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Background: gBRCA1/2mut ABC represents ~5% of all breast cancer (BC), although a fair estimate of gBRCA1/2mut HER2+ BC remains to be determined. HER2-targeted therapy is the current standard of care for these patients with HER2+ BC. While PARP inhibitors (PARPi) are approved for the treatment of gBRCA1/2mut HER2- ABC, recently, NCCN updated its guidelines (v6.2020) to additionally consider the use of PARPi in patients with gBRCA1/2mut HER2+ metastatic BC. However, clinical trials have not evaluated the efficacy of PARPi among patients with gBRCA1/2mut HER2+ metastatic BC. In order to establish a baseline reference point, we assessed real-world treatment patterns and clinical outcomes among patients with gBRCA1/2mut HER2+ ABC. Methods: US Oncologists retrospectively reviewed charts (July 2019-June 2020) of randomly selected patients ≥18 y, with gBRCA1/2mut ABC who received ≥1 cytotoxic chemotherapy (CT) regimen(s) for ABC between Jan 2013-April 2018. A descriptive analysis was performed for the HER2+ patients including 1st line ABC treatment patterns. Clinical outcomes (1st line ABC PFS rates) were estimated using the Kaplan-Meier method. PARPi clinical outcomes data were immature given its recent launch. Additional analyses evaluating outcomes in patients receiving PARPi are planned. Results: Of the 387 patients with gBRCA1/2mut ABC included in the study, 82 (21%) female patients had HER2+ disease. Of the gBRCA1/2mut HER2+ patients, median age was 56y, 72% were white. Clinical characteristics: 62% HR+/HER2+, 37% HR-/HER2+, and 1% had unknown HR/HER2+ ABC. Treatments in the 1st line setting for HR+/HER2+ ABC patients (n=51) included CT (55%) and CT + HER2-targeted therapy (43%). First-line treatments used for HR-/HER2+ ABC patients (n=30) included CT + HER2-targeted therapy (77%) and CT (20%). 12-month PFS rate for 1st line HR+/HER2+ patients was 77% and for HR-/HER2+ patients was 64%. Later line treatments will be presented. Conclusion: In this analysis of HER2+ patients with gBRCA1/2mut ABC, unexpectedly low rates of HER2-targeted therapy were observed in patients with HR+/HER2+ disease. Appropriately high rates of HER2-targeted therapy with CT was observed among gBRCA1/2mut HR-/HER2+ patients. Treatment patterns among patients with non-gBRCA1/2mut HER2+ ABC in a real-world setting need to be evaluated. Clinical outcome findings from this study demonstrate the need to better understand best treatment strategies for this patient population. As PARPi are not yet approved for patients with gBRCA1/2mut HER2+ ABC, studies assessing efficacy of PARPi +/- HER2-targeted therapy are warranted. Funding: Pfizer Citation Format: Elias Obeid, Rohan C Parikh, Elizabeth Esterberg, Bhakti Arondekar, Abigail Hitchens, Lillian Shahied Arruda, Alexander Niyazov. Treatment Patterns and Clinical Outcomes Among Patients with germline BRCA1/2 mutated (gBRCA1/2mut) HER2+ Advanced Breast Cancer (ABC): Results from a US Real-world Study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-53.

Background: Recently, somatic genetic information is being increasingly usedin clinical decisions for treatment of metastatic diseases, including breastcancer. Somatic mutations in the BRCA1/2 genes are not frequently seen.The poly ADP-ribose polymerases inhibitors (PARPi) have been approved astreatments for patients with germline (gBRCA1/2mut) HER2- ABC. Real-world practice shows that these agents arealso being utilized for patients who have sBRCA1/2mut. While we await data from large clinicaltrials such as MATVH and TAPUR, currently, limited information is available onthe effectiveness of these agents in patients with sBRCA1/2mut andestablishing a reference point is necessary to assess the unknown potentialclinical benefit. We assessed real-world treatment patterns and clinicaloutcomes among patients with HER2- sBRCA1/2mut without associatedgermline mutation and who had received treatment for ABC. Methods: US oncologists retrospectivelyreviewed charts (July 2019-June 2020) of quasi-randomly selected patients ≥18y, who received ≥1 cytotoxic chemotherapy (CT) regimen(s) for ABC between Jan2013-April 2018. Descriptive analyses were performed for patients with sBRCA1/2mut(without associated germline mutation), which included evaluation of treatment patternsand safety events for the first 3 lines of therapy. Clinical outcomes(progression free survival [PFS] and overall survival rates) were estimatedusing the Kaplan-Meier method for 1st line of therapy. Given therelatively recent launch of PARPi, clinical outcomes for these agents wereimmature. Results: 32 patients were included who only had sBRCA1/2mut: 96.9%were female, 68.8% were white, and 28.1% were black. Median age was 53.0 yrs. Advanced triplenegative breast cancer was observed in 40.6% of patients and 59.4% had hormonereceptor (HR)+/HER2- ABC. Common treatments for HR+/HER2- sBRCA1/2mutdisease included: 1st line (n=19), cyclophosphamide + doxorubicin (10.5%);2nd line (n=17), docetaxel (11.8%), PARPi monotherapy (11.8%), CDK4/6i + letrozole (11.8%); 3rd line- (n=7), eribulin (42.9%). Treatments for triplenegative sBRCA1/2mut breast cancer included: 1st line (n=13), cyclophosphamide + doxorubicin (30.8%);2nd line (n=9), PARPi (22.2%); 3rd line (n=7),atezolizumab based (71.4%). Median PFS across both subtypes was 10.8 months,95% CI 8.5 - 15.0. Overall, 78.9% of patients were alive at 2 years after 1stCT. Safety data will be presented. Conclusion: In this analysis of sBRCA1/2mut HER2- ABC, an individualapproach to select treatment regimens such as CT was frequently used, withoutadequate knowledge on best sequential therapy to include tumor genetic directedintervention. Poor clinical outcomes highlight the need for more efficacioustreatment options. Further studies assessingclinical outcomes among patients with sBRCA1/2mut ABC receivingPARPi are warranted. Citation Format: Elias Obeid, Rohan C Parikh, Elizabeth Esterberg, Bhakti Arondekar, Abigail Hitchens, Lillian Shahied Arruda, Alexander Niyazov. Treatment patterns and clinical outcomes among patients (pts) with HER2- advanced breast cancer (ABC) and somatic BRCA1/2 mutation(s) (sBRCA1/2mut): Results from a US real-world study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-36.

Background: PD-1 blockade has shown promising clinical activity in mTNBC. We designed an investigator-initiated multi-center clinical trial consisting of a Safety run-in, into a randomized phase II trial of combination pembrolizumab (P) with carboplatin (C) and gemcitabine (G) in patients with mTNBC. A detailed characterization of peripheral immune cell changes may help in understanding responses in mTNBC to immune checkpoint inhibition. Correlative studies for the purpose of understanding the effect of combining chemotherapy (CT) simultaneously with checkpoint inhibition on the peripheral immune response are planned as part of this clinical trial. Methods: Patients with a diagnosis of mTNBC are recruited to this trial with a Safety Run-in (N = 6 subjects), followed by a randomized design of C + G with/without P (2:1 randomization, N = 75). Treatment consists of P 200 mg on day 1 of each 21-day cycle, and C (AUC2) + G (800mg/m2) on days 1 and 8 for cohort A, and C (AUC2) + G (800mg/m2) for cohort B. Patients are consented for a peripheral blood (PB) collection pre-treatment on day 1 of cycle 1, and post-treatment on day 1 of cycle 3, in order to phenotype immune changes by flow-cytometry. Results: A total of 60 patients have been consented, 42 patients were enrolled (6 on safety run-in, 36 on the randomized part II). Of those on the randomized part II, blood samples from 17 patients have been analyzed from cycle 1 day 1 and cycle 3 day 3. A decreased expression of PD-1 on effector and memory subsets of both CD4+ and CD8+ T cells from C1D1 to C3D1 was observed in blood from both cohorts, especially cohort A. We found an increased % NK, CD4+ T and CD8+ T cell subsets expressing the activation marker, CD69, in cohort A, but not cohort B, reflecting activation by pembrolizumab.​ There was a parallel increased expression of the proliferative marker, Ki67, in CD56bright (immature) NK cells and effector memory CD8+ T cells in blood from C1D1 to C3D1 in cohort A. We also found an increased % CD56bright (immature) NK and effector memory CD4+ T cells expressing the exhaustion marker, CD39, which was consistent with increased expression of the activation marker, CD69. Conclusions: Although comprising a limited number of patients in this early analysis, our correlative studies found evidence for effective immune stimulation upon combining CT with the PD-1 blockade. The randomized nature of this trial, with our planned pre and post treatment blood collection will be helpful in understanding response to immune check point inhibition combined with chemotherapy in mTNBC. Correlation with absolute lymphocyte counts and outcomes data is planned and will be presented. Citation Format: Elias Obeid, Judy Fang, Alex W McFarlane, IV, Irina Shchaveleva, Shauna Souchuck, Kerry S Campbell, Lori J Goldstein. Title:peripheral blood immuneimpactsin arandomizedphase iiclinical trial ofprogrammed death 1 (pd-1) blockadecombined with platinum-based chemotherapy in patients with metastatic triple negative breast cancer (mtnbc) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-19.

Background: Invasive lobular carcinoma (ILC) is the second most common type of invasive breast cancer and accounts for 10-15% of all cases. Though ILC has distinct clinical, prognostic and molecular features, studies are limited and include few patients. ILCs show a decreased response to neoadjuvant chemotherapy and an increased resistance to endocrine therapy. Thus, there is a great need to identify alternative therapies, such as immunotherapy, that could improve overall survival. Success of immunotherapy largely depends on tumor immunogenicity which varies with histologic type. Determination of predictive and prognostic biomarkers for ILC will help determine who can benefit the most. Our study investigates canonical markers of immunogenicity - PD-L1 expression and Tumor Mutational Burden (TMB) - in patients with ILC compared to invasive ductal carcinoma (IDC). We further correlate these markers in different subtypes i.e. hormone receptor positive (HR+), HER2 positive (HER2+), and in triple negative breast cancers (TNBC). We also analyze differences in immune cell profiles constituting the tumor microenvironment (TME) and differences in genomic alterations between ILC and IDC. Methods: A retrospective data analysis was performed to identify breast cancer tumors with ILC or IDC histology profiled at Caris Life Sciences (Phoenix, AZ) that were tested for PD-L1 by SP142 assay and had whole transcriptome sequencing data available. ILC and IDC cases were further subtyped as HR+ and HER2+ and TNBC. PD-L1 expression in immune cell was assessed using Ventana PD-L1 (SP142) histochemical assay and PD-L1 expression in tumor cell was assessed by laboratory developed test using SP142 clone with staining higher than 2+ considered positive. TMB was measured by counting somatic non-synonymous missense mutations on the 592 gene panel (Nextseq) next generation sequencing (NGS) assay, and ≥ 10 mutations/megabase (mut/Mb) was considered high. Using the whole transcriptome RNA sequencing (NovaSeq) data we analyzed the difference in immune cell profiles constituting the TME using a computational RNA deconvolution approach. NGS was used to identify significant differences in genomic alterations between ILC and IDC. Results: We identified 1,359 breast cancer patients (ILC: 194 vs IDC: 1,165). Among ILC, 79% were HR +, 11% TNBC, 10% ILC: 1% vs. IDC: 5% p=0.017). PD-L1 expression in tumor cells was also lower in ILC (ILC 1% vs IDC 5%; p =0.0136). All subtypes of ILC had lower PD-L1 expression in immune and tumor cells when compared to IDC. TMB was similar and comparable in IDC and ILC (median TMB 7 mut/Mb). Assessment of TME showed a significantly increased abundance of cytotoxic lymphocytes and monocytic cells in IDC, and stromal endothelial cells in ILC. Androgen receptor (AR) expression, and mutations in CDH1 (ILC 76% vs IDC 2%) and PIK3CA (ILC 44% vs IDC 30%) were more common in ILC. CDH1 mutation was significantly higher in both TN ILC (ILC 60% vs IDC 1%; p Citation Format: Upama Giri, Joanne Xiu, Tatiana Karadimitriou, Sofi Castanon, Foluso Ademuyiwa, Paula Pohlmann, Elias Obeid, Jasgit Sachdev, Elisa Krill-Jackson, Michael Simon, Antoinette Tan, Neelima Denduluri, Lee Schwartzberg, Michael Korn, Evanthia T Roussos Torres. Molecular evaluation of immunogenicity and genomic alterations in invasive lobular breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-27.

Background: Up to 10% of breast cancers are hereditary. Pathogenic variants (PV) in the BRCA1/2 genes are responsible for two thirds of hereditary breast cancer (BC). Additional non-BRCA genes (ATM, CHEK2, PALB2, etc.) have been identified as predisposing for BC. While genetic testing(GT) for hereditary BC traditionally involved testing mostly for mutations in the BRCA1/2 genes, next generation sequencing has enabled multiple BC genes to be simultaneously tested at a cost often lower than testing for BRCA1/2 alone. Consequently, MGP testing has been rapidly replacing BRCA1/2 only testing. Studies have demonstrated that MGP testing doubles the detection of PV. Because prior studies examining MGP findings have been mostly conducted in predominantly white populations, it is unknown if the use of MGP testing in African-American (AA) patients also results in increased detection of non-BRCA mutations and whether there are significant differences in the prevalence of PV between AA and white women with invasive BC. In this study, we sought to compare the rate and spectrum of PV between AA and White women with invasive BC undergoing MGP testing. Methods: In this retrospective study, we assessed the prevalence of PV and spectrum of mutations among a cohort of 680 racially diverse women diagnosed with invasive BC who underwent GT with a MGP between 2014 and 2019 at a single cancer center. This analysis included participants who had a documented diagnosis of invasive BC and completed MGP testing. Fisher’s exact tests were used to analyze differences between racial groups. Subjects previously signed informed consent to participate in research. Results: 680 women with invasive BC were included in the study. The study population was 79.4% non-Hispanic white, 10.6% AA, and 10% other. PV were identified in 13.4 % of the overall population. The prevalence of PV was 15.5% (84/540) in AA compared to 8.3% (6/72) in white women, but this difference was not statistically significant (p=0.14). In white women, the prevalence of PV was 5.9% (32/540) in BRCA1/BRCA2 and 9.6% (52/540) in non-BRCA genes. MGP testing allowed for the detection of 52 non-BRCA PV, including BC genes (CHEK2-17, ATM-7, PALB2-4, CDH1-2, BARD1-1, TP53-1, RAD50-1) and non-BC genes (MUTYH-8, NTHL1-2, BRIP1-2, PMS2-2, RAD51C-1, RAD51D-1, MSH6-1, FH-1, MITF-1). In AA patients, the prevalence of PV was 6.9% in BRCA1/2 and 1.4% in non-BRCA genes. MGP testing in AA women with invasive BC detected only one non-BRCA mutation in the gene MUTYH. VUS rates were higher in AA, 29.2% compared to whites, 19.3% with a trend towards a statistically significant difference (p=0.07). Conclusions: While MGP testing more than doubled the detection rate of PV in white patients with BC by detecting various non-BRCA PV, for AA patients the use of MGP testing did not result in many additional non-BRCA PV being identified in this analysis. However, MGP testing did result in a high VUS rate, 19.3%, without the added value of detecting additional PV that could be helpful to the patient and their family members by expanding opportunities for cancer prevention and early detection. We acknowledge that in this study sample of 10.6% AA women, this is an under-representation. Large population-specific studies should be done to confirm those findings. Given the known psychological harms to the patient and their family members in response to the uncertainty of VUS findings as well as the possible mismanagement of VUS results, well-designed studies should investigate the selection of who to consider for MGP testing rather than BRCA1/2 testing for hereditary BC to ensure that the benefits of MGP testing over BRCA1/2 only testing outweigh the risks associated with panel testing. Citation Format: Kristen Whitaker, Nicole Ventriglia, Karthik Devarajan, Elias Obeid. Differences in the benefit of multi-gene panel (MGP) genetic testing between African American and white women with invasive breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS8-16.

To better understand the etiology of inflammatory breast cancer (IBC) and identify potential therapies, we studied genomic alterations in IBC patients. Targeted, next-generation sequencing (NGS) was performed on cell-free DNA (cfDNA) (n = 33) and paired DNA from tumor tissues (n = 29) from 32 IBC patients. We confirmed complementarity between cfDNA and tumor tissue genetic profiles. We found a high incidence of germline variants in IBC patients that could be associated with an increased risk of developing the disease. Furthermore, 31% of IBC patients showed deficiencies in the homologous recombination repair (HRR) pathway (BRCA1, BRCA2, PALB2, RAD51C, ATM, BARD1) making them sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. We also characterized the tumor-infiltrating lymphocytes (TILs) in tumor tissue biopsies by studying several markers (CD4, CD8, FoxP3, CD20, PD-1, and PD-L1) through immunohistochemistry (IHC) staining. In 7 of 24 (29%) patients, tumor biopsies were positive for PD-L1 and PD-1 expression on TILs, making them sensitive to PD-1/PD-L1 blocking therapies. Our results provide a rationale for considering PARP inhibitors and PD-1/PDL1 blocking immunotherapy in qualifying IBC patients.

Recent studies show that the prevalence of germline pathogenic and likely pathogenic variants (also known as mutations) in DNA repair genes in metastatic prostate cancer is higher than previously recognized and higher than in unaffected men. Specific gene dysfunction is important in prostate cancer initiation and/or evolution to metastases. This article reviews key literature on individual genes, recognizing BRCA2 as the gene most commonly altered in the metastatic setting. This article discusses the importance of representative and diverse inclusion, and efforts to advance management for at-risk carrier populations to maximize clinical benefit.

Purpose Multigene panels are commercially available for the evaluation of prostate cancer (PCA) predisposition, which necessitates tailored genetic counseling (GC) for men. Here we describe emerging results of Genetic Evaluation of Men, prospective multigene testing study in PCA to inform personalized genetic counseling, with emerging implications for referrals, cancer screening, and precision therapy. Patients and Methods Eligibility criteria for men affected by or at high risk for PCA encompass age, race, family history (FH), and PCA stage/grade. Detailed demographic, clinical, and FH data were obtained from participants and medical records. Multigene testing was conducted after GC. Mutation rates were summarized by eligibility criteria and compared across FH data. The 95% CI of mutation prevalence was constructed by using Poisson distribution. Results Of 200 men enrolled, 62.5% had PCA. Eleven (5.5%; 95% CI, 3.0% to 9.9%) had mutations; 63.6% of mutations were in DNA repair genes. FH of breast cancer was significantly associated with mutation status ( P = .004), and FH that met criteria for hereditary breast and ovarian cancer syndrome was significantly associated with PCA (odds ratio, 2.33; 95% CI, 1.05 to 5.18). Variants of uncertain significance were reported in 70 men (35.0%). Among mutation carriers, 45.5% had personal/FH concordant with the gene. A tailored GC model was developed based on emerging findings. Conclusion Multigene testing for PCA identifies mutations mostly in DNA repair genes, with implications for precision therapy. The study highlights the importance of comprehensive genetic evaluation for PCA beyond metastatic disease, including early-stage disease with strong FH. Detailed FH is important for referrals of men for genetic evaluation. The results inform precision GC and cancer screening for men and their male and female blood relatives.

Purpose: To define the prevalence of HER2 positive breast cancer (HER2+ BC) in women with gBRCA1/2-BC and to determine whether there are significant differences in the prevalence of HER2 positivity in BRCA1 mutation carriers compared to BRCA2 mutation carriers. Background: It is estimated that 5-10% of patients with breast cancer have a BRCA1 or BRCA2 mutation. Two poly ADP ribose polymerase inhibitors (PARPi) have been approved for metastatic HER2-negative gBRCA1/2-BC, as trials excluded those with HER2+ BC and gBRCA1/2 mutations. Most often, breast tumors in BRCA1 carriers lack the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 receptor or gene amplification (HER2). BRCA2 tumors have similar rates of ER positivity as sporadic controls, but are less likely to be HER2+. The prevalence of HER2 positivity among BRCA1 and BRCA2 mutation carriers has been variably reported in the literature. The prevalence of HER2 positivity has generally been reported as lower among BRCA1 carriers than BRCA2 carriers. The prevalence of HER2 positivity in BRCA1 carriers and BRCA2 carriers has ranged from 0-10% and 0-13% respectively. The true prevalence of HER2+ breast cancer in gBRCA1/2-BC remains poorly defined. Methods: In this study, we assessed the prevalence of HER2 positivity among a cohort of 137 BRCA1 and BRCA2 mutation carriers who consented for participation in a single institution risk assessment program registry between 2009 and 2019. To be eligible for this study, participants had to have a documented diagnosis of invasive breast cancer and be a confirmed BRCA1 or BRCA2 mutation carrier. Participants with all stages of invasive breast cancer were included. Fisher’s exact tests and univariate logistic regression were used to analyze differences between BRCA1 and BRCA2 mutation carriers. Results: 69 BRCA1 mutation carriers and 68 BRCA2 carriers were included in the study. Only 38 BRCA1 mutation carriers and 41 BRCA2 mutation carriers had complete HER2 data and were included in this analysis for prevalence. 12.6 % (10/79) of the study participants had HER2+ invasive breast cancer; 3 of these participants were BRCA1 carriers and 7 were BRCA2 carriers. The prevalence of HER2 positivity in BRCA1 carriers was 7.9%. The prevalence of HER2 positivity among BRCA2 carriers was 17.0% (7/41). In this small sample, the prevalence of HER2 positivity in BRCA 2 mutation carriers was numerically higher than that in BRCA1 mutation carriers, although this difference was not statistically significant (p= 0.3145). Conclusion: In this analysis, the rates of HER2 positivity among BRCA1 mutation carriers are consistent with the range of rates previously reported (0-10%). However, the rates of HER2 positivity in BRCA2 mutation carriers (17.0%) are higher than those previously reported (0-13%). This study included participants who received breast cancer treatment at our institution where their HER2 status was verified with a pathology report, but also participants who received their breast cancer treatment at outside institutions. In the latter, HER2 status most often was obtained by verbal self-reporting. It is possible that this led to over-reporting of positive HER2 status in either BRCA1 or BRCA2 mutation carriers. Thus, estimates of HER2 positivity might be slightly overestimated. Despite some variation in HER2 positivity rates among BRCA1 and BRCA2 mutation carriers, this study demonstrates that HER2 positive breast cancers may not be as rare in gBRCA1/2-BC as previously reported in initial studies (0-3% in either BRCA1 or BRCA2 carriers). Given that BRCA1/2 mutation carriers could potentially derive therapeutic benefit from drugs, such as PARPi, it is important that future studies include gBRCA1/2-BC with HER2 positive breast cancer. Citation Format: Kristen Whitaker, Elias Obeid, Lori Goldstein, Mary Daly. Prevalence of HER2 positivity in germline BRCA 1/2-associated breast cancers (gBRCA1/2-BC) [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 P6-08-21.

Characterization of breast cancer phenotypes has improved our ability to predict breast cancer behavior. Triple-negative (TN) breast cancers have higher and earlier rates of distant events. It has been suggested that this behavior necessitates treating TNs faster than others, including use of neoadjuvant chemotherapy (NACT) if time to surgery is not rapid.A review of women diagnosed with non-inflammatory, invasive breast cancer was conducted using the National Cancer Database for patients not having NACT, diagnosed between 2010 and 2014. Changes in overall survival due to delay were measured by phenotype.Overall, 351,087 patients met the inclusion criteria, including 36,505 (10.4%) TNs, 77.9% hormone receptor-positive (HR+) and 11.7% human epidermal growth factor receptor 2 (HER2)-enriched (HER2+). Phenotype, among other factors, was predictive of treatment delays. Adjusted median days from diagnosis to surgery and chemotherapy were 29.9, 31.6 and 31.5 (p 0.001), and 72.7, 78.0 and 74.4 (p 0.001) for TNs, HR+ and HER2+ cancers, respectively. After diagnosis, OS declined for all patients per month of preoperative delay (hazard ratio 1.104; p 0.001). In models separating or combining surgery and chemotherapy, this survival decline did not vary by breast cancer phenotype (p 0.3).Delays cause small but measurable effects overall, but the effect on survival does not differ among breast cancer phenotypes. Our data suggest that urgency between diagnosis and surgery or chemotherapy is similar for breast cancers of different subtypes. Although NACT is sometimes advocated solely to avoid treatment delays, this study does not suggest a greater surgical urgency for TNs compared with other breast cancer phenotypes.

Women who inherit a BRCA1 or BRCA2 mutation have an increased risk of breast cancer. Preliminary evidence suggests they may also have defects in bone marrow function. To test this hypothesis, we conducted a multicenter, retrospective, matched cohort study, comparing women with localized breast cancer requiring cytotoxic chemotherapy who carried an inherited BRCA1 or BRCA2 mutation to similar wild‐type patients treated between 1995 and 2017 and matched based on age, race, site, and chemotherapy regimen. The proportion who developed specific hematologic toxicities, timing of these toxicities, and patterns of blood count fluctuations over time were compared among BRCA1 carriers vs matched wild‐type patients and among BRCA2 carriers vs matched wild‐type patients. 88 BRCA1 carriers and 75 BRCA2 carriers were matched to 226 and 242 wild‐type patients, respectively. The proportions and timing of experiencing any grade or grade 3/4 cytopenias during chemotherapy were not significantly different for BRCA1 carriers or BRCA2 carriers vs matched wild‐type patients. Proportions requiring treatment modifications and time to first modification were also similar. Patterns of blood count fluctuations over time in mutation carriers mirrored those in wild‐type patients overall and by the most common regimens. Women with an inherited mutation in BRCA1 or BRCA2 experience similar frequency, severity, and timing of hematologic toxicities during curative intent breast cancer chemotherapy as matched wild‐type patients. Our findings suggest that BRCA1 or BRCA2 haploinsufficiency is sufficient for adequate bone marrow reserve in the face of short‐term repetitive hematopoietic stressors., In this multicenter, retrospective, matched cohort study, we investigated whether women with an inherited mutation in BRCA1 or BRCA2 experience more severe hematologic toxicities during curative intent chemotherapy for breast cancer than similar women without a mutation. We found that the frequency, severity, and timing of toxicities were similar in these two groups. This study is reassuring that women with an inherited mutation are able to tolerate the repetitive bone marrow stress of modern chemotherapy regimens with usual supportive care measures as well as those without a mutation.

BACKGROUND: The management of small skin-involved (SI) invasive breast cancers is controversial because, although considered “unresectable,” prior data shows that their prognosis is far better than their Stage III classification. This study was undertaken to determine how SI lesions are treated in the United States, and to discern the benefit of systemic therapy. METHODS: Patients diagnosed with stage I-III breast cancer in the National Cancer Database between 2004 and 2011 were reviewed. Treatment patterns were examined and overall survival (OS) was assessed. RESULTS: 3,485 patients had SI and 456,287 patients had non-SI breast cancers. Chemotherapy was administered to 68.5% of SI and 45.9% of non-SI tumors (p

Purpose: To establish a cohort of high-risk women undergoing intensive surveillance for breast cancer. Experimental Design: We performed dynamic contrast-enhanced MRI every 6 months in conjunction with annual mammography (MG). Eligible participants had a cumulative lifetime breast cancer risk ≥20% and/or tested positive for a pathogenic mutation in a known breast cancer susceptibility gene. Results: Between 2004 and 2016, we prospectively enrolled 295 women, including 157 mutation carriers (75 BRCA1, 61 BRCA2); participants' mean age at entry was 43.3 years. Seventeen cancers were later diagnosed: 4 ductal carcinoma in situ (DCIS) and 13 early-stage invasive breast cancers. Fifteen cancers occurred in mutation carriers (11 BRCA1, 3 BRCA2, 1 CDH1). Median size of the invasive cancers was 0.61 cm. No patients had lymph node metastasis at time of diagnosis, and no interval invasive cancers occurred. The sensitivity of biannual MRI alone was 88.2% and annual MG plus biannual MRI was 94.1%. The cancer detection rate of biannual MRI alone was 0.7% per 100 screening episodes, which is similar to the cancer detection rate of 0.7% per 100 screening episodes for annual MG plus biannual MRI. The number of recalls and biopsies needed to detect one cancer by biannual MRI were 2.8 and 1.7 in BRCA1 carriers, 12.0 and 8.0 in BRCA2 carriers, and 11.7 and 5.0 in non-BRCA1/2 carriers, respectively. Conclusions: Biannual MRI performed well for early detection of invasive breast cancer in genomically stratified high-risk women. No benefit was associated with annual MG screening plus biannual MRI screening. See related commentary by Kuhl and Schrading, p. 1693

BACKGROUND: Genetic counseling (GC) presents an opportunity to address modifiable cancer risk factors, such as obesity, which is impacted by non-adherence to physical activity (PA) guidelines. Adherence to PA guidelines has not been assessed among men undergoing GC for prostate cancer (PCA). We conducted a targeted analysis of men undergoing PCA GC to assess adherence to PA recommendations. METHODS: Using a cross-sectional design, a total of 158 men from the Genetic Evaluation of Men (GEM) study at two academic cancer centers with a diagnosis or at-risk for PCA completed a structured lifestyle survey, including questions about the number of days and intensity of PA over the past year. One-sample t-tests assessed adherence of participants to PA recommendations. Chi-square analyses compared differences in PA adherence by PCA status, aggressiveness, family history and body mass index. Logistic regression analyses identified predictors of PA adherence. RESULTS: High proportions of GEM participants were overweight (44.9%) or obese (38.0%), p = 0.002). Men with PCA engaged in less moderate (p = 0.019) and vigorous (p = 0.005) aerobic activity than men without PCA. Higher education was predictive of adherence to light (p = 0.008), moderate (p = 0.019), and vigorous (p = 0.002) intensity PA. Older age (p = 0.015) and higher education (p = 0.001) were predictive of adherence to strength-based recommendations. CONCLUSIONS: High proportions of men receiving PCA GC were overweight /obese and lacked adherence to PA recommendations. GC represents a teachable moment to address PA to reduce cancer risk and promote cancer survivorship.

BACKGROUND Genetic testing (GT) for prostate cancer (PCA) is rising, with limited insights regarding genetic counseling (GC) needs of males. Genetic Evaluation of Men (GEM) is a prospective multigene testing study for inherited PCA. Men undergoing GC were surveyed on knowledge of cancer risk and genetics (CRG) and understanding of personal GT results to identify GC needs. METHODS GEM participants with or high-risk for PCA were recruited. Pre-test GC was in-person, with video and handout, or via telehealth. Post-test disclosure was in-person, by phone, or via telehealth. Clinical and family history data were obtained from participant surveys and medical records. Participants completed measures of knowledge of CRG, literacy, and numeracy pre-test and post-test. Understanding of personal genetic results was assessed post-test. Factors associated with knowledge of CRG and understanding of personal genetic results were examined using multivariable linear regression or McNemar's test. RESULTS Among 109 men who completed pre- and post-GT surveys, multivariable analysis revealed family history meeting hereditary cancer syndrome (HCS) criteria was significantly predictive of higher baseline knowledge (P = 0.040). Of 101 men who responded definitively regarding understanding of results, 13 incorrectly reported their result (McNemar's P

Background: Recent data indicate a promising response to immune checkpoint inhibition in patients with metastatic TNBC. Ample research showed that PD-L1, a PD-1 ligand, is expressed in multiple tumor types, including TNBC, and may be a predictor of response to PD-1/PD-L1 blockade. Quantification of the stromal composition, particularly PD-1 and PD-L1 expression, continues to be controversial in its relationship to immune checkpoint inhibition in several cancer types, and it remains unclear whether PD-L1 expression is necessary to predict response. Here, we aimed to determine the distribution of PD-1 and PD-L1 in a large set of centrally ascertained specimens of TNBC. Methods: The study cohort consisted of 993 tumor samples (both primary and metastatic TNBC) analyzed for either PD-1 or PD-L1 expression in one laboratory (Caris Life Sciences; Phoenix, AZ). Estrogen receptor and progesterone receptor status was assessed by immunohistochemistry (IHC). HER2/Neu expression or amplification was assessed by either IHC or in-situ hybridization. PD-1 and PD-L1 expression were confirmed using IHC with validated antibodies. For PD-L1, clone SP142 (Roche Diagnostics) was utilized and a sample was considered positive if there was > 5% membranous staining of tumor cells. For PD-1, clone EH21.1 (BD Biosciences) was used. Tumor infiltrating lymphocytes (TILs) expressing PD-1 were counted and a sample was considered positive if there was at least one PD-1 positive TIL per 40x microscopic field. Results: The median age in this cohort was 56 years (range: 22 – 88). A total of 363 TNBC specimens were tested for PD-1 via IHC. One hundred fifty eight (158; 43.5%) were negative for PD-1 expression. Two hundred five (205; 56.5%) were positive for PD-1. Of those that were PD-1 positive, 116 (56.6%), were in samples from a primary site (breast) and 89 (43.4%) in samples from a metastatic site. A total of 630 TNBC specimens were tested for PD-L1 via IHC. Five hundred seventy four (574; 91.1%) were negative for PD-L1. Fifty-six (56; 8.9%) were positive for PD-L1. Of those that were PD-L1 positive, were equally distributed between primary site and metastatic sites (28/324, and 28/306, respectively). Conclusion: In this retrospective analysis, we describe, to the best of our knowledge, the distribution of PD-1 and PD-L1 expression in one of the largest datasets reported in TNBC. Unlike prior reports showing a high PDL-1 expression in excess of 50% in TNBC, this analysis show a low distribution of PD-L1 positivity. Our cohort represents a biased sample as those were unselected patients with recurrent breast cancer. Additionally, other factors can be implicated, including a change in the antibody used. These findings call for future standardization of the PD-L1 assay, particularly if further exploration showed PD-L1 to be a predictive or prognostic biomarker in mTNBC, particularly in relationship to therapy with immune checkpoint blockade. Citation Format: Baker TM, Gatalica Z, Goldstein LJ, Obeid E. Programmed death 1 (PD-1) and PD-1 ligand (PD-L1) distribution in triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-05-09.

Background/Objective Delays in times to surgery, chemotherapy, and radiotherapy impair survival in breast cancer patients. Neoadjuvant chemotherapy (NAC) confers equivalent survival to adjuvant chemotherapy (AC), but it remains unknown which approach facilitates faster initiation and completion of treatment. Methods Women ≥18 years old with nonrecurrent, noninflammatory, clinical stage I‐III breast cancer diagnosed between 2004 and 2015 who underwent both surgery and chemotherapy were reviewed from the National Cancer Database. Results Among 155 606 women overall, 28 241 patients received NAC and 127 365 patients received AC. NAC patients had higher clinical T and N stages (35.8% T3/4 vs 4.9% T3/4; 14.4% N2/3 vs 3.7% N2/3). After adjusting for stage and other factors, NAC patients had longer times to begin treatment (36.1 vs 35.4 days adjusted, P = .15), and took significantly longer to start radiotherapy (240.8 vs 218.2 days adjusted, P, This study evaluated the time to initiation and completion of treatment in breast cancer patients undergoing neoadjuvant chemotherapy (NAC) vs adjuvant chemotherapy. We found that NAC did not expedite the start or completion of treatment.

BACKGROUND: Genetic counseling (GC) and genetic testing (GT) for prostate cancer (PCA) is a rapidly growing, affording opportunity for healthy lifestyle promotion in men aligned with cancer survivorship and cancer prevention goals. We conducted a targeted dietary analysis of men undergoing GC/GT for PCA for adherence to the United States Department of Agriculture (USDA) Food Pattern recommendations which align with preventing cancer and recurrences in the Genetic Evaluation of Men (GEM) study at two academic centers to inform future strategies for diet intervention. METHODS: Participants of GEM with PCA or at-risk for PCA completed a structured food frequency questionnaire indicating number of servings consumed per day or per week of fruits, vegetables, red meat, seafood, processed meat, and foods high in saturated fat. Adherence to the USDA recommendations was assessed for the total sample and by PCA status and aggressiveness, family history, and body mass index (BMI) through χ 2 contingency analyses. One-sample t tests were used to compare the dietary behaviors of men to USDA Recommendations. Levels of α were set a priori at P

e13063 Background: The median age at diagnosis of breast cancer is 62 with 45% of patients over the age of 65. At diagnosis, up to 5% of patients will have metastatic breast cancer (MBC) and up to 30% of patients with early-stage disease will develop MBC. There are no clear guidelines on how to treat older adults with MBC (OA-MBC) due to their poor representation in clinical trials. This lack of recommendations can often lead to under treatment of OA-MBC. This study evaluated the self-reported treatment patterns of practitioners in community practices for OA-MBC and evaluated the actual treatment their OA-MBC patients received. Methods: This is a secondary analysis of a multi-phase trial which initially evaluated the gaps in practice patterns that exist in the assessment and management of OA-MBC and did a prospective comparison between the older patient’s geriatric assessment and provider’s clinical assessment. In this analysis we focused on the practice patterns in the community. Physicians completed questionnaires detailing their front-line treatment choices for each subcategory of MBC in women over the age of 65. Data was then collected on patients in these physicians’ practices including their current line of treatment, treatment regimen, comorbidities, performance status and demographics. The appropriateness of treatment choice was then evaluated based on MBC subcategory and line of treatment using the NCCN guidelines for breast cancer. Patient and physician characteristics and treatment choices were summarized using descriptive statistics. Results: 44 providers from 9 community practices located in PA, DE, NJ, MT, and WA participated. Majority of providers were Caucasian (57%) and had been in practice for >11 years (53%). 100 patients were evaluated from these practices between December 2016 – April 2019. Median age 73 (65-90). In response to front-line therapy choices, 27/44 (61%) providers selected endocrine only therapy for HR+ but in practice, 29/37 (78%) of HR+ patients were treated with combination endocrine & CDK 4/6 inhibitors. For HER2+, 20/44 (45%) providers selected trastuzumab + chemotherapy for front-line therapy and in practice 8/8 (100%) of patients received this combination. For TNBC, 37/44 (84%) providers agreed with sequential single agent chemotherapy over combination and in practice 6/7 (86%) patients received this. Including all lines of therapy, 84/100 patients were treated in accordance with NCCN guidelines. Conclusions: Despite the lack of older adult guidelines, our community-based practitioners are treating the majority of their OA-MBC patients appropriately and in accordance with NCCN guidelines. In our cohort of OA-MBC there was no evidence of under treatment, however, due to the lack of sufficient data in this patient population it is not clear that this approach is beneficial. Additional research is needed to refine the treatment approach of this unique patient population.

Obstetrician/gynecologists and gynecologic oncologists serve an integral role in the care of women at increased hereditary risk of cancer. Their contribution includes initial identification of high risk patients, screening procedures like bimanual exam, trans-vaginal ultrasound and endometrial biopsy, prophylaxis via TAH and/or BSO, and chemoprevention. Further, gynecologists also serve a central role in the management of the secondary repercussions of efforts to mitigate increased cancer risks, including vasomotor symptoms, sexual function, bone health, cardiovascular disease, and mental health. The past several years has seen multiple new high and moderate penetrance genes introduced into the clinical care of women at increased risk of gynecologic malignancy. Awareness of these new genes and the availability of new multi-gene panel tests is critical for providers on the front-line of women's health.

Background: Quadruple-negative breast cancer (QNBC) is a subgroup of triple-negative breast cancer (TNBC) that lacks androgen receptor (AR) expression. While TNBC patients with AR expression have shown a promising response to AR-targeted therapies, QNBC patients' treatment options remain limited, with no targeted therapy We investigated the biomarker profiles of large cohorts of AR+TNBC and QNBC to identify their molecular differences. Method: TNBC tumors (defined as negative by IHC for ER, PR, Her2 and ISH for Her2) referred to Caris Life Sciences (Phoenix, AZ) between 2009 and 2015 were evaluated by board-certified pathologists with a combination of immunohistochemistry (AR, cKIT, cMET, EGFR, ER, ERCC1, Her2, MGMT, PD-1, PD-L1, PGP, PR, PTEN, RRM1, SPARC, TLE3, TOPO2A, TOPO1, TS and TUBB3), fluorescent/chromogenic in-situ hybridization (cMET, EGFR, Her2, TOP2A), and sequencing (Next-generation and Sanger). Tumors evaluated included a mix of primary tumors and metastases. QNBC tumors were defined as TNBC tumors that showed negative AR expression ( Results: Among 2,071 TNBC tumors identified, 1,952 tumors had AR IHC performed, out of which 1,612 (83%) were QNBC and 340 (17%) were AR+ TNBC tumors. Tumor expression of PD-L1 (Ab: SP142, Spring Bioscience/130021, R&D Systems, cutoff used: 2+, 5%) was significantly higher in QNBC compared to AR+TNBC tumors (18% vs. 8%, p=0.01), while PD-1 (Ab: NAT105, Ventana) expression on tumor-infiltrating lymphocytes was comparable between the two cohorts (60% vs. 62%). QNBC tumors were significantly more likely to express proteins of cKIT (26% vs. 15%, p=0.01), EGFR (69% vs. 56%, p=0.03), TS (49% vs. 33%, p Conclusion: Biomarker comparisons between two molecular subgroups of the TNBC tumors confirm the molecular heterogeneity of this aggressive type of breast cancer. Our biomarker results suggests that for AR+TNBC tumors, future clinical trial design can consider fluoropyrimidines, taxanes, and agents targeting PI3K/AKT/mTOR pathway as well as pan-HER inhibitors, and those agents may be combined with anti-androgen therapies. On the other hand, clinical trials for immune checkpoint inhibitors, TOP2A inhibitors, as well as agents that target cKIT and EGFR should be considered for QNBC tumors. Our findings highlight the molecular differences that should be considered in the design of future clinical trial strategies, warranting further investigation for improving targeted therapy and outcomes in TNBC. Citation Format: Xiu J, Obeid E, Gatalica Z, Reddy S, Goldstein LJ, Link J, Waisman J. Biomarker comparison between androgen receptor – Positive-triple-negative breast cancer (AR+ TNBC) and quadruple-negative breast cancer (QNBC). [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 P3-07-26.

Background: Triple-negative breast cancer (TNBC) is one type of breast cancer that remains challenging because of its aggressive nature and the lack of effective targeted therapy for it. Molecular profiling has revealed different subtypes, indicating a potential for promising targeted therapy such as androgen blockade and PARP inhibition in some TNBCs. The purpose of this study is to identify differences in BRCA1/2 mutated and non-mutated TNBC to shed light on potential therapeutic options in both subtypes, utilizing a multiplatform approach. Methods: A cohort of 386 triple-negative breast cancer specimens were tested via a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ) consisting of gene sequencing (next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]) and gene amplification (fluorescence or chromogenic in situ hybridization [FISH or CISH]). Primary and metastatic specimens were evaluated. Tumor specimens with any BRCA1 and/or BRCA2 mutation (i.e. pathogenic or variant of unknown significance) were categorized as "BRCA1/2-mutated", while all others were considered "BRCA1/2 non-mutated". Results: In our cohort, 16.3% (63/386) of specimens were BRCA1/2-mutated while 83.7% (323/386) had no BRCA1/2 alteration detected. Amongst the highest rates of protein expression in BRCA1/2-mutated and non-mutated specimens were biomarkers like TOPO1 (63.5% and 63.4%), EGFR (65.2% and 67.4%), and the immune checkpoint biomarker, PD-1 (65.1% and 61.9%), with non-statistically significant differences. Differences noted between BRCA1/2-mutated and non-mutated specimens were detected by IHC in AR (11.1% versus 22.0%, p=0.0585) and PTEN (47.6% versus 59.6%, p=0.0941), with both trending but not achieving statistical significance. The highest overall mutation rate in both BRCA1/2-mutated and non-mutated were TP53 (80.6% and 73.1%, p=0.2659). Differences were also noted between BRCA1/2-mutated and non-mutated specimens by NGS in APC (6.3% versus 1.9%, p = 0.0644) and PIK3CA (11.1% versus 25.8%, p = 0.0137), with PIK3CA being statistically significant. Conclusion: Multiplatform tumor profiling identified differences in molecular profiles between BRCA1/2 mutated and BRCA1/2 non-mutated TNBC. Our findings raise the possibility for future investigation of potential combination therapeutic targeted therapy. Increased AR overexpression in BRCA1/2 non-mutated specimens is consistent with reports from other institutions. Further studies utilizing tumor profiling to elucidate the biological differences in in TNBC subtypes are warranted, to optimally include patients on clinical trials with specific targeted therapy and possibly improve treatment options. Citation Format: Arguello D, Abbott B, Reddy S, Gatalica Z, Obeid E, Goldstein L. Molecular profiling comparison of BRCA1/2-mutated and BRCA1/2 non-mutated triple-negative breast cancer (TNBC). [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 P3-07-30.

IntroductionNeighborhood socioeconomic (nSES) factors have been implicated in prostate cancer (PCa) disparities. In line with the Precision Medicine Initiative that suggests clinical and socioenvironmental factors can impact PCa outcomes, we determined whether nSES variables are associated with time to PCa diagnosis and could inform PCa clinical risk assessment.Materials and methodsThe study sample included 358 high risk men (PCa family history and/or Black race), aged 35-69 years, enrolled in an early detection program. Patient variables were linked to 78 nSES variables (employment, income, etc.) from previous literature via geocoding. Patient-level models, including baseline age, prostate specific antigen (PSA), digital rectal exam, as well as combined models (patient plus nSES variables) by race/PCa family history subgroups were built after variable reduction methods using Cox regression and LASSO machine-learning. Model fit of patient and combined models (AIC) were compared; p-valuesResultsIn combined models, nSES variables were significantly associated with time to PCa diagnosis. Workers mode of transportation and low income were significant in White men with a PCa family history. Homeownership (%owner-occupied houses with >3 bedrooms) and unemployment were significant in Black men with and without a PCa family history, respectively. The 5-year predicted probability of PCa was higher in men with a high neighborhood score (weighted combination of significant nSES variables) compared to a low score (e.g., Baseline PSA level of 4ng/mL for men with PCa family history: White-26.7% vs 7.7%; Black-56.2% vs 29.7%).DiscussionUtilizing neighborhood data during patient risk assessment may be useful for high risk men affected by disparities. However, future studies with larger samples and validation/replication steps are needed.

e13679 Background: The role of germline genetic testing (GGT) is rapidly changing for men with PCa. We describe the characteristics of men with PCa diagnosed with pathogenic (P) and likely pathogenic (LP) mutations on GGT. Methods: We conducted a retrospective single-institution study for all men with PCa who received single gene or multi-gene GGT from 1997-2019, unselected for disease stage, Gleason score, or age at diagnosis, and while most had a family history of cancer, some did not. All participants were from the Risk Assessment Program (RAP) database at FCCC and consented for research purposes at the time of GGT. Results: 160 men with PCa had GGT. 72/160 (45%) patients had no mutations. 41/160 (26%) patients had a variant of undetermined significance (VUS) (13 with 2 VUS, 1 with 3 VUS). 47/160 (29%) men were found to have a P or LP germline mutation. 26/47 (55%) with recurrent disease, and 1/47 (2%) unknown. 46 were Caucasian, and 1 was African American ( PALB2). 28/47 (60%) had Gleason Scores (GS) ≤7. 6/47 (13%) had a Prostate Specific Antigen (PSA) at diagnosis < 4.0 ng/mL. 23/47 (49%) were diagnosed < 60 years of age, and 8/47 (17%) at ≤ 50. 19/23 (83%) PCa cases with P/LP diagnosed below age 60 had DNA repair genes: BRCA2 (8), BRCA1 (4), CHEK2 (4), ATM (2), and PALB2 (1). 74/160 (46%) were tested after PCa NCCN genetics guidelines changed (October 2017), of which 19/74 (25%) had P/LP, and of those positive for P/LP, 6/19 (32%) had non-metastatic disease. Two patients had small cell neuroendocrine PCa ( CHEK2 and BRCA2), the remaining had adenocarcinoma PCa. Please see Table for full results. Conclusions: To our knowledge, this is the largest single-institution study reporting PCa characteristics and incidence of P/LP germline mutations. Rates of DNA-repair gene mutations were higher than previously reported, possibly reflecting our specialized cancer center’s population. While BRCA1/2 mutations were the most represented (55%), we describe PCa patients with mutations in ATM, CHEK2, NBN, PALB2, CFTR, and MUTYH, recognizing a few are not known to be linked to PCa. More than half of P/LP mutation carriers had GS ≤7. Additionally, 13% of the men with P/LP germline mutations had low PSA ( < 4.0 ng/mL) at diagnosis. Our findings highlight the importance of the new guidelines and GGT importance in some men with PCa, particularly if they could benefit from a different therapeutic approach, or be influenced into cascade GGT. [Table: see text]

360 Background: Genetic counseling (GC) and genetic testing (GT) for prostate cancer (PCA) is growing rapidly for men with or at risk for PCA. GC provides opportunities to promote a healthy lifestyle and is understudied in men. To inform future lifestyle interventions, we assessed adherence to physical activity (PA) guidelines among a sample of men undergoing PCA GC/GT at two academic institutions. Methods: Participants enrolled in the Genetic Evaluation of Men study completed a structured lifestyle questionnaire to assess frequency of PA over the past year, including intensity of aerobic activity and strength-based activities. Data were evaluated as M±SD by PCA status, PCA aggressiveness (Gleason>7, T3, or metastatic disease), family history, and body mass index (BMI) with Chi-Square contingency analyses and adjusted residuals. Demographic characteristics predictive of PA adherence with current Department of Health and Human Services and American College of Sports Medicine PA guidelines were assessed using logistic regression analyses. Alpha levels were set a priori to p

In order to better understand the etiology of inflammatory breast cancer (IBC), we performed a retrospective study to evaluate genomic alterations in 32 IBC patients using circulating DNA from blood. In 20 patients, mutation analyses were also conducted on tumor tissue or tumor cells from pleural effusions; in 15 of these patients, blood and tissue or pleural effusions were collected at the same time. Next generation sequencing (NGS) and a panel of 93 breast cancer related genes (Qiagen) were used for these studies. We found that of the 32 total patients, 11 (34.4%) carried at least one putative pathogenic germline variant, and another 8 patients (25%) carried at least one likely pathogenic germline variant. Ten patients (31.3%) carried only germline variants of uncertain significance and in 3 patients (9.4%) germline variants were not detected. Putative germline pathogenic variants were observed in the BRCA2 (2/32), TP53 (2/32), BRCA1 (1/32), PALB2 (1/32), CHEK2 (1/32), ATM (1/32), PMS1 (1/32), MUTYH (1/32), and MSH2 (1/32) genes. In addition, putative germline likely pathogenic variants were observed in the BARD1 (10/32), RB1 (2/32), APC (1/32), FANCC (1/32), AR (1/32), RAD51C (1/32), RAD51D (1/32) and CASP8 (1/32) genes. Most of the patients in our study had a family history of cancer and seventeen of the patients (53.1%) had family history of breast cancer in particular. Of those patients, 7 had a family history of breast cancer at a young age ( Citation Format: Jennifer S. Winn, Zachary Hasse, Jianming Pei, Michael Slifker, Sebastian M. Arisi-Fernandez, Jacqueline N. Talarchek, Elias Obeid, Karthik Devarajan, Hong Wu, Yulan Gong, Massimo Cristofanilli, R.Katherine Alpaugh, Sandra Viviana Fernandez. Germline and somatic variants in patients with inflammatory breast cancer (IBC) detected using cell-free DNA [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 P5-03-11.

We studied genomic alterations in 19 inflammatory breast cancer (IBC) patients with advanced disease using samples of tissue and paired blood serum or plasma (cell-free DNA, cfDNA) by targeted next generation sequencing (NGS). At diagnosis, the disease was triple negative (TN) in eleven patients (57.8%), ER+ Her2- IBC in six patients (31.6%), ER+ Her2+ IBC in one patient (5.3%), and ER- Her2+ IBC in one other patient (5.3%). Pathogenic or likely pathogenic variants were frequently detected in TP53 (47.3%), PMS2 (26.3%), MRE11 (26.3%), RB1 (10.5%), BRCA1 (10.5%), PTEN (10.5%) and AR (10.5%), other affected genes included PMS1, KMT2C, BRCA2, PALB2, MUTYH, MEN1, MSH2, CHEK2, NCOR1, PIK3CA, ESR1 and MAP2K4. In 15 of the 19 patients in which tissue and paired blood were collected at the same time point, 80% of the variants detected in tissue were also detected in the paired cfDNA. Higher concordance between tissue and cfDNA was found for variants with higher allele fraction in tissue (AFtissue &ge, 5%). Furthermore, 86% of the variants detected in cfDNA were also detected in paired tissue. Our study suggests that the genetic profile measured in blood cfDNA is complementary to that of tumor tissue in IBC patients.

Background: BC and CRC are heterogeneous diseases with several distinct disease subtypes. A 50-gene qPCR assay (PAM50) identifies 5 intrinsic biological subtypes: luminal A, luminal B, HER2-enriched, basal-like, and normal-like in breast cancer. Consensus molecular subtype in CRC (CMS) identifies 4 subtypes: CMS1-4. PC can be classified by specific genomic rearrangements, such as the TMPRSS2-ERG fusion occur or whether specific mutations such as SPOP and FOXA1 or germline BRCA is present, yet 25% of PC remains difficult to classify based on molecular drivers. We used comprehensive genomic and transcriptomic data to determine the association of somatic and germline mutations in molecular PC subtypes using the CMS and 50-gene breast cancer classifiers. Methods: Retrospective analysis on Whole exome (WES) DNA tumor and paired germline and matched deep whole transcriptomic sequencing (RNA-Seq) (∼200x106reads per tumor) data from NantHealth was performed. BC Intrinsic Subtypes and CMS sorting based on RNAseq assay was used to classify PC into 5 BC subtypes and CMS 1-4. Results: 90 PC patients were classifiable using RNAseq and WES DNA. BC subtype distribution was 64.4% Luminal A, 31.1% Luminal B, 2.2% HER2-enriched, 2.2% normal-like, and 0 classified as Basal-like. The CMS subtype distribution was 83.3% CMS4, 15.6% CM1, 1.1% CMS3, and 0 CMS2. Overlap comparison revealed that almost all LumA are CMS4 (56/58, 96.6%) and CMS1 are LumB (11/14, 78.6%). Analysis of germline DDR mutations in LumB compared to LumA showed LumB has significantly more DDR mutants than LumA (OR 2.68, p = 0.035 one-sided Fishers exact test). Conclusions: PC molecularly profiled using 50-gene and CMS classification we found LumA subtype as the predominant subgroup characterized by low TMB and high CMS4. LumB was characterized as higher TMB and greater CMS1 suggesting potential immunotherapy eligibility in this subtype. The presence of potentially pathogenic germline variants in DDR genes is associated with subsequent somatic increase in TMB, however, somatic expression subtyping (by BC or CRC types) is a stronger indicator of TMB than germline pPV in DDR genes. Citation Format: Jacob J Adashek, Sumanta K Pal, Saihitha Veerapaneni, Elias Obeid, Christopher W Szeto, Sandeep K Reddy, Roberto Nussenzveig, Neeraj Agarwal. 50 gene breast cancer (BC) RNA subtype classifier and colorectal cancer (CRC) CMS subtype classifier applied to 90 prostate cancer (PC) patients reveals distinct subtype differences [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B093. doi:10.1158/1535-7163.TARG-19-B093

Background/aim African Americans (AA) have the highest incidence and mortality of any racial/ethnic group in the US for most cancer types. Heterogeneity in the molecular biology of cancer, as a contributing factor to this disparity, is poorly understood. To address this gap in knowledge, we explored the molecular landscape of colorectal cancer (CRC), non-small cell lung cancer (NSCLC) and high-grade glioma (HGG) from 271 AA and 636 Caucasian (CC) cases. Materials and methods DNA from formalin-fixed paraffin-embedded tumors was sequenced using next-generation sequencing. Additionally, we evaluated protein expression using immunohistochemistry. The Exome Aggregation Consortium Database was evaluated for known ethnicity associations. Results Considering only pathogenic or presumed pathogenic mutations, as determined by the American College of Medical Genetics and Genomics guidelines, and using Bonferroni and Benjamini-Hochberg corrections for multiple comparisons, we found that CRC tumors from AA patients harbored significantly more mutations of phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) than those from CC patients. CRC tumors in AA patients also appeared to harbor more mutations of mitogen-activated protein kinase kinase 1 (MAP2K1/MEK1), MPL proto-oncogene (MPL), thrombo-poietin receptor, and neurofibromin 1 (NF1) than those from CC patients. In contrast, CRCs from AA patients were likely to carry fewer mutations of ataxia-telangiectasia mutated (ATM), as well as of proto-oncogene B-Raf (BRAF), including the V600E variant, than those from CC patients. Rates of immunohistochemical positivity for epidermal growth factor receptor (EGFR) and DNA topoisomerase 2-alpha (TOP2A) tended to be higher in CRCs from AA patients than in CC patients. In NSCLC adenocarcinoma, BRAF variants appeared to be more frequent in the AA than in the CC cohort, whereas in squamous cell lung carcinoma, programmed death-ligand 1 (PD-L1) expression tended to be lower in the AA than in CC group. Moreover, HGG tumors from AA patients showed a trend toward harboring more mutations of protein tyrosine phosphatase non-receptor 11 (PTPN11), than HGG tumors from the CC cohort. In contrast, mutations of phosphatase and tensin homolog (PTEN) and tumor protein 53 (TP53) appeared to be higher in HGG tumors in CC patients than in their AA counterparts. Conclusion Our data revealed significant differences and trends in molecular signatures of the three cancer types in AA and CC cohorts. These findings imply that there may be differences in carcinogenesis between AA and CC patients and that race may be a factor that should be considered regarding cancer incidence and outcome.

Purpose Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-driven working framework for comprehensive genetic evaluation of inherited PCA in the multigene testing era addressing genetic counseling, testing, and genetically informed management. Methods An expert consensus conference was convened including key stakeholders to address genetic counseling and testing, PCA screening, and management informed by evidence review. Results Consensus was strong that patients should engage in shared decision making for genetic testing. There was strong consensus to test HOXB13 for suspected hereditary PCA, BRCA1/2 for suspected hereditary breast and ovarian cancer, and DNA mismatch repair genes for suspected Lynch syndrome. There was strong consensus to factor BRCA2 mutations into PCA screening discussions. BRCA2 achieved moderate consensus for factoring into early-stage management discussion, with stronger consensus in high-risk/advanced and metastatic setting. Agreement was moderate to test all men with metastatic castration-resistant PCA, regardless of family history, with stronger agreement to test BRCA1/2 and moderate agreement to test ATM to inform prognosis and targeted therapy. Conclusion To our knowledge, this is the first comprehensive, multidisciplinary consensus statement to address a genetic evaluation framework for inherited PCA in the multigene testing era. Future research should focus on developing a working definition of familial PCA for clinical genetic testing, expanding understanding of genetic contribution to aggressive PCA, exploring clinical use of genetic testing for PCA management, genetic testing of African American males, and addressing the value framework of genetic evaluation and testing men at risk for PCA—a clinically heterogeneous disease.

Background Randomized data examining adjuvant radiation therapy (RT) alone in elderly women with low-risk, hormone receptor-positive (HR + ) breast cancer is lacking. We investigated the outcomes for elderly women treated with adjuvant RT alone versus RT plus endocrine therapy (ET) after breast-conserving surgery. Patients and Methods We queried our institutional breast cancer database for the following patients: age > 65 years, stage T1-T2N0, HR + , and treatment with breast-conserving surgery, including adjuvant RT. The χ 2 analysis identified significant baseline differences between the groups. Cox proportional hazard methods identified predictors of endpoints on multivariate analysis. Kaplan-Meier estimates of survival were compared using the log-rank test. Results A total of 504 patients were identified, 311 had undergone RT plus ET (62%) and 193, RT alone (38%). The median follow-up time was 88 months. The RT-alone group versus RT plus ET group had different median age (72 vs.71 years, P P P = .05), and fewer close or positive margins (11% vs. 19%, P = .01). The adherence rate to prescribed ET was 70%. Tumor size predicted an increased risk of distant metastasis (DM) (hazard ratio, 1.96; 95% confidence interval [CI], 1.23-3.13) and worse disease-free survival (DFS) (hazard ratio, 1.86; 95% CI, 1.22-2.86). ET nonadherence versus adherence predicted for risk of DM (hazard ratio, 5.03; 95% CI, 1.98-12.66) and DFS (HR, 4.24; 95% CI, 1.9-10.3). Of the women with DM, 83.8% had tumors > 1 cm in size. Conclusion ET nonadherence and tumor size > 1 cm predicted an increased risk of DM and worse DFS, favoring the addition of ET in this group. However, RT alone for women with tumors less than or equal to 1 cm may be appropriate.

Despite conflicting guidelines, a significant subset of high-risk men decide to undergo routine prostate cancer screening. Yet, there is a scarcity of available programs, and no studies evaluating interventions to support men in dealing with the psychosocial impact of screening. In this study, one of the first to explore the responses of high-risk men enrolling in a Prostate Cancer Risk Assessment Program ( N = 128), patients underwent a prostate cancer risk counseling visit immediately followed by either a cognitive–affective preparation session designed to help them process the information they received or a general health education session. All men in this self-selected sample chose to participate in prostate cancer screening. Men were assessed 3 weeks and 6 months post-counseling. The impact of the enhanced counseling condition on knowledge, perceived risk, expectancies, and intrusive ideation was a function of racial and coping style group. Implications for tailored interventions to maximize preparedness for risk and screening counseling are discussed.

Background: Breast cancer (BC) is a heterogeneous disease. It is estimated that 5 to 10% of all BC to have a germline genetic predisposition. A 50-gene assay (PAM50) identifies 5 intrinsic molecular subtypes (IMS): Luminal A, Luminal B, HER2-enriched, Basal-like, and Normal-like. Basal-like breast cancers are enriched for BRCA1/2 germline mutations. Deleterious mutations in BRCA1/2 or other DNA-damage repair (DDR) genes may increase tumor mutational burden (TMB), a biomarker for response to checkpoint inhibition therapy. We sought to determine the spectrum of germline mutations in molecular BC subtypes (IMS), and their relation to somatic TMB. Methods: We performed a retrospective analysis of data from NantHealth database. RNAseq was used to classify breast tumors into IMS. Germline variants within putative driver genes (COSMIC v.76) were detected in analysis of 181 whole-genomes and 89 whole-exomes sequenced using Illumina chemistry. Classification of germline variants into potentially pathogenic variants (pPv) was determined using ClinVar database annotation. Patients were categorized as TMB-high by thresholding on >200 non-synonymous exonic somatic mutations as was previously reported. Results: A total of 270 BC patients with comprehensive omics profiling (germline DNAseq, somatic DNAseq, and somatic RNAseq) were available for this analysis. The mean age (±SD) was 56.4 (± 12.5) years (range 20.8-86.5). Forty-six patients (17.0%) were classified TMB-high. The IMS distribution was 40.7% Luminal A, 31.5% Luminal B, 5.9% HER2-enriched, 21.5% Basal-like, and 0.37% Normal-like. Over 200 unique germline variants were detected of which 98 were pPv according to ClinVar annotation. These pPv spanned 21 genes, 7 of which are directly related to DDR. One hundred and four patients had ≥1 pPv (78 had only 1 pPv, and 26 had >1 pPv). The most common pPv were APC (5.9%), BRCA2 (5.2%), TSC2 (4.4%), BRCA1 (3.7%), SDHB (3.3%), SDHD (3.3%), TSC1 (3.0%), PMS2 (3.0%), MUTYH (2.6%), MSH2 (1.5%) and MSH6 (1.5%). BRCA1 and especially BRCA2 pPv were mostly seen in the basal-like patients. Luminal B had distinctly more germline pPv in PMS2, BRCA1 & BRCA2 than Luminal A. TMB-high patients were not significantly enriched for germline pPv (OR 0.73, p=0.41), even when limited to pPv in DDR genes (OR 0.69, p=0.52). TMB-high patients were present in all 4 major IMS types; Her2-enriched 37.5%, Luminal B 23.5%, Basal-like 17.2%, and Luminal A 9.1%. Conclusion: We identified differential distribution of germline pPv in BC IMS. Of the pPv found, APC was the most commonly detected pPv across subtypes, while BRCA1/2 pPv were clustered in Basal-like subtype, and PMS2 in Luminal B subtype. 17% of all patients had a pPv within at least one DDR gene, that potentially may benefit from targeted therapy. Despite IMS types having distinct germline pPv profiles especially in DDR genes, there was no association with subsequent somatic TMB. This suggests that either 1. somatic events are the primary drivers of TMB, or 2. that germline variants with either unknown or benign significance need to be revisited. Future analysis in a larger demographically well-annotated dataset (commercial data, ExAC, other) or via functional studies should be considered. Citation Format: Obeid E, Reddy SB, Goldstein LJ, Daly MB, Benz SC, Hall MJ, Szeto C. Germline potentially pathogenic variants in breast cancer intrinsic molecular subtypes are not associated with somatic TMB [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-03-03.

Up to 40% of breast cancers have been shown to express the glucocorticoid receptor (GR), and activation of the GR is associated with poor prognosis in ER-negative breast cancer. We hypothesize that GR activation in breast cancer cells initiates anti-apoptotic signaling contributing to chemotherapy resistance. Based on our compelling preclinical data demonstrating that GR antagonism with mifepristone (mif) increases paclitaxel (pac) induced breast cancer cell death in vitro and in vivo, we conducted the first clinical trial of the combination of anti-GR therapy and chemotherapy in patients (pts) with metastatic breast cancer (MBC). Because the combination of mif and nab-paclitaxel (nab) had not previously been administered to pts, and because nab can result in cumulative neurotoxicity, a randomized, placebo-controlled, phase I design was used. Mif is known to inhibit CYP2C8, an enzyme involved in the metabolism of pac, thus plasma pac levels were monitored to evaluate for significant changes in clearance. A 3+3 dose escalation scheme was planned, with an initial nab dose of 100mg/m2 weekly and a mif dose of 300 mg/d for 2 days (day prior to and of nab infusion). For each dose level (DL), patients were randomized 3:2 to mif:placebo (p) for cycle 1 (C1). After C1, pts randomized to p were crossed over to receive mif at their assigned DL for the duration of study treatment. DL1 was deemed intolerable due to neutropenia, so the nab dose was decreased to 80 mg/m2 for DL2, and dose escalation of mif beyond 300 mg was halted. Serum cortisol and ACTH levels—biomarkers of effective GR blockade—were measured before and after mif treatment. Archival tumor was collected to determine tumor GR expression, and peripheral blood lymphocytes (PBLs) were collected to evaluate GR-target gene expression after mif. 9 pts were enrolled. Median age was 56 yrs (range 47-74). Median number of prior therapies for MBC was 2 (range 0-3). 8 pts had triple-negative breast cancer (TNBC), and 1 had ER+ disease. 8 of 9 pts had recurred after taxane-based therapy. 1 pt had a CR, 4 pts a PR, and 4 pts POD. 4 of 5 pts who responded to nab plus mif had previously relapsed after taxane-based therapy. 4 pts were treated at DL1 (2 mif, 2 p). Both pts randomized to mif experienced a dose-limiting toxicity (DLT) of neutropenia during C1. 5 pts were treated at DL2 (3 mif, 2 p), and 2 of the 3 pts randomized to mif for C1 experienced a DLT (neutropenia). Plasma pac levels were consistent with delayed clearance of nab when co-administered with mif for most pts. All pts were found to have a 2-fold or greater rise in their serum cortisol levels, demonstrating effective adrenal GR inhibition. Mif delays clearance of nab in most pts, and results in DLT. Given the inter-patient variability in delay of nab clearance by mif, co-administration produces unpredictable toxicity. However, given the responses seen in taxane-pretreated TNBC pts, GR antagonism is a promising approach for treating aggressive TNBCs. As neither carboplatin nor gemcitabine are metabolized, mif is unlikely to affect clearance of these agents. As they are widely used for advanced TNBC, both agents represent attractive chemotherapy partners for future clinical investigation. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-21.

It is well established that the tumor microenvironment plays a major role in the aggressive behavior of malignant solid tumors. Among cell types associated with tumor microenvironment, tumor-associated macrophages (TAMs) are the most influential for tumor progression. Breast cancer is characterized by having a large population of TAMs, and experimental models have exposed multiple mechanisms by which TAMs interact with and influence the surrounding tumor cells. The process of metastasis involves tumor cells gaining access to the tissue outside the immediate tumor environment and invading the confining extracellular matrix (ECM). Supporting this process, TAMs secrete proangiogenic factors such as VEGF to build a network of vessels that provide nutrition for tumor cells, but also function as channels of transport into the ECM. Additionally, TAMs release factors to decrease the local pro-inflammatory antitumor response, suppressing it and providing a means of escape of the tumor cells. Similarly, hypoxia in the tumor microenvironment stimulates macrophages to further produce VEGF and suppress the T-cell immune responses, thus, enhancing the evasion of tumor cells and ultimately metastasis. Given the multiple roles of TAMS in breast cancer progression and metastasis, therapies targeting these cells are in development and demonstrate promising results.

Purpose Glucocorticoid receptor (GR) overexpression is associated with poor prognosis ER-negative breast cancer. GR antagonism with mifepristone increases chemotherapy-induced breast cancer cell death, therefore we conducted a phase I clinical trial of mifepristone and nab-paclitaxel in advanced breast cancer. Methods A novel randomized phase I design was used to assess the effect of mifepristone on nab-paclitaxel pharmacokinetics and toxicity. Patients were randomized to placebo or mifepristone for the first cycle; mifepristone was given to all for subsequent cycles. Results Nine patients were enrolled. All were found to have a twofold or greater increase in serum cortisol after mifepristone administration, reflecting effective GR inhibition. Neutropenia occurred at both nab-paclitaxel dose levels studied (100 and 80 mg/m2), and was easily managed with dose reduction and/or growth factor administration. Pharmacokinetic data suggest an interaction between nab-paclitaxel and mifepristone in some patients. Two patients had complete responses (CR), three partial responses (PR), one stable disease (SD), and three progressive disease (PD). Immunohistochemical staining for GR found six of nine tumors were GR-positive. All six GR-positive tumors were triple-negative at the time of recurrence. Of these six patients, two had CRs, two PRs, one SD, and one PD. Conclusions GR appears to be a promising target in TNBC, and GR inhibition plus chemotherapy produces manageable toxicity. While neutropenia was observed in some, a nab-paclitaxel dose of 100 mg/m2 plus mifepristone 300 mg was found to be tolerable, and a randomized phase II trial of nab-paclitaxel with/without mifepristone is planned in GR-positive advanced TNBC. Electronic supplementary material The online version of this article (doi:10.1186/s40064-016-2457-1) contains supplementary material, which is available to authorized users.

Background: ESR1 mutations and fusions arise in hormone receptor positive (ER+ and/or PR+) breast cancer (HR+ BC) patients after aromatase inhibitor (AI) therapy (low estrogen states), to become constitutively active in a ligand-independent manner. Patients with ESR1 mutations exhibit worse prognosis and outcome with no particular benefit of chemotherapy vs tamoxifen treatment (Augusto, et al. ASCO 2016). A retrospective analysis of the ESR1 mutation frequency and co-occurring alterations that could guide subsequent therapy approaches was investigated. Methods: Molecular profiles of 416 breast cancer patients [HR+ (n=237), HER2+ (n=29) and TNBC (n=139)] were assessed. Protein expression (IHC) and gene amplification (ISH) were performed. Genomic testing included 592-gene hybrid-capture NGS [NextSeq Illumina platforms] and ArcherDx fusion assay based on anchored multiplex PCR (AMP) FusionPlex Solid Tumor. ESR1 variant (ESR1var) (mutation/fusion) profiles and HR+ BC patients lacking genomic ESR1 alterations (ESR1 WT) were compared; Pearson's chi-squared test was used to test for significant differences. Results: An ESR1 mutation (point mutations, insertion-deletions [n=49] and fusions [n=4]) was detected in 13% (53 /416) of the specimens, and this constitutes 21% (50/237) of all HR+ breast cancers. Two TNBC patients exhibited ESR1 variants (H398Y in exon 7 and A491S in exon 9, both are classified as variants of unknown significance). ESR1 mutations were not detected in HER2+ BC. Seventy-seven percent of patients with ESR1 mutations were detected in metastatic specimens (p=0.03), with liver (19/53 or 36%) and bone (8/53 or 15%) specimens as the most frequent sources for ESR1 variant (ESR1var) positivity. The most common alleles detected were: D538G (24%), Y537S (18%), E380Q (14%) and L536H (4%); 15 other additional alleles were detected (each 2%). ESR1 fusions were detected in 4 ESR1 WT patients: ESR1-ATP2B2, ESR1-MKL1/ESR1-TNRC6B, ESR1-ARNT2 and ESR1-C6ORRF211. We next compared ESR1var (mutation/fusion) profiles to HR+ breast patients lacking genomic ESR1 alterations (ESR1 WT). ER expression was present in 100% and 96% of ESR1var and ESR1 WT BC, respectively, however expression of PR was negative in 22% and 38% of ESR1var and WT BC, respectively (p=0.05). Significantly higher rates of other gene amplification events observed in ESR1var vs. ESR1 WT BC included: c11orf30 [EMSY, BRCA2 interacting transcriptional repressor] (20% vs. 7%), CCND1 (51% vs.28%), CCND2 (6% vs. 0%), FGF3 (37% vs. 16%), FGF4 (40% vs. 12%) and FGF19 (40% vs. 15%), whereas cMYC was more frequently amplified in ESR1 WT BC (17% vs. 2%); all p-values Conclusions: ESR1 mutations and fusions are detected in 21% of HR+ BC, the majority of which are in metastatic sites. Amplifications of genes involved in downstream regulatory pathways were present and may contribute to the poor prognosis of ESR1var HR+ BC. Correlation with antecedent therapy is currently underway. Citation Format: Tan A, Feldman R, Pohlmann P, Lynce F, Swain S, Nunes MR, Gatalica Z, Ghazalpour A, Swensen J, Vidal G, Obeid E, Vacirca J, Isaacs C, Schwartzberg L. ESR1 mutations, ESR1 fusions and co-occurring alterations assessed in breast cancer tumors [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-04-01.

BACKGROUND: Germline TP53 mutations predispose to early onset breast cancer in women and are associated with Li-Fraumeni syndrome. Published data on the pathological characteristics of breast cancer among women with TP53 mutations is limited. METHODS: We retrospectively reviewed the clinical records of women who underwent genetic testing for suspected germline TP53 mutations and who were diagnosed with breast cancer between 2000 and 2011. The pathological characteristics of the breast tumors from patients testing positive for a mutation (cases) were compared with those testing negative (controls). RESULTS: Patients who tested positive for germlineTP53 mutations (n = 30) were compared with controls (n = 79). Human epidermal growth factor receptor 2 (HER2) amplification and/or overexpression was found in 67% of the tumors from the cases, compared with 25% for the controls (P = .0001). Among patients with a mutation, 70% had estrogen receptor- and/or progesterone receptor-positive tumors, compared with 68% in the control group (P = .87). After adjusting for age at breast cancer diagnosis, having a HER2-positive tumor increased the odds of testing positive for a germline TP53 mutation (odds ratio, 6.9; 95% confidence interval, 2.6-18.2). For each yearly increment in age at breast cancer diagnosis, there was decreased likelihood of having a TP53 mutation of 5% (odds ratio, 0.95; 95% confidence interval0.91-0.99). CONCLUSIONS: This study suggests an association between germline TP53 mutations and early onset HER2-positive breast cancer. If confirmed in a larger cohort, these results could guide genetic testing strategies, lead to chemoprevention trials incorporating HER2-targeted therapies, and elucidate some of the molecular pathways involved in breast cancer. Cancer 2012;. © 2011 American Cancer Society.

1536Background: Uptake of genetic evaluation (GE) remains limited in cancer pts. MGPT is recommended for GE of women with ovarian cancer (OC), but many will never be tested. For pts w/incident colo...

1519Background: Genetic counseling (GC) for men with or at-risk for prostate cancer (PCA) is growing with advancements in genetic testing (GT). GC provides a unique opportunity to promote a healthy...

10085Background: Chemotherapy is often associated with treatment side-effects that negatively affect HRQOL. The aim of this study was to examine the feasibility and preliminary efficacy of a novel ...

Purpose: To develop a novel approach for early detection of breast cancer and examine molecular features of screen detected cancers in prospectively ascertained high-risk women undergoing semi-annual dynamic contrast-enhanced breast magnetic resonance imaging (DCE-MRI) for women at high genetic risk. Background: Women with a personal or family history of breast cancer and genetic mutation carriers of BRCA1 and BRCA2 have a higher than normal risk of breast cancer. An intensified screening surveillance regimen is an early detection strategy in high-risk women. The American Cancer Society recommends annual DCE-MRI in addition to annual mammogram based off several pivotal screening studies that demonstrated improved sensitivity and cancer detection rates and decreased interval cancer rates with the addition of annual DCE-MRI. Questions remain regarding the optimal screening modality and interval regimen in these high-risk women. Methods: Between 2004 and 2016, we assembled a prospective cohort of high-risk women undergoing semi-annual DCE-MRI and annual mammography. To be eligible, women had a lifetime breast cancer risk >20% and/or tested positive for a pathogenic mutation using a cancer gene panel including BRCA1, BRCA2, CDH1, PALB2, CHEK2 and other cancer susceptibility genes in the DNA repair pathway. Somatic mutation events in screen-detected tumors were investigated using UW-OncoPlex cancer gene panel using DNA extracted from FFPE shavings. Results: 295 women were recruited to the study; 44% of the study participants had pathogenic mutations in BRCA1 or BRCA2 genes. At a median follow-up of 3.3 years (range 0-12 years), 3 DCIS and 13 early stage invasive breast cancers were detected, of which 14 occurred in subjects with identifiable pathogenic mutations (11 BRCA1, 2 BRCA2, 1 CDH1). The incidence rate is 1.3% in all subjects, but 3.5 % per year in BRCA1 carriers. DCE-MRI identified all 13 invasive cancers at a mean size of 0.61 cm (range 0.1-1.0 cm); none had lymph node metastasis. No interval cancers occurred. In addition, 7 of the breast cancers were detected on DCE-MRI imaging obtained at the 6 months screening interval; they would be interval cancers if only annual screening were implemented. There was very little DNA for somatic mutation testing in the majority of cases. However, as expected, there was heterogeneity in the spectrum of mutations but the most commonly somatically mutated gene in the early cancers was TP53. Conclusions: DCE-MRI every 6 months performed well for early detection of invasive breast cancer in high-risk women, accomplishing the ultimate goal of breast cancer screening—detecting node-negative, invasive tumors less than 1 cm. Semi-annual DCE-MRI performed especially well in BRCA1 mutation carriers at risk for the most aggressive subtype of breast cancer. Further interventional studies evaluating this novel screening approach are warranted to personalize breast cancer risk assessment and prevention. Citation Format: Whitaker K, Guindalini R, Abe H, Sheeth D, Huo D, Hong S, Churpek J, Verp M, Obeid E, Zheng Y, Amico A, Yoshimatsu T, Olopade O. Breast cancer surveillance in high-risk women with dynamic contrast-enhanced magnetic resonance imaging every 6 months: Results from a single institution study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-02-10.

Background: Recent data indicate a promising response to immune check point blockade (ICB) in patients with breast cancer. Pembrolizumab, a humanized monoclonal antibody against programmed death 1 (PD-1) receptor and one of several ICB agents in development, was given an FDA approval for all MSI (microsatellite instability)-high solid tumors. MSI incidence in breast cancer is not fully elucidated. Other biomarkers being explored in possible relationship to ICB activity include PD-1 ligand (PD-L1) status and tumor mutational load (TML). In this study, we aimed to explore the incidence of these biomarkers in invasive breast cancers. Methods: A retrospective data analysis of patients profiled by commercial next-generation sequencing (NGS) at Caris Life Sciences was performed. MSI results were either high, stable, or equivocal. MSI was calculated by comparing repeat-insertions or deletions across over 7,000 microsatellite sequences in the patient sample to the hg19 reference genome. Samples with repeat variances in more than 45 microsatellites were classified as MSI-High PD-L1 expression was evaluated using immunohistochemical analysis (IHC), with clone SP-142 (Roche Diagnostics). A sample was considered positive if there was >5% membranous staining of tumor cells. Tumor mutational load was calculated as a total number of non-synonymous somatic mutations identified per megabase of the genome coding area with high being greater than or equal to 17. Results: A total of 9,627 breast cancer cases were queried from the Caris Life Sciences database. The mean age (±SD) was 56.8 ± 12.4 years (range 20-90). The tumor distribution was 60.7% hormone receptor (HR) positive (ER and/or PR) and HER2 negative, 9.5% HER2 positive (with HR negative or positive), and 29.8% triple negative (negative for ER, PR and HER2). Of all cases, there were 5,203 tested for PD-L1 status, 354 (6.8%, 95% CI 6.2-7.5%) were positive. Of 1,440 tumors tested for MSI status, 15 (1.04%, 95% CI 0.58-1.71%) were either high (8) or equivocal (7), the rest were MSI-low. Tumor mutational load (TML) was available on 1,766 tumors, of which 55 (3.1%, 95% CI 2.4-4.0%) were high. Seven out of the 8 MSI-high tumors were also TML-high. Four out of the 8 MSI-high breast cancers were triple negative. Conclusion: In this large dataset of molecularly profiled breast cancer, MSI was observed in about 1% of the breast tumors tested. Overall, modest positivity of TML, PD-L1, and MSI of all invasive breast cancers was observed. The percentage of patients that had at least one of these biomarkers that may confer responsiveness to ICB is planned and will be further stratified by subtype. MSI-high breast cancers mostly overlapped with those that were TML-high. Future research is needed to show the clinical utility of these biomarkers in response to ICB. Updated data will be presented. Citation Format: Obeid E, Ellerbrock A, Handorf E, Goldstein L, Gatalica Z, Arguello D, Swain SM, Isaacs C, Vacirca J, Tan A, Schwartzberg L. Distribution of microsatellite instability, tumor mutational load, and PD-L1 status in molecularly profiled invasive breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD6-03.

1516 Background: Genetic counseling (GC) for prostate cancer (PCA) risk is an emerging field, with limited insights regarding needs of males considering genetic testing (GT). Genetic Evaluation of Men is a prospective multigene testing study to identify inherited mutations linked to PCA, with testing following GC. We surveyed men pre-GT and post-GT on knowledge of cancer risk and genetics (KCRG) and understanding of personal GT results to identify GC needs. Methods: Eligibility for males affected or high-risk for PCA encompass age, race, family history (FH), and PCA stage/grade. Demographic, clinical, and FH data were obtained from participants and medical records. Pre-GT survey included questions on KCRG (15 items) and health literacy/numeracy (6 items). Post-GT survey additionally included understanding of GT results (9 items). Personal and FH were categorized into three hereditary cancer syndromes (HCS) linked to PCA. Factors associated with baseline KCRG were assessed by univariable models followed by multivariable linear regression. McNemar’s test was used to assess concordance of understanding GT results vs. actual results. Results: Among 109 men (mean age 63 years, 81% White, 59% PCA diagnosis) who completed pre- and post-surveys, factors associated with higher pre-test KCRG included meeting HCS criteria (p = 0.006) and higher numeracy (p = 0.025). On multivariable analysis, HCS remained significantly predictive of higher KCRG (p = 0.040). However, of 101 men who responded definitively regarding understanding of personal GT results, 13 responded incorrectly on mutation status indicating significant disagreement with actual results (McNemar’s p < 0.001). Of these 13 men, 12 had > = 1 variant of uncertain significance (VUS). Additionally, 6 men were unsure whether they carried a mutation when their GT results found VUS but no mutations. Conclusions: This is the first report of knowledge and understanding of genetics and cancer risk in the context of multigene testing for PCA. While personal/FH of HCS was associated with higher KCRG, understanding of personal GT results was lacking, and warrants tailored GC strategies for multigene testing for inherited PCA.

1585 Background: Genetic testing for hereditary cancer predisposition has rapidly changed over the past few years with the introduction of multigene panel testing. Multigene testing has evolved from disease-agnostic comprehensive (C) panels alone to include disease-specific but expanded (DSE) panels as well as guideline-based (GB) panels. We analyzed trends in utilization of genetic testing over a two-year period in one NCI-designated Cancer Center, hypothesizing that over time genetic testing usage would trend toward more disease-specific panels. Methods: We conducted a retrospective analysis of our program’s database for all germline genetic tests ordered from 9/1/2013 to 8/31/2015 (n = 619; 246 in year 1, and 373 in year 2). Tests were categorized into three groups based on specificity: GB (range: 2-12 genes tested), DSE (12-35 genes tested), and C (28-80 genes tested). The Chi-square test was used to analyze test types ordered in year 1 (9/1/2013-8/31/2014) and year 2 (9/1/2014 – 8/31/2015) and the proportions of resulting mutation types. Results: A total of 604 germline genetic tests met the inclusion criteria: 39 GB (20 year 1, 19 year 2), 171 DSE (43 year 1, 128 year 2), and 394 C (180 year 1, 214 year 2). Compared to year 1, a larger proportion of DSE tests (35% v. 18%, p < 0.001), and a smaller proportion of C tests (59% v. 74%, p < 0.001) and GB tests (5% vs. 8%, p = 0.146) were ordered. DSE panels revealed a pathogenic variant (PV) at a rate of 16% and a variant of unknown significance (VUS) at a rate of 24%. C tests revealed a PV and VUS at rates of 14% and 29%, respectively. GB tests revealed a PV and VUS at rates of 21% and 18%, respectively. No statistically significant differences in detection rates of mutation types (PV or VUS) were found between GB, DSE, or C tests. Conclusions: The rates of PV detection were not significantly different between test types, but the profile of tests ordered changed over time to favor DSE panels. Exploration of factors contributing to changing trends in genetic testing are warranted as counselors and clinicians adapt to the quickly expanding number of genes associated with hereditary cancer risks, many of them moderate-risk, and the evolving landscape of multigene panel testing.