g. intrauterine devices, implants, injections) is unknown. We undertook a matched case-control study to evaluate the relationship between type of contraception and risk of ovarian cancer among women with BRCA mutations. Methods A total of 1733 matched pairs were included in this analysis. Women were matched according to year of birth, date of study entry, country of residence, BRCA mutation type and history of breast cancer. Detailed information on hormonal, reproductive and lifestyle exposures were collected from a routinely administered questionnaire. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) associated with each contraceptive exposure. Results Ever use of any contraceptive was significantly associated with reduced risk of ovarian cancer (OR = 0.62; 95% CI 0.52–0.75; P < 0.0001), which was driven by significant inverse associations with oral contraceptives (OR = 0.66; 95% CI 0.54–0.79; P < 0.0001) and contraceptive implants (OR = 0.30; 95% CI 0.12–0.73; P = 0.008). We observed a similar effect with use of injections (OR = 0.37; 95% CI 0.10–1.38; P = 0.14), but this did not achieve significance. No significant associations were observed between patterns of intrauterine device use and risk of ovarian cancer. Conclusions These findings support a protective effect of oral contraceptives and implants on risk of ovarian cancer among women with BRCA mutations. The possible protective effect of injections requires further evaluation.

XLSX file - 23K, Mapping statistics for genome sequencing of tumor and germline DNA from mTNBC

mp3 file (9 MB). In the June edition of the Cancer Discovery podcast, Science Writer Elizabeth McKenna talks with Kornelia Polyak about her paper, which uses a combined experimental and computational approach to reveal that the loss of wild-type BRCA1 may not be the first event in the majority of BRCA1-associated breast tumors and may not be present in all cancer cells within tumors.

PDF file - 2.2MB

XLSX file - 45K, Genes containing breakpoint from translocation in mTNBC

XLSX file - 273K, Somatic genic focal copy number changes in mTNBC

XLSX file - 598K, edgeR differential expression results in mTNBC for select cancer related genes

PDF file - 171K, Optimization and validation of the techniques used.

XLSX file - 607K, Outlier differential expression results in mTNBC for select cancer related genes

XLSX file - 61K, List of somatic point mutations in mTNBC detected by NGS sequencing analysis

XLSX file - 42K, Ingenuity Canonical Pathways results for mTNBC based on edgeR differential expression results

XLSX file - 40K, Characteristics of mTNBC study population

PDF file - 149K, Evolutionary paths and BRCA1 expression in breast tumors.

PDF file - 1635K, PET/CT images of mTNBC2 breast lesion before and after treatment on combination MEK and AKT inhibitors

BRCA1-associated breast tumors display loss of BRCA1 and frequent somatic mutations of PTEN and TP53. Here we describe the analysis of BRCA1, PTEN, and p53 at the single cell level in 55 BRCA1-associated breast tumors and computational methods to predict the relative temporal order of somatic events, on the basis of the frequency of cells with single or combined alterations. Although there is no obligatory order of events, we found that loss of PTEN is the most common first event and is associated with basal-like subtype, whereas in the majority of luminal tumors, mutation of TP53 occurs first and mutant PIK3CA is rarely detected. We also observed intratumor heterogeneity for the loss of wild-type BRCA1 and increased cell proliferation and centrosome amplification in the normal breast epithelium of BRCA1 mutation carriers. Our results have important implications for the design of chemopreventive and therapeutic interventions in this high-risk patient population.Significance: Defining the temporal order of tumor-driving somatic events is critical for early detection, risk stratification, and the design of chemopreventive therapies. Our combined experimental and computational approach reveal that the loss of wild-type BRCA1 may not be the first event in the majority of BRCA1-associated breast tumors and may not be present in all cancer cells within tumors. Cancer Discov; 2(6); 503–11. ©2012 AACR.This article is highlighted in the In This Issue feature, p. 473

XLSX file - 48K, Transcriptome sequencing (RNA-seq) run statistics for mTNBC

PDF file - 135K, Validation of RB1 39bp homozygous deletion in mTNBC1

Figure S1: Forest plot of hazard ratios by subgroup in the ITT population (planned analysis) for (A) DFS and (B) OS

Figure S2: Distribution of central Ki-67 scores in (A) ER-positive/HER2-negative breast cancer (n=824) and (B) TNBC (n=454)

Supplementary Data from Determinants of Response to Talazoparib in Patients with HER2-Negative, Germline BRCA1/2-Mutated Breast Cancer

Figure S3: Forest plots for DFS comparing patients with central Ki-67 high versus low based on quartile cutoffs (exploratory analysis) in (A) ER-positive/HER2-negative breast cancer (n=824) and (B) TNBC (n=454)

Purpose:PARP inhibitors (PARPi) have demonstrated efficacy in tumors with germline breast cancer susceptibility genes (gBRCA) 1 and 2 mutations, but further factors influencing response to PARPi are poorly understood.Experimental Design:Breast cancer tumor tissue from patients with gBRCA1/2 mutations from the phase III EMBRACA trial of the PARPi talazoparib versus chemotherapy was sequenced using FoundationOne CDx.Results:In the evaluable intent-to-treat population, 96.1% (296/308) had ≥1 tumor BRCA (tBRCA) mutation and there was strong concordance (95.3%) between tBRCA and gBRCA mutational status. Genetic/genomic characteristics including BRCA loss of heterozygosity (LOH; identified in 82.6% of evaluable patients), DNA damage response (DDR) gene mutational burden, and tumor homologous recombination deficiency [assessed by genomic LOH (gLOH)] demonstrated no association with talazoparib efficacy.Conclusions:Overall, BRCA LOH status, DDR gene mutational burden, and gLOH were not associated with talazoparib efficacy; however, these conclusions are qualified by population heterogeneity and low patient numbers in some subgroups. Further investigation in larger patient populations is warranted.

Supplementary Table 1 from Genetic Variation in IGF2 and HTRA1 and Breast Cancer Risk among BRCA1 and BRCA2 Carriers

Background:BRCA1 and BRCA2 mutation carriers have a lifetime breast cancer risk of 40% to 80%, suggesting the presence of risk modifiers. We previously identified significant associations in genetic variants in the insulin-like growth factor (IGF) signaling pathway. Here, we investigate additional IGF signaling genes as risk modifiers for breast cancer development in BRCA carriers.Methods: A cohort of 1,019 BRCA1 and 500 BRCA2 mutation carriers were genotyped for 99 single-nucleotide polymorphisms (SNP) in 13 genes. Proportional hazards regression was used to model time from birth to diagnosis of breast cancer for BRCA1 and BRCA2 carriers separately. For linkage disequilibrium (LD) blocks with multiple SNPs, an additive genetic model was used. For an SNP analysis, no additivity assumptions were made.Results: Significant associations were found between risk of breast cancer and LD blocks in IGF2 for BRCA1 and BRCA2 mutation carriers (global P values of 0.009 for BRCA1 and 0.007 for BRCA2), HTRA1 for BRCA1 carriers (global P value of 0.005), and MMP3 for BRCA2 carriers (global P = 0.0000007 for BRCA2).Conclusions: We identified significant associations of genetic variants involved in IGF signaling. With the known interaction of BRCA1 and IGF signaling and the loss of PTEN in a majority of BRCA1 tumors, this suggests that signaling through AKT may modify breast cancer risk in BRCA1 carriers.Impact: These results suggest potential avenues for future research targeting the IGF signaling pathway in modifying risk in BRCA1and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev; 20(8); 1690–702. ©2011 AACR.

Purpose: Brain metastases develop in one third of patients with advanced HER2+ breast cancer. Effective therapy for patients with central nervous system (CNS) progression after cranial radiation is extremely limited and represents a major clinical challenge. Lapatinib, an epidermal growth factor receptor/HER2 inhibitor, was associated with regressions of CNS lesions in a small phase 2 trial. The current study was done to further evaluate the CNS activity of lapatinib. The study was later amended to allow patients who progressed on lapatinib the option of receiving lapatinib plus capecitabine.Experimental Design: Eligible patients had HER2+ breast cancer, progressive brain metastases, prior trastuzumab, and cranial radiotherapy. The primary end point was CNS objective response, defined as ≥50% volumetric reduction of CNS lesion(s) in the absence of increasing steroid use, progressive neurologic signs and symptoms, or progressive extra-CNS disease.Results: Two-hundred and forty-two patients entered the study. CNS objective responses to lapatinib were observed in 6% of patients. In an exploratory analysis, 21% of patients experienced a ≥20% volumetric reduction in their CNS lesions. An association was observed between volumetric reduction and improvement in progression-free survival and neurologic signs and symptoms. Of the 50 evaluable patients who entered the lapatinib plus capecitabine extension, 20% experienced a CNS objective response and 40% experienced a ≥20% volumetric reduction in their CNS lesions.Conclusions: This study confirms the modest CNS antitumor activity of lapatinib. Additional responses were observed with the combination of lapatinib and capecitabine. Further studies of lapatinib-based regimens for CNS metastases from HER2+ breast cancer are warranted.

Supplementary Tables S1-5. Table S1. Baseline demographic and disease characteristics of patients with central Ki-67 data available. Table S2. Concordance between central and local Ki-67 scores. Table S3. Percentage of patients with a DFS event or death in lobular versus ductal early breast cancer (exploratory analysis). Table S4. 7-year DFS and OS by central Ki-67 scores (exploratory analysis). Table S5. 5-year DFS and OS by local Ki-67 scores (exploratory analysis).

Supplementary Figure from Determinants of Response to Talazoparib in Patients with HER2-Negative, Germline BRCA1/2-Mutated Breast Cancer

Supplementary Data from Multicenter Phase II Study of Lapatinib in Patients with Brain Metastases from HER2-Positive Breast Cancer

Purpose: We conducted a randomized phase III study to determine whether patients with early breast cancer would benefit from the addition of capecitabine (X) to a standard regimen of doxorubicin (A) plus cyclophosphamide (C) followed by docetaxel (T).Experimental Design: Treatment comprised eight cycles of AC→T (T dose: 100 mg/m2 on day 1) or AC→XT (X dose: 825 mg/m2 twice daily, days 1–14; T dose: 75 mg/m2 on day 1). The primary endpoint was 5-year disease-free survival (DFS).Results: Of 2,611 women, 1,304 were randomly assigned to receive AC→T and 1,307 to receive AC→XT. After a median follow-up of 5 years, the study failed to meet its primary endpoint [HR, 0.84; 95% confidence interval (CI), 0.67–1.05; P = 0.125]. A significant improvement in overall survival, a secondary endpoint, was seen with AC→XT versus AC→T (HR, 0.68; 95% CI, 0.51–0.92; P = 0.011). There were no unexpected adverse events. Of patients with estrogen receptor (ER)–positive/HER2-negative disease, 70% of whom were node-positive, 26% and 59% had tumors with a centrally assessed Ki-67 score of Conclusions: The very low event rate in patients with ER-positive, low Ki-67 cancers, regardless of nodal status, strongly suggests that these patients should not be enrolled in adjuvant trials that assess 5-year DFS rates and that central Ki-67 analyses can identify these patients. Clin Cancer Res; 21(19); 4305–11. ©2015 AACR.

Inherited BRCA1/2 mutations confer elevated ovarian cancer risk. Knowledge of factors that can improve ovarian cancer risk assessment in BRCA1/2 mutation carriers is important because no effective early detection for ovarian cancers exists. A cohort of 1,575 BRCA1 and 856 BRCA2 mutation carriers was used to evaluate haplotypes at ATM, BARD1, BRIP1, CTIP, MRE11, NBS1, RAD50, RAD51, and TOPBP1 in ovarian cancer risk. In BRCA1 carriers, no associations were observed with ATM, BARD1, CTIP, RAD50, RAD51, or TOPBP1. At BRIP1, an association was observed for one haplotype with a multiple testing corrected P (Pcorr) = 0.012, although no individual haplotype was significant. At MRE11, statistically significant associations were observed for one haplotype (Pcorr = 0.007). At NBS1, we observed a Pcorr = 0.024 for haplotypes. In BRCA2 carriers, no associations were observed with CTIP, NBS1, RAD50, or TOPBP1. Rare haplotypes at ATM (Pcorr = 0.044) and BARD1 (Pcorr = 0.012) were associated with ovarian cancer risk. At BRIP1, two common haplotypes were significantly associated with ovarian cancer risk (Pcorr = 0.011). At MRE11, we observed a significant haplotype association (Pcorr = 0.012), and at RAD51, one common haplotype was significantly associated with ovarian cancer risk (Pcorr = 0.026). Variants in genes that interact biologically withBRCA1 and/or BRCA2 may be associated with modified ovarian cancer risk in women who carry BRCA1/2 mutations. [Cancer Res 2009;69(14):5801–10]

Supplementary Table 2: Revised 7-14-09 from Modification of Ovarian Cancer Risk by BRCA1/2-Interacting Genes in a Multicenter Cohort of BRCA1/2 Mutation Carriers

Supplementary Table 4 from Modification of Ovarian Cancer Risk by BRCA1/2-Interacting Genes in a Multicenter Cohort of BRCA1/2 Mutation Carriers

Supplementary Table 3 from Modification of Ovarian Cancer Risk by BRCA1/2-Interacting Genes in a Multicenter Cohort of BRCA1/2 Mutation Carriers

Supplementary Table 2 from Modification of Ovarian Cancer Risk by BRCA1/2-Interacting Genes in a Multicenter Cohort of BRCA1/2 Mutation Carriers

Supplementary Table 1 from Modification of Ovarian Cancer Risk by BRCA1/2-Interacting Genes in a Multicenter Cohort of BRCA1/2 Mutation Carriers

Background: POLARIS is an ongoing, prospective, real-world, noninterventional, multicenter study in patients with HR+/HER2- ABC receiving palbociclib in the United States and Canada. This report describes PRO data from a real-world setting of patients with ABC receiving palbociclib. Methods: POLARIS has a targeted enrollment of 1500 patients from ~110 sites in the United States and Canada. Key inclusion criteria included patients with HR+/HER2- ABC with evidence of metastatic disease. QoL was assessed with the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30). A clinical problem threshold for 5 functioning and 9 symptom scales of the EORTC QLQ-C30 was established with anchor questions assigned for each domain to assess functional health and symptom burden. Results: As of March 16, 2021, 1240 patients were treated with palbociclib and had EORTC QLQ-C30 data collected and analyzed (at baseline, n=1240; after 6 months of palbociclib treatment, n=1076; after 12 months of palbociclib treatment, n=926). At baseline, the median age of patients was 64 years (Table 1). The majority of patients were white (82%) and 98.8% were female. Nearly 95% of patients had stage 4 metastatic disease, 5.1% had locally advanced stage (III), 68% had a recurrent disease from the earlier stage (0-III), and 27.3% had de novo stage IV disease diagnosed at enrollment. In this cohort, 98.3% of patients were estrogen receptor-positive (ER+)/progesterone receptor-positive (PR+), 94% were HER2-, with 99% of patients HER2- also ER+/PR+ at or nearest to the enrollment date. The percentages of patients with functioning scale scores (physical [baseline=54.6%; month 6=50.2%; month 12=50.4%], role [baseline=28.6%; month 6=20.1%; month 12=18.6%], social [baseline=24.2%; month 6=15%; month 12=15%], emotional [baseline=37.1%; month 6=29.6%; month 12=29.4%], and cognitive [baseline=34.2%; month 6=34.5%; month 12=31.7%]) below the clinical problem threshold remained stable over the first 12 months of palbociclib treatment (Table 2). A similar trend across time was observed with the symptom scales with the percentages of patients (fatigue, pain, nausea and vomiting, insomnia, appetite loss, constipation, dyspnea, diarrhea, and financial difficulties) above the clinical problem threshold also remaining stable over the first 12 months (Table 2). Conclusions: In this PRO analysis, palbociclib treatment did not have any significant adverse impact on QoL in patients with HR+/HER2- ABC as assessed by QLQ-C30 functioning and symptom scales. Pfizer (NCT03280303) Table 1.Patient Demographic CharacteristicsCharacteristicTotal. (N=1240)Age at study enrollmentMedian (range), y64 (22-97)Distribution, n (%)1 to 2 mo247 (19.9)>2 to 3 mo71 (5.7)>3 to 4 mo22 (1.8)>4 to 5 mo23 (1.9)>5 to 6 mo12 (1.0)>6 mo350 (28.2)aMinority. bMinority among White. ABC=advanced breast cancer; mBC=metastatic breast cancer. Table 2.Percentages of Symptoms and Functional ImprovementScaleClinical problem (threshold)Baselinea n (%)Month 6a n (%)Month 12a n (%)Functioning ScalesbPhysical functioningc39421 (36.5)256 (35.2)144 (30.4)Mean (SD)36.7 (26.9)34.2 (23.0)33.0(24.4)Painc>25614 (53.3)341 (46.9)221 (46.6)Mean (SD)34.8 (31.7)26.7 (26.4)26.6 (27.2)Nausea and vomitingc>8423 (36.7)233 (32.0)153 (32.3)Mean (SD)12.4 (21.2)9.4 (17.4)9.7 (17.3)Insomniaf>50279 (24.2)156 (21.5)89 (18.8)Mean (SD)31.7 (31.1)29.3 (28.9)26.8 (29.0)Appetite lossf>50205 (17.8)72 (9.9)48 (10.1)Mean (SD)23.3 (30.2)16.9 (25.0)15.9 (25.2)Constipationc>50142 (12.3)71 (9.8)46 (9.7)Mean (SD)18.9 (27.6)15.7 (23.7)15.3 (23.8)Dyspneag>17547 (47.6)323 (44.5)207 (43.7)Mean (SD)23.0 (28.8)19.1 (24.8)18.5 (24.5)Diarrheah>17327 (28.5)209 (28.7)120 (25.4)Mean (SD)12.9 (23.5)12.8 (22.6)10.5 (20.1)Financial Impact of Diseasei>17563 (49.0)322 (44.3)198 (42.0)Mean (SD)26.9 (33.2)22.5 (30.3)20.2 (27.9)aThe number of patients eligible at a visit is based on data expected to be available through the latest date of exposure, visit date, or questionnaire date. Baseline, N=1240; Month 6, N=1076; Month 12, N=926. bPercentages for functional and symptom scales were calculated based on “n,” the number of measurements available. Values for Mean (Standard Deviation, SD) were also based on “n”. cn (missing), Baseline=1152 (88); Month 6=727 (349); Month 12=474 (452) dn (missing), Baseline=1151 (89); Month 6=726 (350); Month 12=473 (453) en (missing), Baseline=1151 (89); Month 6=727 (349); Month 12=473 (453) fn (missing), Baseline=1151 (89); Month 6=727 (349); Month 12=474 (452) gn (missing), Baseline=1149 (91); Month 6=726 (350); Month 12=474 (452) hn (missing), Baseline=1149 (91); Month 6=727 (349); Month 12=473 (453) in (missing), Baseline=1149 (91); Month 6=727 (349); Month 12=471 (455) Note: For functioning scales, scoring below the clinical problem threshold indicates a clinically important problem whereas, for the symptom scales, scores above the clinical problem threshold indicate such a problem. Citation Format: Meghan S. Karuturi, Gabrielle B. Rocque, Joseph C. Cappelleri, Joanne L. Blum, Steven L. McCune, Bijoy Telivala, Sobha Kurian, Daniel M. Anderson, Michaela Tsai, Timothy Pluard, John Migas, Yao Wang, Monica Z. Montelongo, Debu Tripathy. Real-world quality of life (QoL) in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), advanced breast cancer (ABC) treated with palbociclib: A patient-reported outcome (PRO) analysis from POLARIS [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-25.

Background: POLARIS is a prospective, real-world study of palbociclib in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC) in the United States and Canada. These analyses evaluated the difference in tumor mutation profiles of patients receiving palbociclib in the first line versus second line or greater and examined the applicability of circulating tumor DNA (ctDNA) monitoring in a real-world setting. Methods: The clinical database cut-off date was March 16, 2021. Patients in the biomarker analysis group provided consent for serial blood sample collections, received ≥1 dose of initial palbociclib combination treatment, and had ≥1 ctDNA measurement available. The Guardant360 platform with somatic single-nucleotide variants in complete or critical exons of 73 genes was used. The association between early changes in ctDNA mutation allele fractions at Cycle 2 Day 1 (C2D1) and disease progression at Week 24 was evaluated using univariate and multivariable logistic regression analysis adjusting for line of therapy. Results: Among patients with HR+/HER2– ABC (N=347), 93.9% (n=326) had ctDNA measured at baseline, of which 85.9% (n=280) had ≥1 ctDNA alteration detected; 66.6% of patients received palbociclib treatment in the first line and 33.4% as second line or greater ABC setting. The frequencies of gene mutations at baseline were generally higher in patients receiving palbociclib as a second-line or greater therapy compared to those who received it as first-line therapy, particularly for ESR1 mutations (30% vs 15%) and FGFR1 mutations (13% vs 9%). With a median (range) follow-up duration of 18.5 (0.1-46.3) months, patients with total ctDNA increase at C2D1 (log ratio change >0) were 3.74 times more likely to have disease progression at Week 24 (odds ratio, 3.74 [95% CI, 1.71-8.17]; P=0.001) compared with those without change or with a decrease in ctDNA at C2D1 (log ratio change ≤0). The observed significant association remained after adjusting for line of therapy in the multivariable regression analysis (odds ratio, 2.62 [95% CI, 1.14-6.04]; P=0.023). Conclusions: Among patients with HR+/HER2- ABC receiving palbociclib, early changes in ctDNA mutations were significantly associated with disease progression. Further studies are needed to confirm these findings and to evaluate the clinical utility of ctDNA-guided “adaptive” early therapeutic interventions to improve outcomes in patients with metastatic breast cancer. Pfizer; NCT03280303 Citation Format: Debu Tripathy, Zhe Zhang, Joanne L. Blum, Meghan S. Karuturi, Steven L. McCune, Bijoy Telivala, Shailendra Lakhanpal, Kamal Patel, Richard C. Frank, Kit Lu, Chetan Deshpande, Yao Wang, Yuan Liu, Aditya Bardia. Early changes in circulating tumor DNA and its effect on clinical outcomes in patients with advanced breast cancer receiving the CDK4/6 inhibitor palbociclib: Genotyping results from POLARIS [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-05.