BRCA Mutation Status Research Articles

Exploring impact of mutations in non-BRCA DNA damage response (DDR) and non-DDR genes on efficacy in phase III EMBRACA study of talazoparib (TALA) in patients (pts) with germline BRCA1/2 mutated (gBRCAm) HER2-negative (HER2-) advanced breast cancer (ABC).

1018 Background: Loss-of-function mutations in genes encoding components of the homologous recombination DNA damage response (DDR) machinery, notably BRCA1/2, are associated with tumor sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi). In EMBRACA, the PARPi TALA showed an improvement in progression-free survival (PFS) (HR [95% CI] 0.54 [0.41-0.71], P < 0.001) vs physician's choice of chemotherapy (PCT) in g BRCAm HER2− ABC. Methods: Baseline tumor tissue from 308 pts (71%; intent-to-treat) was sequenced using the FoundationOne CDx panel. Mutations summarized below were known/likely pathogenic single-nucleotide variants, insertions, deletions, or rearrangements. Best tumor response (BOR) was using RECIST 1.1 by Investigator (confirmation of CR or PR not required). Results: 296/308 (96%) of evaluable pts exhibited ≥1 tumor BRCA mutation, with 7 of the remaining 12 exhibiting BRCA copy number alterations deemed pathogenic. Mutations in other genes implicated in DDR and/or potential sensitization to PARPi were rare, with mutations detected in BARD1, CDK12, FANCG, STAG2 (each 0.3%), ATR, BRD4, FANCC, PALB2, RAD51B (0.6%), ATM, BRIP1 (1.0%), NBN (1.3%), CHEK2, FANCA (1.6%), and ARID1A (2.3%). No association was observed between total number of DDR mutations, including BRCA1/2, and best tumor response (BOR) [odds ratio of 1 vs ≥2 DDR mutations (95% CI): TALA, 0.76 (0.31-1.87), P = 0.55; PCT, 0.98 (0.27-3.51), P = 0.97]. TP53 and PIK3CA were the most commonly mutated non- BRCA genes in BRCAm tumors (52.0 and 10.8%, respectively). TP53 mutations were more prevalent in BRCA1m vs BRCA2m tumors (85.2 vs 24.8%). PIK3CA mutations were more prevalent in BRCA2m vs BRCA1m tumors (15.9 vs 5.2%). With TALA, PFS was significantly shorter in pts with TP53 mutations than without [HR (95% CI) 1.693 (1.186-2.418), P = 0.0033]. A similar, non-significant, trend was evident with PCT [HR (95% CI) 1.439 (0.859-2.411), P = 0.1614]. PIK3CA mutational status had no impact on PFS in either arm. Conclusions: Selection based on g BRCA mutational status is appropriate to identify HER2─ ABC pts with potential for clinical benefit from TALA, with the total number of tumor mutations in BRCA1/2 and other DDR genes not impacting response (within the g BRCAm subset). TP53 mutations were associated with shorter PFS, likely reflecting the worse outcomes observed in g BRCA1m patients. Additional correlative analyses are ongoing. Clinical trial information: NCT01945775 .

Olaparib maintenance monotherapy for non-germline BRCA1/2-mutated (non-gBRCAm) platinum-sensitive relapsed ovarian cancer (PSR OC) patients (pts): Phase IIIb OPINION interim analysis.

6057 Background: In the Phase II Study 19 trial (NCT00753545; Ledermann et al. Lancet Oncol 2014), maintenance olaparib improved progression-free survival (PFS) vs placebo in PSR OC pts, including those in the non-BRCAm subgroup. A significant PFS benefit was also seen with maintenance olaparib vs placebo in gBRCAm PSR OC pts in the Phase III SOLO2 trial (NCT01874353; Pujade-Lauraine et al. Lancet Oncol 2017). To investigate olaparib maintenance monotherapy in non-gBRCAm PSR OC pts who had received ≥2 previous lines of platinum-based chemotherapy, we performed the Phase IIIb, single-arm, OPINION study (NCT03402841). Methods: Pts had high-grade serous or endometrioid OC and had responded to platinum-based chemotherapy. Pts initiated maintenance olaparib tablets (300 mg bid) until disease progression or unacceptable toxicity. Primary endpoint was investigator-assessed PFS (modified RECIST 1.1). Secondary endpoints included PFS by homologous recombination repair deficiency (HRD; assessed with the Myriad myChoice HRD plus test; HRD+ve: score ≥42) and somatic BRCA mutation (sBRCAm) status. An interim analysis was planned after ~135 PFS events. Results: 279 pts were enrolled from 17 countries (mean age: 64 yrs); 94.3% were confirmed non-gBRCAm by local testing. At data cut-off (Nov 15, 2019), the median PFS was 9.2 months (95% confidence interval [CI]: 7.6–10.9 months), with 152 PFS events (54.5% maturity). The Table presents PFS outcomes by key subgroups. The median exposure to olaparib was 8.1 months. Grade ≥3 adverse events (AEs) occurred in 72 (26%) pts. 19% of pts reported serious AEs. No deaths related to AEs were reported. AEs led to dose interruption, dose reduction and treatment discontinuation in 39%, 15% and 7% of pts, respectively. Conclusions: Maintenance olaparib demonstrated activity in non-gBRCAm PSR OC pts. There were no new safety signals. Clinical trial information: NCT03402841. [Table: see text]

Pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) for advanced breast cancer patients with high risk for Hereditary Breast and Ovarian Cancer Syndrome (HBOC).

e13549 Background: Local Advanced Breast Cancer (LABC) is associated with high risk of death. NAC is a safe and effective approach for these populations. pCR is a proven prognostic factor in several studies of NAC. HBOC is associated to high risk of breast cancer usually in young age and especially for BRCA1 mutations with a basal phenotype. The aim of this study was to evaluate the influence of BRCA mutational status on frequence of pCR. Methods: this is part of a retrospective, observational study of prevalence of HBOC among patients admitted for cancer therapy in our institution. Since August, 2018 over 300 pte suspected for HBOC (by NCCN criteria) have been screened for NGS with a 31-gene painel. Statistical analysis performed Person X2/Fisher and logistic regression ( p< 0.05; SPSS 20.0). Results: Most pte were women (80%), with median age of 38y (22-72y), most tumors were (80%) stage III, Luminal B (23%) and TNBC (36%). Pathogenic mutations were identified in 34%(n = 28) of the sample ( BRCA1 50%, BRCA2 16.7%, PALB2 16.7%, follow by TP53, PMS2, XRCC2, MUTYH, BARD1 and ATM with 2.8% each).The majority of patients had more than 1 NCCN criteria: age < 45y (83%), family member with BC < 50y (24%) or TNBC (33%) the most common. TNBC tumors had stronger association with germline mutation ( p< 0.001). Regarding response rate there were 13 stable disease (SD), 5 progressive disease (PD), 43 pCR and 39 pathological partial response (pPR). There were no differences in pRC among mutated or no mutated pte, p= 0,170. However, among mutated TNBC there were strong correlation with more pCR, p< 0,006. There was no difference on pCR rate related to mutation status (BRCA vs Non-BRCA), p = 0,84. Conclusions: the present study corroborates other data about the impact of germline mutation status over pCR after NAC for LABC, except for mutated TNBC population, whose seems to be more NAC sensitive.

DUO-E/GOG-3041/ENGOT-EN10: a randomized phase III trial of first-line carboplatin (carb) and paclitaxel (pac) in combination with durvalumab (durva), followed by maintenance durva with or without olaparib (ola), in patients (pts) with newly diagnosed (nd) advanced or recurrent endometrial cancer (EC).

TPS6108 Background: There is a high unmet need for advances in EC treatment that provide progression-free survival (PFS) and overall survival (OS) benefits. EC tumors are sensitive to carb/pac (Pectasides et al. Gynecol Oncol 2008). Maintenance therapy with the poly(ADP-ribose) polymerase inhibitor (PARPi) ola (with or without bevacizumab) led to significant PFS benefits in advanced ovarian cancer pts with either nd (SOLO1, Moore et al. NEJM 2018; PAOLA-1, Ray-Coquard et al. NEJM 2019) or recurrent (SOLO2, Pujade-Lauraine et al. Lancet Oncol 2017; Study 19, Friedlander et al. Br J Cancer 2018) platinum-sensitive disease, regardless of BRCA mutation status (PAOLA-1; Study 19), and in BRCA-mutated metastatic pancreatic cancer pts (POLO, Golan et al. NEJM 2019). Molecular features of EC could predict sensitivity to PARPi (de Jonge et al. Clin Cancer Res 2019; Auguste et al. Mod Pathol 2018). PARPi has been shown to prime the immune microenvironment in a preclinical BRCA1 mutant ovarian model (Higuchi et al. Cancer Immunol Res 2015). Clinical trials have demonstrated antitumor activity of the anti-programmed cell death ligand-1 (anti-PD-L1) blocker durva (Antill et al. J Clin Oncol 2019) and anti-programmed cell death-1 (anti-PD-1) antibody therapies (Makker et al. ESMO 2019; Oaknin et al. SGO 2019) in EC pts. The DUO-E trial (EUDRACT 2019-004112-60, D9311C00001, NCT04269200) will investigate whether the addition of durva to carb/pac, followed by durva (with or without ola) maintenance treatment, improves PFS in pts with nd advanced or recurrent EC. Methods: Eligible pts for this multicenter, double-blind, Phase III trial must have nd Stage III/IV or recurrent EC and be naïve to first-line chemotherapy. Pts will be randomized (1:1:1; n=~233 per arm) to: arm A) carb/pac + placebo (pbo) (q3w for six cycles) followed by pbo maintenance treatment; arm B) carb/pac + durva (1120 mg; q3w for six cycles) followed by maintenance treatment with durva (1500 mg q4w) + pbo (tablets bid); or arm C) carb/pac + durva (1120 mg; q3w for six cycles) followed by maintenance treatment with durva (1500 mg q4w) + ola (300 mg bid tablets). Pts received maintenance treatment until disease progression. Primary endpoint: investigator-assessed PFS (RECIST 1.1) of arm B vs. arm A. Key secondary endpoints: PFS of arm C vs. arm A; OS of arm B vs. arm A, and of arm C vs. arm A. Enrollment began in Q1 2020. Clinical trial information: 2019-004112-60.

The impact of poly ADP ribose polymerase (PARP) inhibitors on clonal hematopoiesis.

1513 Background: Poly (ADP-ribose) polymerase (PARP) inhibitors are an important new class of anti-cancer therapies. Therapy-related myeloid neoplasia (tMN) has been reported following PARPi therapy, and is associated with adverse outcomes. Further insight is required into the risk of tMN conferred by PARPi therapy, independent of germline genetic background and prior therapy. We have shown that oncologic therapy selects for acquired mutations in the blood (clonal hematopoiesis; CH) particularly those in the DNA damage response pathway (DDR) including PPM1D, TP53 and CHEK2 and that CH confers an increased risk of tMN. We hypothesized that characterization of the relationship between CH and PARPi therapy provides insight into its potential for leukemogenesis and may offer opportunities for tMN prevention. Methods: We assessed for CH in the blood of 10,156 cancer patients, including 54 who received PARPi therapy, 5942 who received another systematic therapy or radiation therapy and 4160 untreated prior to blood draw. Results: Patients exposed to PARPi therapy were more likely to have CH (33%) compared to those exposed to other systemic therapies or radiation (18%) or untreated patients (16%). This was particularly pronounced for DDR CH; 25% of PARPi treated patients had DDR CH compared to 2% of untreated patients. In a multivariable model accounting for demographics, exposure to chemotherapeutic agents, radiation therapy and germline BRCA mutation status, exposure to PARPi conferred an increased risk of DDR CH (OR = 3.6, 95% CI 1.5-8.5, p = 0.004). This effect was attenuated after accounting for cumulative exposure to therapy (OR = 2.8, 95% CI 0.97-8.2, p = 0.06) suggesting a multifactorial contribution to the enrichment of CH following PARPi therapy. To characterize this further we performed a prospective collection of patients with CH over a median follow-up time of 58 months. During the follow-up period, 17 patients received PARPi, 360 received cytotoxic therapies or radiation and 232 were untreated or received targeted therapies. The growth rate of DDR CH was significantly higher among those who were exposed to PARPi (median, +2.8% increase in VAF per year) compared to untreated patients (+0.08% per year, p = 0.02) and those exposed to other cytotoxic therapies (+1% per year, p = 0.04). Conclusions: Taken together our data suggests that PARPi therapy promotes the expansion of DDR CH. Future studies should examine the potential of CH to identify individuals at high risk of tMN following PARPi therapy and to develop therapies aimed to prevent tMN in patients with CH.

The prognostic role of somatic BRCA mutations in ovarian cancer: Preliminary results from an observational multicenter cohort study.

e13674 Background: BRCA germline (gBRCA) mutations occur in 11-15% of women with unselected ovarian cancers (OC), whereas somatic BRCA (sBRCA) mutations occur in approximately 5-7% of cases. The impact of sBRCA mutations on OC outcome is still debated. Methods: With the aim to explore the prognostic role of sBRCA mutations, the BRCA mutational status of 149 non-mucinous and non-borderline OC and their clinical-pathological features were evaluated. BRCA1 and BRCA2 mutational profiles, either for sequence variants or copy number alterations, were evaluated by amplicon next-generation sequencing (NGS) technology. Results: 29 (19.5%) patients carried a gBRCA mutation (12.7% BRCA1 and 6.7% BRCA2). 26 (17.5%) patients presented a sBRCA mutation (6.7% BRCA1, 10% BRCA2, 0.6% BRCA1+BRCA2). Patients carrying a gBRCA mutation were slightly younger (57 years) than the others (60 years). The FIGO stage at the diagnosis was III-IV in 77.2% of cases, with no significant difference among subgroups. The most frequent histotype was serous for all the subgroups (93.1% in gBRCA, 84.6% in sBRCA, 77.7% in BRCA-negative, p = 0.08). 80.7% of sBRCA mutation carriers, 62.1% of gBRCA mutation carriers and 62.7% of BRCA-negative patients underwent upfront surgery (p = 0.46). 29.1% of sBRCA mutation carriers, 17.8% of gBRCA mutation carriers and 25.6% of BRCA-negative patients presented macroscopic residual disease after surgery (p = 0.68). Although non-statistically significant, gBRCA-associated OC were more likely to be platinum-sensitive (96.6%) than the other patients (92% in sBRCA and 87.1% in BRCA-negative patients). Overall, the median platinum-free interval (PFI) resulted shorter in sBRCA mutation patients compared to gBRCA and BRCA-negative patients (p = 0.051). No patient took PARP inhibitors as maintenance after the first line therapy. Also progression free survival 2 (PFS2) resulted shorter for sBRCA mutation patients (p = 0.008). Three sBRCA and 5 gBRCA mutation carriers took a PARP inhibitor as maintenance after the second line therapy. Finally, sBRCA mutated patients showed worse overall survival (OS) compared to the other subgroups (p = 0.014). Conclusions: Overall, 19.5% of OC patients presented a gBRCA mutation, while 17.5% of patients showed sBRCA mutations. sBRCA-related OC did not show significantly differences in clinical-pathological features (stage at diagnosis, histotype, time to surgery and residual after surgery). To our knowledge this is the first study showing shorter PFI, PFS2 and OS in patients carrying sBRCA mutations.

DUETTE: A randomized phase II study to assess a second maintenance treatment with olaparib (ola) or ola+ceralasertib (cer), in patients (pts) with platinum-sensitive relapsed (PSR) epithelial ovarian cancer who have previously received PARP inhibitor maintenance treatment (NCT04239014).

TPS6104 Background: Ovarian cancer is the leading cause of death from gynecological cancers in the USA, and the fifth most common cause of cancer death in women. Ola is a PARPi approved for first-line maintenance treatment of BRCA-mutated advanced ovarian cancer in women who achieve a complete or partial response to platinum-based chemotherapy. Ola is also efficacious in combination with bevacizumab in the same population, independent of BRCA mutation status. Cer is a potent, oral, selective inhibitor of ATR. ATR is a critical DDR kinase that is activated in response to replication stress and stalled replication forks. There is no second maintenance standard of care for patients with PSR ovarian cancer who have previously received a PARPi in the maintenance setting. Pre-clinical models have shown that several mechanisms of PARPi resistance may be overcome by ATR inhibition, such as BRCA reversion, replication fork protection and DDR rewiring. DUETTE will select pts with tumor response or stable disease after second or third-line platinum-based treatment, with the expectation to enrich for non-BRCA reversion PARPi resistance mechanisms. The study will address the role of a second maintenance treatment following prior 1L or 2L maintenance, an emerging population of unmet need, and includes translational studies that aim to further our knowledge of clinical PARPi resistance mechanisms and predictors of treatment response. Methods: DUETTE is a global, multi-center, phase II study. 192 pts with PSR epithelial ovarian cancer who have previously received PARPi maintenance treatment, will be retreated with platinum and those who have not progressed after ≥ 4 cycles will be randomized (1:1:1) to 3 treatment arms: Arm 1, open-label: cer 160 mg once daily (qd) days 1 to 7 plus ola 300 mg twice daily (bd); Arm 2, blinded: ola monotherapy 300 mg bd and Arm 3, blinded: ola-placebo. Treatment is administered in 28-day cycles. All pts will be stratified by BRCA status (mutation or wildtype) and response to most recent line of platinum-based chemotherapy (CR/PR or SD). The primary endpoint is to assess the efficacy of maintenance ola monotherapy and cer+ola combination therapy compared with placebo by PFS using blinded, independent central review. Secondary endpoints are overall survival, PFS2, ORR, DoR, safety and tolerability. Enrolment is planned to start in April 2020.

Expanding use of rucaparib as maintenance therapy in recurrent ovarian cancer: updates from the ARIEL3 trial

Among the novel innovative drugs being studied and investigated in recurrent ovarian cancer, poly(ADP-ribose) polymerase (PARP) inhibitors have an emerging role. There is a particular interest in these drugs as maintenance therapy and as an alternative to bevacizumab in platinum-sensitive recurrent ovarian cancer. 1 Tomao F Bardhi E Di Pinto A et al. PARP inhibitors as maintenance treatment in platinum sensitive recurrent ovarian cancer: An updated meta-analysis of randomized clinical trials according to BRCA mutational status. Cancer Treat Rev. 2019; 80101909 Summary Full Text Full Text PDF PubMed Scopus (44) Google Scholar , 2 Musella A Bardhi E Marchetti C Rucaparib: an emerging parp inhibitor for treatment of recurrent ovarian cancer. Cancer Treat Rev. 2018; 66: 7-14 Summary Full Text Full Text PDF PubMed Scopus (46) Google Scholar PARP inhibitors, including olaparib, niraparib, and rucaparib, have recently been approved in platinum-sensitive recurrent disease after a platinum-based chemotherapy with different approval policies worldwide, particularly dependent on BRCA1 or BRCA2 mutations. 3 Mirza MR Monk BJ Herrstedt J et al. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016; 375: 2154-2164 Crossref PubMed Scopus (1349) Google Scholar , 4 Pujade-Lauraine E Ledermann JA Selle F et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017; 18: 1274-1284 Summary Full Text Full Text PDF PubMed Scopus (983) Google Scholar , 5 Coleman RL Oza AM Lorusso D et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017; 390: 1949-1961 Summary Full Text Full Text PDF PubMed Scopus (857) Google Scholar According to ESMO–ESGO guidelines, their use in this setting of the ovarian cancer treatment is strongly recommended (evidence level 1a). 6 Colombo N Sessa C Bois AD et al. ESMO–ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease. Ann Oncol. 2019; 30: 672-705 Summary Full Text Full Text PDF PubMed Scopus (370) Google Scholar Rucaparib for patients with platinum-sensitive, recurrent ovarian carcinoma (ARIEL3): post-progression outcomes and updated safety results from a randomised, placebo-controlled, phase 3 trialIn these exploratory analyses over a median follow-up of more than 2 years, rucaparib maintenance treatment led to a clinically meaningful delay in starting subsequent therapy and provided lasting clinical benefits versus placebo in all three analysis cohorts. Updated safety data were consistent with previous reports. Full-Text PDF

Real world outcomes in platinum sensitive relapsed ovarian, fallopian tube, or peritoneal cancer treated in routine clinical practice in the United Kingdom prior to poly-ADP ribose polymerase inhibitors

IntroductionThe introduction of poly-ADP ribose polymerase inhibitors in ovarian cancer has demonstrated significantly improved progression free survival in four randomized controlled clinical trials in patients with platinum sensitive relapsed ovarian...

Clinicopathological Characteristics and Clinical Outcome in Egyptian Female Breast Cancer Patients With and Without BRCA1/2 Mutations

Introduction: Germline mutations in BRCA1 and BRCA2 genes confer high risk of developing breast cancer. We sought to examine whether the clinicopathological characteristics and the clinical outcome differ in patients with and without BRCA mutations. Patients and Methods: A series of 103 Egyptian female patients were recruited from Breast Cancer Unit, Clinical Oncology Department, Ain Shams University, Egypt. The enrolled patients, unselected for age of onset or family history, were tested for BRCA1/2 mutations using HRM analysis and direct sequencing. The clinical and pathological features of the patients were retrospectively assessed and comparisons were made using Chi-square. Disease free survival (DFS) was estimated by Kaplan–Meier method and compared in the two groups with log-rank. Results: The overall rate of BRCA1/2 mutations was 44%. Novel deleterious mutations were detected and submitted to NCBI Clinvar database. Deleterious mutations were identified in 29 cases and unclassified variants in 32 cases, 15 of which had a co-occuring deleterious mutation. Patients with BRCA mutations tended to have early onset breast cancer compared to non-carriers ( P=0.002), more often premenopausal ( P=0.006), with a familial history of breast cancer as well as other cancers ( P=0.005). BRCA-related breast cancers were more likely to have T3-T4 stage than wild type (41% versus 28%, P=0.02), positive lymph node involvement (78 versus 53%, P=0.007) and develop bilateral breast cancers (24% versus 9%, P =0.007). The incidence of ER negative and PR negative tumors was higher in BRCA carriers, but not statistically significant ( P=0.17 and 0.15, respectively). No difference in HER-2/ neu status was observed ( P=0.25). Early age at onset, positive lymph node involvement, family history of any cancer were independent predictive factors for occurrence of BRCA1/2 mutations. The median follow-up time for the cohort was 5.53 years. Patients with BRCA mutations had poorer 5-year DFS compared to non-carriers (47.7% versus 67.4%, P=0.041); but Cox regression analysis failed to demonstrate a significant independent influence of BRCA mutation status on DFS. Conclusion: This study shows that BRCA-related breast cancers in the Egyptian population have distinctive clinical and tumor features as well as outcome. This data has important health implications for guiding cancer control policies.

Abstract P6-10-16: High circulating levels of adrenomedullin are associated with metabolic syndrome and low cardiorespiratory fitness in BRCA1 and BRCA2 mutation carriers

Abstract BACKGROUND: Risk factors for cardiovascular disease (CVD) and breast cancer overlap substantially. Identification of the underlying mechanisms associated with this co-occurrence is of great public health importance. Adrenomedullin (AM) is an almost ubiquitously expressed peptide with vasodilator and natriuretic properties. Previous studies have observed a link between high AM levels and worse prognosis in patients with myocardial infarction and heart failure, indicating a crucial role in the pathophysiology of CVD. Moreover, AM is expressed in 80% of sporadic breast cancers, and the degree of expression is associated with tumour growth, local tumour progression and bone metastases. High plasma AM levels are linked to arterial hypertension, diabetes, obesity and smoking. Preliminary evidence suggests that AM influences the osteoclast differentiation mediated by Receptor Activator of NF-κB Ligand (RANKL), an important signalling pathway in BRCA1-associated breast tumorigenesis. OBJECTIVE: Besides an elevated risk of breast cancer, recent studies revealed that BRCA mutation carriers are potentially at higher cardiovascular risk. The value of AM in BRCA mutation carriers is unknown. The aim of this study was to examine circulating plasma AM levels in BRCA mutation carriers and assess their association with modifiable risk factors. METHODS: AM concentrations were measured in 290 BRCA1/2 mutation carriers without overt CVD, participating in the randomized controlled LIBRE study (NCT numbers: NCT02087592, NCT02516540), by an immunoassay (sphingotest® bio-ADM®). Subjects were classified into high versus low AM levels based on the median plasma AM level in the entire cohort (13.9 pg/mL). Univariate logistic regression models were used to estimate the odds ratio (OR) of having high circulating AM levels by metabolic syndrome (MetS), cardiorespiratory fitness (CRF), body mass index (BMI), circulating insulin, smoking, current age, BRCA mutation status (BRCA1 or BRCA2) and previous diagnosis of breast cancer. MetS was defined in accordance with the criteria of the Third Adult Treatment Panel (ATP III). CRF was measured by peak oxygen uptake (VO2peak) assessed on a cycle ergometer via standardized cardiopulmonary exercise testing. RESULTS: Of all women (median age: 43 years), 57.9% had a previous diagnosis of breast cancer. The median time between diagnosis and study entry was 3 years (range: 0-32 years). Women fulfilling the criteria of metabolic syndrome had over 17 times higher odds of having increased AM levels compared to those who did not meet the criteria (OR = 17.49, p < 0.001). Moreover, high AM levels were associated with lower VO2peak (OR = 0.91, p < 0.001), higher BMI (OR = 1.24, p < 0.001) and higher circulating insulin levels (OR = 1.1, p < 0.001). AM levels were higher in women who have ever smoked (OR = 1.73, p = 0.022), and AM levels increased with the number of pack-years smoked (OR = 1.03, p = 0.06). AM levels were not associated with age (p = 0.143), BRCA mutation status (p = 0.51) or previous diagnosis of breast cancer (p = 0.48). After adjustment for confounding variables, we observed that MetS (OR = 10.78, p = 0.002) and VO2peak (OR = 0.92, p = 0.001) were independent determinants of circulating AM. CONCLUSIONS: This is the first study in BRCA mutation carriers that has linked circulating AM levels to MetS and CRF. The long-term clinical implications of these findings are yet to be determined. Conflict of interest: The study is funded by the German Cancer Aid (Deutsche Krebshilfe) within the Priority Program “Primary Prevention of Cancer” (Grant no. 110013). JS and OH are employed by Sphingotec GmbH, a company having patent rights in and commercializing the bio-ADM assay. SG and MK received grants from Sphingotec GmbH. JL, MYD, MB and MH have nothing to disclose. Citation Format: Jacqueline Lammert, Sabine Grill, Maryam Yahiaoui-Doktor, Maryam Basrai, Joachim Struck, Oliver Hartmann, Martin Halle, Marion Kiechle. High circulating levels of adrenomedullin are associated with metabolic syndrome and low cardiorespiratory fitness in BRCA1 and BRCA2 mutation carriers [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 P6-10-16.

Abstract P3-08-51: Association between BRCA mutational status and survival in patients with breast cancer: A meta-analysis

Abstract Background: BRCA mutated breast cancer is associated with an aggressive phenotype with marked differences in histological grade and distant metastases and sensitive to PARPi and platinum therapy. Studies evaluating role of BRCA mutations on the survival outcomes in breast cancer (BC) patients have given confounding results due to the differences in clinical and pathological status among study population. Therefore, we assessed the impact of BRCA mutations on survival of BC patients, based on their baseline characteristics and follow-up durations. Methods: Using PICO framework, articles comparing survival outcomes of BC patients having BRCA mutations against sporadic BRCA phenotype were retrieved from PubMed, EMBASE and Cochrane Library. Overall survival (OS) was the primary outcome, with disease free survival (DFS), distant metastasis free survival (DMFS) and breast cancer specific survival (BCCS) as the secondary outcomes. Hazard ratio (HR) with 95% confidence interval (CI) was used for analysis. Sub-group analysis was performed for survival based on age, tumor stage, estrogen receptor status, triple negative breast cancer (TNBC) status, tumor stage (Stage I-III vs I-IV) and follow-up durations. Results: Altogether, 30 articles with 35,972 patients (mean age 45.6 years) were included in the analysis. In BRCA1/2+ group, no significant difference in OS and DFS than BRCA- group were observed (HR: 0.98, 1.36, respectively),have a better DMFS in BRCA- patients than that in BRCA1/2+ patients (HR: 1.32; 95% CI: 0.71, 2.44). However, the difference observed between the groups was insignificant (P = 0.3825). BRCA1+ patients had significantly lower OS (HR [95%CI]: 1.2 [1.08, 1.33]; P<0.001),poor BCSS at 10 years follow-up. DMFS was significantly poor in BRCA1+ patients compared with BRCA- patients both at 5 years follow-up (HR [95%CI]: 1.07 [1.04, 1.10]; P<0.0001) and 10 years follow-up (HR [95%CI]: 1.21 [1.13, 1.29]; P<0.0001).BRCA2+ patients had significantly lower DFS (HR [95%CI]: 1.35 [1.1, 1.67]; P = 0.0049) and BCSS (HR [95%CI]: 1.46 [1.26, 1.7]; P<0.0001) than BRCA2- patients. Among TNBC patients, OS was non-significantly better in BRCA1/2+ patients (HR 0.96, P = 0.803) than in BRCA- patients. However, DFS was significantly poor in BRCA1+ TNBC patients than BRCA1-/TNBC patients (HR [95% CI]:1.65 [1.08, 2.54]; P = 0.0216).Conclusion: BRCA1/2 mutation is associated with poor prognosis in patient with breast cancer. Hence, BRCA testing might help assess patient prognosis and treatment such as PARPi and platinum. Citation Format: Miao Liu, Shu Wang. Association between BRCA mutational status and survival in patients with breast cancer: A meta-analysis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-51.

Abstract P4-09-06: Brain metastases (BM) in patients with metastatic breast cancer (MBC) and circulating cell-free DNA (cfDNA) somatic BRCA mutations

Abstract Background: BM in MBC patients cause significant morbidity and mortality. BRCA1 germline mutations have previously been shown to be associated with an increased risk of developing BM (Lee et al, 2011), with an incidence as high as 15% (Zavitsanos et al, 2016). We previously reported that a subset of MBC patients may have somatic BRCA mutations in the absence of germline BRCA mutations (Vidula N, SABCS, 2017). In this study, we evaluated the incidence and clinical characteristics of BM in MBC patients with somatic BRCA mutations detected by cfDNA. Methods: MBC patients with somatic BRCA1 or 2 mutations detected by cfDNA (Guardant360TM, next generation sequencing, 73 gene panel; mutations classified as somatic by Guardant360TM) with at least 4 months of follow-up post-testing at an academic institution were identified. From this cohort, we identified patients who developed BM post cfDNA testing. A retrospective review of medical records and Guardant360TM reports was conducted to identify demographics, tumor subtype, type of cfDNA BRCA mutation, whether the BRCA mutation was known to be pathogenic, germline BRCA mutation status, mutant allele fraction (MAF), clonality (MAF ratio of BRCA mutation/gene mutation with highest MAF ≥ 0.25 for clonal, and <0.25 for subclonal) and the coexisting genomic environment. Clinical and genomic features of BM and non-BM patients (patients without BM) were compared using a chi-squared test for categorical variables and Wilcoxon rank-sum test for continuous variables. Brain tumor tissue from available cases of BM patients was used to evaluate somatic BRCA mutation status on the tumor tissue and correlated with cfDNA results. Results: Of 36 MBC patients with somatic BRCA mutations, 9 (25%) developed BM and 27 (75%) did not have BM (non-BM). The median time to development of BM was 6.7 months after cfDNA testing. Of the BM patients, 5 (56%) had triple-negative (TN) and 4 (44%) had hormone receptor positive (HR+)/HER2- MBC in comparison with the non-BM cases where 5 (19%) had TN, 19 (70%) had HR+/HER2-, and 3 (11%) had HER2+ MBC. Very few patients (1 BM and 2 non-BM) had known co-existing separate germline BRCA mutations (rest not known BRCA carriers confirmed by negative germline testing and/or absence of family history suggestive of a germline BRCA phenotype). The median age at MBC diagnosis was similar for BM and non-BM patients (57 years). PIK3CA and TP53 mutations were commonly seen in both BM and non-BM cases. Additionally, MYC, EGFR, and CCNE1 mutations were commonly seen in BM cases. As outlined in Table 1, among patients with BM, the somatic BRCA mutations were commonly BRCA1, clonal, known to be pathogenic (56%), and present at a higher MAF, but these findings did not reach statistical significance possibly due to the small sample size. Brain tumor tissue mutation status in BM patients and correlation with cfDNA results will be presented at the meeting. Conclusions: We observed a relatively high incidence (25%) of BM in MBC patients with somatic BRCA mutations detectable by cfDNA, which were often known to be pathogenic mutations (56%), and often associated with co-existing MYC, EGFR, and CCNE1 mutations. Further research using a larger cohort with adequate statistical power is needed to validate these findings, and may help identify MBC patients at risk for BM using a liquid biopsy. Table 1.Characteristic BMNon-BMPrior anthracycline and/or platinum6 (67%)16 (59%)Type of somatic BRCA mutationBRCA16 (67%)11 (41%)BRCA22 (22%)15 (56%)BRCA1 and 21 (11%)1 (4%)Median BRCA MAF0.40.17ClonalityClonal6 (67%)13 (48%)Subclonal3 (33%)14 (52%)Mutation known to be pathogenic5 (56%)7 (26%)Common co-existing mutationsPIK3CA5 (56%)12 (44%)TP535 (56%)15 (56%)MYC5 (56%)8 (30%)EGFR5 (56%)8 (30%)CCNE15 (56%)6 (22%)KIT3 (33%)5 (19%) Citation Format: Neelima Vidula, Andrzej Niemierko, Giuliana Malvarosa, Priscilla Brastianos, Erica Blouch, Kristen Shannon, Steven Isakoff, Seth Wander, Laura Spring, Jerry Younger, Kristin Price, Beverly Moy, Dejan Juric, Leif Ellisen, Aditya Bardia. Brain metastases (BM) in patients with metastatic breast cancer (MBC) and circulating cell-free DNA (cfDNA) somatic BRCA mutations [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-09-06.

Abstract P2-13-09: Trajectories of fear of cancer recurrence in young breast cancer survivors

Abstract Background: Fear of cancer recurrence (FCR) is prevalent among breast cancer survivors and more intense in younger women. Given that FCR is a powerful determinant of quality of life and is associated with healthcare utilization, identifying who may be at risk for experiencing elevated FCR without resolution can inform the timing and targeting of interventions. Methods: Participants included women diagnosed (dx’d) at age ≤40 enrolled in the Young Women’s Breast Cancer Study, a multi-site prospective cohort surveyed at baseline and regularly in follow-up. Surveys include the 3-item Lasry Fear of Recurrence Index which measures the degree of concern about recurrence and current health using 4-point Likert response options that provide a score ranging from 3-12; higher scores indicate greater concern. Group-based trajectory modeling was used to classify distinct FCR patterns from baseline (median of 5 months from dx) through 3 years post-dx. Multinomial logistic regression was used to identify the associated patient (socio-demographics and BRCA status), disease (stage, ER/PR/HER2) and treatment (surgery, chemotherapy) characteristics associated with each trajectory. Variables significant at p<0.05 in univariable models were entered into the final multivariable model. Results: 965 women with Stages 0-III breast cancer were included in the analysis, with a median age at dx of 37. Participants were predominantly non-Hispanic White (85%), partnered (76%) and had completed college (84%). There was a significant decrease in median FCR scores from baseline to year 3 (9 vs. 8, Wilcoxon signed-rank test P<0.01). Five FCR trajectories (Table) were identified: 1) 10.5% of participants reported low/stable FCR from baseline over follow-up; 2) 33.1% had moderate FCR that improved over time; 3) 5.5% had moderate FCR scores at baseline that worsened over time; 4) 30% had high FCR scores at baseline that improved over time; 5) 20.8% had high FCR at baseline that remained high at all time points. In the fully adjusted multinomial model, younger age at dx and Stage 3 and 2 (vs. 1) disease were associated with higher odds of being in the high/stable trajectory. Having a lumpectomy (vs. mastectomy) was associated with higher odds of being in a high/stable as well as moderate/improving trajectory while White (vs. non-White) women had higher odds of being in a trajectory of improving FCR. Receipt of chemotherapy and financial discomfort were significantly associated with assignment to specific FCR trajectories in univariate analyses, however did not remain significant in the adjusted model. Being partnered, BRCA mutation status, and ER/PR/HER2 status were not significantly associated with any FCR trajectory classification in univariate or multivariate analyses. Conclusion: While FCR improves over time for many young women with breast cancer, a substantial minority (26%) had FCR that was severe and did not improve or worsened over time. Younger women with higher stage disease who are at risk for high levels of unresolved FCR may benefit from intervention including early referral to mental health professionals. Ongoing monitoring of women at risk for developing FCR following active treatment is warranted. Table Mean FCR score for each trajectoryBaselineYear 1Year 2Year 3TrajectoriesLow/Stable (N=103)5.725.605.545.45Moderate/Improving (N=331)7.907.487.287.09Moderate/Worsening (N=34)6.748.329.6410.54High/Improving (N=294)9.889.419.088.67High/Stable (N=203)11.0211.0811.0310.88 Citation Format: Lidia Schapira, Yue Zheng, Shari Gelber, Philip Poorvu, Kathryn J Ruddy, Rulla Tamini, Jeffrey Peppercorn, Steve Come, Virginia Borges, Ann Partridge, Shoshana Rosenberg. Trajectories of fear of cancer recurrence in young breast cancer survivors [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 P2-13-09.

Abstract P3-07-11: BRCA mutations and association with discordance in a large oncotype database

Abstract BACKGROUND: BRCA mutated tumors have been shown to be associated with higher recurrence scores as compared to BRCA negative breast cancer patients. Prior studies have demonstrated 7-19% discordance between oncotype RS and tumor grade (TG) in breast cancer patients. We developed a large oncotype database to determine if BRCA mutation status is associated with discordance. METHODS: We identified 723 patients (32 (4%) BRCA positive patients and 691 (96%) BRCA negative patients) with early-stage, hormone positive BC treated between 2006-2018, with tumor characteristics available for analysis. Discordance was defined as one or two-step difference between RS (low, intermediate, high risk) and TG (well (WD), moderately (MD) and poorly (PD) differentiated). BRCA status was defined as BRCA 1 deleterious mutation, BRCA 2 deleterious mutation, BRCA mutation of unknown type, BRCA variant of undetermined significance (VUS) or other mutation. N(%) or median were used to describe patients’ characteristics between groups and compared by Mann-Whitney U test at the confidence level of 5%. RESULTS: Among these patients, there were 32 patients (4% of total) who had any documented mutation or VUS. 16% had documented deleterious mutation in BRCA 1, 22% BRCA 2, 6% BRCA unknown type, 25% BRCA VUS, and 31% other VUS (most commonly CHEK2 and ATM). Median RS was 23.5 in patients with deleterious BRCA mutations (1, 2 or unknown) vs. 16 in patients in the BRCA negative database which was statistically significant (p<0.01). One step and two-step discordance was present in 46% and 8% respectively of patients with deleterious BRCA mutations vs. 53% and 11% respectively in the BRCA negative database. CONCLUSIONS: Patients with deleterious BRCA mutations demonstrated no difference in rates of discordance as compared to BRCA negative patients. We further demonstrated that patients with BRCA positive tumors display higher recurrence scores than patients with BRCA negative tumors. Citation Format: Julia Blanter, Brittney Zimmerman, Serena Tharakan, Krystal Cascetta, Meng Ru, Amy Tiersten. BRCA mutations and association with discordance in a large oncotype database [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-07-11.

Abstract P4-07-02: Clinicopathological features and BRCA 1/2 status in a large prospective cohort of young women with breast cancer

Abstract Background: Breast cancer arising in young women is more likely to have higher risk features than in older women and more likely to be associated with germline BRCA1 or BRCA2 mutations. We previously reported a higher distribution of luminal B-like tumors among young women. Here we present the clinical and pathologic features of invasive disease in a large prospective cohort of young women with breast cancer, and associations between surrogate molecular subtype and BRCA 1/2 mutation status. Methods: Among 1,297 young women (aged ≤40 years) with breast cancer enrolled from 2006-2016, tumor histopathological features were examined by central review, and biomarker status was extracted from pathology reports. Based on histologic grade and biomarker expression, invasive tumors were categorized as luminal A-like (LA=ER/PR+ and HER2-, histologic grade 1 or 2), luminal B-like (LB=ER/PR+ and HER2+, or ER/PR+, HER2-, and grade 3), HER2 enriched (E) (ER/PR- and HER2+) or triple negative (TN=ER-, PR- and HER2-). Tumor stage, clinical characteristics, and BRCA status were retrieved by medical record review (and patient survey for BRCA status if not in medical record). Results: The majority of women presented with early stage invasive disease (8% stage 0, 32% stage 1, 40% stage 2, 15% stage 3; 5% stage 4). Among invasive tumors with evaluable molecular phenotype (n=1,136), 57% were high grade and the distribution of subtypes was: 33% LA, 42% LB, 8% HER2E, and 16% TN (Table 1). Among different age groups (≤ 30, 31-35, and 36-40 years), there were no significant differences in molecular phenotype, tumor stage, tumor grade or histopathological features including presence of tumor necrosis, lymphocytic infiltration, and central fibrotic focus. 96% of women were tested for BRCA1 and BRCA2 germline mutations, and 127 (11%) tested positive: 65% were BRCA1+, and 35% were BRCA2+ (table 2). Among BRCA1+ patients, 2% of cancers were LA, 30% LB, 5% HER2E, and 62% TN; among BRCA2+, 29% were LA, 56% LB, 2% HER2E, and 13% TN. These proportions were relatively consistent across age groups. BRCA1+ patients’ tumors were proportionately more TN and BRCA2+ patients’ tumors more likely to be LB/HER2 negative (p<0.0001), irrespective of age category. Conclusion: In a large cohort of women diagnosed with breast cancer at age ≤40, there was no association between age group (≤ 30, 31-35, vs. 36-40 years) and tumor stage, grade, or tumor molecular phenotype among women with invasive disease. As in older women, tumor molecular phenotype does vary by BRCA1 or BRCA2 mutation status, which has implications for prevention and treatment. Table 1. Subtype by age groupTotal (n=1136)≤30 yrs (n=144)31-35 yrs (n=314)36-40 yrs (n=678)p=0.42Luminal A-like377 (33%)48 (33%)99 (32%)230 (34%)Luminal B-like477 (42%)59 (41%)137 (44%)281 (41%)• ER/PR+, HER2-, grade 3245 (22%)27 (19%)68 (22%)150 (22%)• ER/PR+, HER2+232 (20%)32 (22%)69 (22%)131 (19%)HER2E95 (8%)13 (9%)34 (11%)48 (7%)Triple Negative187 (16%)24 (17%)44 (14%)119 (18%) Table 2. Subtype by BRCA statusTotal(n=1136)BRCA1+(n=82)BRCA2+(n=45)No mutation/not tested(n=1009)p<0.0001Luminal A-like377 (33%)2 (2%)13 (29%)362 (36%)Luminal B-like477 (42%)25 (30%)25 (56%)427 (42%)• ER/PR+, HER2-, grade 3245 (22%)21 (26%)18 (40%)206 (20%)• ER/PR+, HER2+232 (20%)4 (5%)7 (16%)221 (22%)HER2E95 (8%)4 (5%)1 (2%)90 (9%)Triple Negative187 (16%)51 (62%)6 (13%)130 (13%) Citation Format: Yaileen D Guzman-Arocho, Shoshana M. Rosenberg, Philip Poorvu, Kathryn J. Ruddy, Greg Kirkner, Craig Snow, Rulla M. Tamimi, Jeffrey Peppercorn, Lidia Schapira, Virginia F. Borges, Steven E. Come, Elena F. Brachtel, Ellen Warner, Ann H. Partridge, Laura C. Collins. Clinicopathological features and BRCA 1/2 status in a large prospective cohort of young women with breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-07-02.

Abstract P2-15-02: BRCA1/2 status, treatment patterns, and safety outcomes in HER2- advanced breast cancer (ABC): Results from the European component of a multi-country real-world study

Abstract Background: Mutations in breast cancer susceptibility genes 1 and 2 (BRCA1/2) are known risk factors for developing breast cancer. Using the Adelphi Disease Specific Program, we assessed differences in real-world treatment patterns and safety outcomes based on BRCA1/2 mutation status in 5 European countries. Methods: Oncologists extracted data from medical charts in adult women with human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) across France, Germany, Italy, Spain and the United Kingdom (EU5) via the Adelphi Advanced Breast Cancer Disease Specific Program. Data drawn from two different years of data collection (2015 and 2017) were merged across common variables (e.g. age, hormone receptor status, BRCA1/2 testing rates, BRCA status). Patients (pts.) were categorized into 3 mutually exclusive cohorts; BRCA mutation (BRCAm), wild type (BRCAwt), and unknown status (BRCAunk). BRCA1/2 testing rates were analyzed via z-tests. Treatments received and adverse event (AE) rates were compared between BRCAm and BRCAwt using Fisher Exact tests. Results: The study included 4,876 adult women from the EU5 who had HER2- ABC; 75% pts. were hormone receptor (HR)+/HER2-, 23% triple negative breast cancer (TNBC), and 2% had an unknown HR status. Overall, 21% of pts. received ≥1 BRCA1/2 at the time of data abstraction (18% HR+/HER2-, 33% TNBC (p<0.001)). Out of the BRCA1/2 tested pts. (n=1,048) 123 (12%) pts. were identified as BRCAm, 577 (55%) as BRCAwt, and 348 (33%) as BRCAunk. Pts. with HR+/HER2- ABC and BRCAm were more likely to receive a 1st line chemotherapy (CT) based regimen compared to BRCAwt (67% vs 50%; P=0.027) and less likely to receive endocrine +/- targeted therapies (30% vs 48%; P=0.027) [Table 1]. TNBC treatments consisted primarily of CT based regimens and were similar between BRCAm vs BRCAwt, (95% vs 98%; P=0.375) [Table 1]. Pts. with BRCAm (HR+/HER2-, TNBC and unknown HR status) were significantly more likely to experience ≥1 AEs compared with those with BRCAwt (64% vs 44%; P<0.001). Conclusions: In this study of EU5 adult women with HER2- ABC, BRCA1/2 testing rates were low, especially among HR+/HER2- pts. Pts. with HR+/HER2- and BRCAm were significantly more likely to utilize a chemotherapy-based regimen and less likely to receive endocrine +/-targeted therapy than HR+/HER2- and BRCAwt. Pts. with BRCAm were significantly more likely to report experiencing ≥1 adverse event than those with BRCAwt. Opportunities exist to improve safety outcomes in HER2- ABC pts. with BRCAm. Funding: Pfizer Inc. Table 1. 1st line ABC Treatment Patterns Based on BRCA Status and HR SubtypeHR+ HER2-TNBCTreatments Received No. (%)BRCAm (N=46)BRCAwt (N=321)P valuesBRCAm (N=58)BRCAwt (N=170)P valuesCT based31 (67)159 (50)0.02755 (95)166 (98)0.375Endocrine +/-targeted14 (30)154 (48)0.0271 (2)2 (1)>0.999Othera1 (2)8 (2)>0.9992 (3)2 (1)0.268aIncludes “best supportive care” or “other therapy” Citation Format: Michael P. Lux, Katie Lewis, Alex Rider, Alexander Niyazov. BRCA1/2 status, treatment patterns, and safety outcomes in HER2- advanced breast cancer (ABC): Results from the European component of a multi-country real-world study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-15-02.

Salvage lymphadenectomy in recurrent ovarian cancer patients: Analysis of clinical outcome and BRCA1/2 gene mutational status

ObjectiveThis study is aimed to analyze the clinical outcome of recurrent ovarian cancer patients bearing isolated lymph-node recurrence (ILNR) who underwent salvage lymphadenectomy (SL). The prognostic role of clinicopathological variables and the mutational status of BRCA1/2 have also been investigated. MethodsThis retrospective, single-institutional study included women with platinum-sensitive lymph node recurrence underwent to SL between June 2008 and June 2018. Univariate and multivariate analysis was performed to evaluate the impact of clinical parameters, and BRCA1/2 mutational status on post salvage lymphadenectomy progression-free survival (PSL-PFS). ResultsAs of June 2019, the median follow-up after SL was 30 months, and the relapse has been documented in 48 (56.5%) patients. In the whole series, the median PSL-PFS was 21 months, and the 3-year PSL-PFS was 36.7%. The median PSL-PFS, according to patients with ILNR (N = 71) versus patients with lymph-nodes and other sites of disease (N = 14), was 27 months versus 12 months, respectively.Univariate analysis of variables conditioning PSL-PFS showed that platinum-free interval (PFI) ≥12 months, normal Ca125 serum levels, and number of metastatic lymph-nodes ≤3 played a statistically significant favorable role. In multivariate analysis, PFI duration ≥12 months and the number of metastatic lymph nodes ≤3 were shown to keep their favorable, independent prognostic value on PSL-PFS. ConclusionsIn the context of SL, the patients with long PFI and low metastatic lymph node numbers at ILNR diagnosis have the best outcome. The BRCA mutational status seems not associated with clinical variables and PSL-PFS, differently from other sites of disease in ROC patients.

BRCA Mutational Status is a Promising Predictive Biomarker for Platinum- based Chemotherapy in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) can be distinguished from other breast malignancies by the lack of expression of estrogen receptors (ER), progesterone receptors (PR) as well as human epidermal growth factor receptor 2 (HER2). TNBC is associated with adverse clinical outcomes and high risk of metastasis. Currently, several clinical and translational reports are focusing on developing targeted therapies for this aggressive cancer. In addition to approved targeted drugs such as poly(ADP-ribose) polymerase inhibitors (PARPi) and immune-checkpoint inhibitors, platinum-based chemotherapy is still a cornerstone therapeutic option in TNBC. However, despite the observed improved outcomes with platinum- based chemotherapy in TNBC, there is still a large proportion of patients who do not respond to this treatment, hence, the need for predictive biomarkers to stratify TNBC patients and therefore, avoiding unwanted toxicities of these agents. With the emergence of genetic testing, several recent studies suggested mutations in breast cancer susceptibility gene (BRCA) in TNBC patients as important predictors of outcomes. These mutations alter the homologous recombination repair (HRR) mechanisms leading to genomic instability. Consequently, sensitivity to platinum-based treatments in this subpopulation of TNBC patients may be explained by cell death enhanced by deoxyribonucleic acid (DNA) damage induced by these potent anticancer drugs. Through this paper, we review several recent studies on this topic to better understand the mechanisms and discuss the potential of BRCA mutational status as a predictive biomarker of platinum-based chemotherapy in TNBC.

Recreational Physical Activity Is Associated with Reduced Breast Cancer Risk in Adult Women at High Risk for Breast Cancer: A Cohort Study of Women Selected for Familial and Genetic Risk.

Although physical activity is associated with lower breast cancer risk for average-risk women, it is not known if this association applies to women at high familial/genetic risk. We examined the association of recreational physical activity (self-reported by questionnaire) with breast cancer risk using the Prospective Family Study Cohort, which is enriched with women who have a breast cancer family history (N = 15,550). We examined associations of adult and adolescent recreational physical activity (quintiles of age-adjusted total metabolic equivalents per week) with breast cancer risk using multivariable Cox proportional hazards regression, adjusted for demographics, lifestyle factors, and body mass index. We tested for multiplicative interactions of physical activity with predicted absolute breast cancer familial risk based on pedigree data and with BRCA1 and BRCA2 mutation status. Baseline recreational physical activity level in the highest four quintiles compared with the lowest quintile was associated with a 20% lower breast cancer risk (HR, 0.80; 95% confidence interval, 0.68-0.93). The association was not modified by familial risk or BRCA mutation status (P interactions >0.05). No overall association was found for adolescent recreational physical activity. Recreational physical activity in adulthood may lower breast cancer risk for women across the spectrum of familial risk. SIGNIFICANCE: These findings suggest that physical activity might reduce breast cancer risk by about 20% for women across the risk continuum, including women at higher-than-average risk due to their family history or genetic susceptibility.See related commentary by Niehoff et al., p. 23.