Efficacy of PARP inhibition combined with EZH2 inhibition depends on BRCA mutation status and microenvironment in breast cancer

FEBS Journal ◽  
2021 ◽  
Author(s):  
Mei‐Kuang Chen
Keyword(s):  
Breast Cancer ◽  
Brca Mutation ◽  
Parp Inhibition ◽  
Mutation Status

Differential outcomes in patients treated with endocrine therapy for early or locally advanced breast cancer based on BRCA mutation status

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e22065-e22065 ◽  
Author(s):  
R. Wesolowski ◽  
A. G. Shealy ◽  
J. Tao ◽  
H. C. Moore
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Endocrine Therapy ◽  
Hormone Receptor ◽  
Brca Mutation ◽  
Breast Cancer Patients ◽  
Brca1 And Brca2 ◽  
Mutation Status ◽  
Hormone Receptor Positive ◽  
History Of

e22065 Background: Mutations in BRCA1 and BRCA2 genes lead to defects in DNA repair. Estrogen receptor modulates transcription of genes responsible for cell division, which depends on cell's ability to repair DNA for genomic integrity. Differential efficacy of endocrine therapy for breast cancer, therefore, may be possible depending on the tumor's BRCA mutation status. Methods: Through an IRB approved registry, breast cancer patients tested for BRCA1 and BRCA2 mutations and treated with endocrine therapy for hormone-receptor positive non-metastatic disease were identified. Primary and secondary endpoints were overall survival (OS) and progression-free survival (PFS) respectively. Fisher's exact test or Wilcoxon rank sum test were used to assess differences among subgroups with respect to their characteristics. Cox proportional hazard analysis was used to identify univariate and multivariate risk factors for OS and PFS. Results: Of 115 breast cancer patients tested for BRCA mutations, 63 met the inclusion criteria of whom 16 patients were BRCA 1 or 2 mutation positive and 47 were negative. In the BRCA(+) group, 14 patients (87.5%) had stage I-III disease at diagnosis. In the BRCA(-) group, 5 patients (10.6%) had stage 0 disease while 41 patients (87.2%) had stage I-III disease at diagnosis. Stage at diagnosis was unavailable for 2 BRCA(+) and 1 BRCA(-) patients. Both groups were similar with respect to Her-2 expression status, history of ovarian suppression, age of diagnosis, and age of menopause. Median age was 48 yo in BRCA(+) group, 42 yo in BRCA(-), (p=0.12). Median follow up was 76.1 mos in BRCA(+) and 62.9 mos in BRCA(-) group. OS was worse in BRCA(+) group (HR 7.38, 95% [CI] 1.49–36.4 p=0.014). After adjustment for stage and history of ovarian suppression, the difference remained significant (HR 16.6, 95% [CI] 1.95–142, p=0.010). There was no difference in PFS (HR 2.02, 95% [CI] 0.82–4.96, p=0.13). Conclusions: Patients with BRCA mutation, hormone-receptor positive hereditary breast cancer treated with endocrine therapy had inferior survival compared with similar patients who are BRCA mutation negative. Prospective studies to evaluate the differential effects of endocrine therapy in these populations are warranted. No significant financial relationships to disclose.

scholarly journals Aromatase Inhibitors and Contralateral Breast Cancer in BRCA Mutation Carriers: A long-term Follow-up

2021 ◽  
Author(s):  
Maryam Nemati Shafaee ◽  
Kristina Goutsouliak ◽  
Heather Lin ◽  
Therese B Bevers ◽  
Angelica Gutierrez-Barrera ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Aromatase Inhibitors ◽  
Prophylactic Mastectomy ◽  
Brca Mutation ◽  
Brca1 Mutation ◽  
Brca2 Mutation ◽  
Mutation Status ◽  
Mutation Carriers ◽  
Brca Mutation Carriers

Abstract Background: Deleterious BRCA mutations confer a significant lifetime risk of breast cancer (BC) as well as contralateral BC (CBC) in patients who do not undergo prophylactic mastectomy. Prior reports have suggested that tamoxifen reduces the risk of CBC in BRCA mutation carriers. Whether aromatase inhibitors (AI) have the same effect is unknown. Methods: This is a retrospective review of patients diagnosed with non-metastatic ER+ BC between 2004-2014 with known BRCA mutation status. Patients were followed from primary diagnosis until CBC diagnosis or death. Median follow up was 11.5 years. Risk of CBC was evaluated as time to event. Results: 935 subjects were included in this analysis, with 53 BRCA1 mutation carriers, and 94 BRCA2 mutation carriers. Median age at diagnosis was 42.7 years. Seventy-two percent (676) received tamoxifen and 43% (405) received AI. A total of 66 CBCs occurred, of which 10% (15/147) occurred in BRCA mutation carriers vs %6.5 (51/788) in BRCA wild type. Multivariate analyses indicated that BRCA status and AI use were significantly associated with CBC risk. AI use resulted in a significant reduction in risk of CBC (HR 0.44, p=0.004) regardless of the BRCA mutation status. Tamoxifen use was not associated with reduced risk of CBC. Conclusions: This is the first report showing that AIs reduce the risk of CBC in BRCA mutation carriers. The potential role of AIs as chemoprevention should be validated in larger independent cohorts.

Pathological complete response rate and survival in patients with BRCA-associated triple-negative breast cancer after 12 weeks of de-escalated neoadjuvant chemotherapy: Translational results of the WSG-ADAPT TN randomized phase II trial (NCT01815242).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 579-579
Author(s):  
Lisa Katharina Katharina Richters ◽  
Oleg Gluz ◽  
Nana Weber-Lassalle ◽  
Matthias Christgen ◽  
Heinz Haverkamp ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase Ii ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Pathological Complete Response ◽  
Phase Ii Trial ◽  
Brca Mutation ◽  
Complete Response ◽  
Mutation Status

579 Background: The phase II trial WSG-ADAPT TN randomized triple-negative breast cancer (TNBC) patients to receive 12 weeks of neoadjuvant nab-paclitaxel (nab-pac) combined with carboplatin (carbo) vs gemcitabine (gem) and showed a substantial improvement of pathological complete response (pCR: ypT0/is, ypN0) with carbo (45.9% vs 28.7%). pCR had a strong favorable impact on iDFS after 3-year follow-up. Distribution of tumor mutations in BC-associated genes and impact of BRCA mutation status on pCR and outcome are analyzed here. Methods: NGS-based mutational analysis of BRCA1/2 and 18 further (potentially) BC-associated genes was performed on DNA derived from pretreatment FFPE samples (gem: n = 158, carbo: n = 108) using a customized gene panel. Variants with a variant fraction of ≥5% were included and classified according to IARC and ENIGMA guidelines. Results: In 42 of the 266 analyzed samples, at least one deleterious BRCA1/2-variant was found (15.8%; BRCA1 n = 37, BRCA2 n = 3, BRCA1+ BRCA2 n = 2) one of which displayed an additional STK11-mutation. In the BRCA1/2-negative cohort, a mutation in one of 14 further analyzed (potential) BC-risk genes was found in 19 samples (7.1%; BARD1 n = 3, CHEK2 n = 2, CDH1 n = 2, FANCM n = 3, PALB2 n = 5, RAD50 n = 1, RAD51C n = 1, RAD51D n = 1, XRCC2 n = 1; no deleterious mutations were found in ATM, BRIP1, MRE11A, NBN). At least one deleterious variant in TP53, PIK3CA, PTEN or MAP3K1 was seen in 89.1% (n = 237; TP53 n = 233, PIK3CA n = 22 PTEN n = 15, MAP3K1 n = 1). In 22 samples (8.3%) no deleterious mutation was identified in the analyzed genes. Overall, patients with tumor BRCA mutation (carbo n = 14, gem n = 28) had 45.2% vs 34.4% pCR (OR = 1.58, 95%-CI: 0.81-3.07, p =.18) without a mutation. pCR in the small group with mutation receiving carbo (n = 14) was 64.3% vs. 34.5% in all others (OR = 3.41, 95%-CI: 1.11-10.50; p =.03); direct comparison to BRCA-positive patients receiving gem (n = 28, 35.7%, OR = 3.2, 95%-CI: 0.85-12.36, p = 0.079) did not reach statistical significance. The results suggest that the strong favorable impact of pCR on iDFS is preserved even among BRCA-positive patients (n = 42, p =.07), as well as in the BRCA-negative subgroup (p <.001). No evidence for a predictive impact of BRCA mutation on efficacy of 4xEC additional chemotherapy was seen overall or within pCR subgroups. Conclusions: Twelve weeks of neoadjuvant nab-pac/carbo is a highly effective anthracycline-free regimen that leads to an excellent pCR-rate of 64% in tumor BRCA1/2-mutated cases. BRC A1/2 mutation status could support this de-escalation strategy in early TNBC, but further prospective validation of survival impacts in larger cohorts and with longer follow up is needed. More detailed survival analyses will be presented at the meeting. Clinical trial information: NCT01815242.

Impact of BRCA mutation status on the clinical phenotype and survival of hereditary breast cancer.

2009 ◽  
Author(s):  
M Kiechle ◽  
C Engel ◽  
U Schwarz-Boeger ◽  
D Grund ◽  
S Preisler-Adams ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hereditary Breast Cancer ◽  
Clinical Phenotype ◽  
Brca Mutation ◽  
Mutation Status

scholarly journals Germline BRCA Mutation and Clinical Outcomes in Breast Cancer Patients Focusing on Survival and Failure Patterns: A Long-Term Follow-Up Study of Koreans

Medicina ◽  
2020 ◽  
Vol 56 (10) ◽  
pp. 514
Author(s):  
Hakyoung Kim ◽  
Doo Ho Choi ◽  
Won Park
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Contralateral Breast Cancer ◽  
Brca Mutation ◽  
Contralateral Breast ◽  
Breast Cancer Patients ◽  
Mutation Status ◽  
Free Survival ◽  
Failure Patterns

Background and Objectives: This study aimed to evaluate the effect of a BRCA mutation on survival and failure patterns, focusing on the risk of ipsilateral recurrence and contralateral breast cancer in patients. Materials and Methods: We retrospectively reviewed medical records of 300 patients with breast cancer who underwent genetic screening for BRCA1/2 genes and were treated at Samsung Medical Center between 1 January 2000 and 31 December 2010. Ultimately, clinical outcomes of 273 patients were analyzed. Results: The median follow-up duration was 102 months (range, 1 to 220 months). Patients with BRCA1/2-mutated tumors had a shorter 10-year disease-free survival (DFS) rate compared to those with non-mutated tumors (62.8% vs. 80.0%, p = 0.02). Regarding failure patterns, patients with BRCA1/2-mutated tumors showed a higher incidence of contralateral breast cancer than those with non-mutated tumors (BRCA1/2 non-mutated vs. mutated tumors: 4.9% vs. 26.0%, p < 0.001). BRCA mutation status remained a significant prognostic factor for contralateral breast recurrence-free survival (HR: 4.155; 95% CI: 1.789–9.652; p = 0.001). Korean patients with a BRCA mutation showed inferior DFS compared to those without a BRCA mutation. Conclusions: BRCA mutation status is a strong predictor of recurrence in contralateral breast cancer. Strategies such as prophylactic treatment and active surveillance should be discussed with breast cancer patients who have a BRCA mutation.

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