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Adjuvant therapy; Breast cancer; Olaparib Terapia adyuvante; Cáncer de mama; Olaparib Teràpia adjuvant; Càncer de mama; Olaparib Background The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI −0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals. Funding for this work, which was conducted as a collaborative partnership among the Breast International Group, NRG Oncology, Frontier Science, AstraZeneca, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A. (MSD), was provided by the National Institutes of Health (grant numbers: U10CA 180868, UG1CA 189867, and U10CA 180822) and by AstraZeneca as part of an alliance between AstraZeneca and MSD. Provision of olaparib and placebo was from AstraZeneca.

BACKGROUND: In the BROCADE3 trial, addition of the poly(ADP-ribose) polymerase inhibitor, veliparib, to carboplatin/paclitaxel improved progression-free survival (PFS) (hazard ratio 0.71, 95% confidence interval 0.57-0.88; P = 0.002) in patients with advanced human epidermal growth factor receptor 2-negative, germline BRCA1/2-mutated breast cancer. A subset of patients discontinued both carboplatin and paclitaxel before progression and continued on veliparib/placebo maintenance monotherapy until progression. Analyses in this patient subgroup are reported. PATIENTS AND METHODS: Patients were randomized 2 : 1 to veliparib plus carboplatin/paclitaxel or placebo plus carboplatin/paclitaxel. Veliparib (120 mg twice daily) or placebo was given on days -2 to 5, carboplatin (area under the curve 6 mg/ml) on day 1, and paclitaxel (80 mg/m2) on days 1, 8, and 15 of 21-day cycles. Patients who discontinued both carboplatin and paclitaxel before progression received blinded study drug monotherapy at an increased dose of 300-400 mg twice daily continuously. PFS was the primary endpoint. Exploratory analyses were carried out in the subgroup of patients who received blinded study drug as monotherapy. A time-varying Cox model including data from all patients was also used to evaluate treatment effect in the combination and monotherapy phases. RESULTS: A total of 136 of 337 patients randomized to veliparib plus carboplatin/paclitaxel and 58/172 patients randomized to placebo plus carboplatin/paclitaxel discontinued both carboplatin and paclitaxel before progression and continued on blinded veliparib or placebo monotherapy. In this blinded monotherapy subgroup, investigator-assessed median PFS from randomization was 25.7 months with veliparib versus 14.6 months with placebo. Hazard ratios from a time-varying Cox model favored veliparib during both combination therapy and monotherapy. Any-grade adverse events occurring in the monotherapy phase were primarily gastrointestinal. The most common grade ≥3 adverse events were neutropenia and anemia (4% each with veliparib; 5% and 2%, respectively, with placebo). CONCLUSIONS: Veliparib maintenance monotherapy had a tolerable safety profile and may extend PFS following combination chemotherapy. ispartof: ANNALS OF ONCOLOGY vol:33 issue:3 pages:299-309 ispartof: location:England status: published

Supplementary Figures S1-S2; Supplementary Tables S1-S2.

Supplementary Table 1 - PDF file 57K, Supplementary Table 1. Details of platinum sensitivity and best response to olaparib and post-PARPi chemotherapy of the six patients whose tumor samples were analyzed by massively parallel sequencing. (NE: not evaluable)

Purpose: Klotho is a transmembrane protein which can be shed, act as a circulating hormone and modulate the insulin-like growth factor (IGF)-I and the fibroblast growth factor (FGF) pathways. We have recently identified klotho as a tumor suppressor in breast cancer. Klotho is expressed in the normal pancreas and both the IGF-I and FGF pathways are involved in pancreatic cancer development. We, therefore, undertook to study the expression and activity of klotho in pancreatic cancer.Experimental Design: Klotho expression was studied using immunohistochemistry and quantitative RT-PCR. Effects of klotho on cell growth were assessed in the pancreatic cancer cells Panc1, MiaPaCa2, and Colo357, using colony and MTT assays and xenograft models. Signaling pathway activity was measured by Western blotting.Results: Klotho expression is downregulated in pancreatic adenocarcinoma. Overexpression of klotho, or treatment with soluble klotho, reduced growth of pancreatic cancer cells in vitro and in vivo, and inhibited activation of the IGF-I and the bFGF pathways. KL1 is a klotho subdomain formed by cleavage or alternative splicing. Compared with the full-length protein, KL1 showed similar growth inhibitory activity but did not promote FGF23 signaling. Thus, its administration to mice showed favorable safety profile.Conclusions: These studies indicate klotho as a potential tumor suppressor in pancreatic cancer, and suggest, for the first time, that klotho tumor suppressive activities are mediated through its KL1 domain. These results suggest the use of klotho or KL1 as potential strategy for the development of novel therapeutic interventions for pancreatic cancer. Clin Cancer Res; 17(13); 4254–66. ©2011 AACR.

Supplementary methods Figure S1: The types of samples that were collected for each patient from cohort 2 (recurrence-freee patients). Figure S2: qPCR validations for Nanostring expression measurements. Figure S3: P1 miRNAs expression levels pre- and post-treatment versus normal breast tissue. Figure S4: miR-10b* expression levels. Figure S5: P1 miRNAs and their cell cycle predicted targets BUB1B and CDC25A. Figure S6: P1 scores and Ki67 levels by immunostaining. Figure S7: P1 scores in the METABRIC dataset. Figure S8: P2 miRNAs differentiate between recurrence and recurrence-free patients. Figure S9: P1 and P2 expression levels in ER-positive patients alone. Figure S10: Enrichment of EMT-induced genes in the correlated genes to P5 miRNAs. Figure S11: P5 and P6 miRNAs expression levels at post-treatment lymph nodes approach the levels at recurrence. Figure S12: Effects of the thresholds on the number of miRNAs that were classified to a pattern. Table S1: Miller and Payne grades and RCB classes Table S2: miRNAs' potential role in breast cancer from the literature Table S3: Pathway analysis; shared correlatred pathways across each pattern Table S4: Target genes for P1 miRNAs

Purpose: Molecular evolution of tumors during progression, therapy, and metastasis is a major clinical challenge and the main reason for resistance to therapy. We hypothesized that microRNAs (miRNAs) that exhibit similar variation of expression through the course of disease in several patients have a significant function in the tumorigenic process.Experimental design: Exploration of evolving disease by profiling 800 miRNA expression from serial samples of individual breast cancer patients at several time points: pretreatment, posttreatment, lymph nodes, and recurrence sites when available (58 unique samples from 19 patients). Using a dynamic approach for analysis, we identified expression modulation patterns and classified varying miRNAs into one of the eight possible temporal expression patterns.Results: The various patterns were found to be associated with different tumorigenic pathways. The dominant pattern identified an miRNA set that significantly differentiated between disease stages, and its pattern in each patient was also associated with response to therapy. These miRNAs were related to tumor proliferation and to the cell-cycle pathway, and their mRNA targets showed anticorrelated expression. Interestingly, the level of these miRNAs was lowest in matched recurrent samples from distant metastasis, indicating a gradual increase in proliferative potential through the course of disease. Finally, the average expression level of these miRNAs in the pretreatment biopsy was significantly different comparing patients experiencing recurrence to recurrence-free patients.Conclusions: Serial tumor sampling combined with analysis of temporal expression patterns enabled to pinpoint significant signatures characterizing breast cancer progression, associated with response to therapy and with risk of recurrence. Clin Cancer Res; 22(14); 3651–62. ©2016 AACR.

Purpose: Preclinical data suggest that exposure to PARP inhibitors (PARPi) may compromise benefit to subsequent chemotherapy, particularly platinum-based regimens, in patients with BRCA1/2 mutation carrier ovarian cancer (PBMCOC), possibly through the acquisition of secondary BRCA1/2 mutations. The efficacy of chemotherapy in the PARPi-resistant setting was therefore investigated.Experimental Design: We conducted a retrospective review of PBMCOC who received chemotherapy following disease progression on olaparib, administered at ≥200 mg twice daily for one month or more. Tumor samples were obtained in the post-olaparib setting where feasible and analyzed by massively parallel sequencing.Results: Data were collected from 89 patients who received a median of 3 (range 1–11) lines of pre-olaparib chemotherapy. The overall objective response rate (ORR) to post-olaparib chemotherapy was 36% (24 of 67 patients) by Response Evaluation Criteria in Solid Tumors (RECIST) and 45% (35 of 78) by RECIST and/or Gynecologic Cancer InterGroup (GCIG) CA125 criteria with median progression-free survival (PFS) and overall survival (OS) of 17 weeks [95% confidence interval (CI), 13–21] and 34 weeks (95% CI, 26–42), respectively. For patients receiving platinum-based chemotherapy, ORRs were 40% (19 of 48) and 49% (26/53), respectively, with a median PFS of 22 weeks (95% CI, 15–29) and OS of 45 weeks (95% CI, 15–75). An increased platinum-to-platinum interval was associated with an increased OS and likelihood of response following post-olaparib platinum. No evidence of secondary BRCA1/2 mutation was detected in tumor samples of six PARPi-resistant patients [estimated frequency of such mutations adjusted for sample size: 0.125 (95%-CI: 0–0.375)].Conclusions: Heavily pretreated PBMCOC who are PARPi-resistant retain the potential to respond to subsequent chemotherapy, including platinum-based agents. These data support the further development of PARPi in PBMCOC. Clin Cancer Res; 19(19); 5485–93. ©2013 AACR.

Supplementary Methods, Tables 1-3, Figure 1 from Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction

Emerging evidence reinforce the role of non-genetic adaptive resistance to chemotherapy, that involves rewiring of transcriptional programs in surviving tumors. We combined longitudinal transcriptomics with temporal pattern analysis to dissect patient-specific emergence of resistance in breast cancer. Matched triplets of tumor biopsies (pre-treatment, post-treatment and adjacent normal) were collected from breast cancer patients who received neo-adjuvant chemotherapy. Full transcriptome was analyzed by longitudinal pattern classification to follow patient-specific expression modulations. We found that dynamics of gene expression dictates resistance-related modulations. The results unraveled important principles in emergence of adaptive resistance: 1. Genes with resistance patterns are already dysregulated in the primary tumor, supporting a primed drug-tolerant state. 2. In each patient, multiple resistance-related genes are rewired but converge into few dysregulated modules. 3. Rewiring of diverse genes and pathway dysregulation vary among individuals who receive the same treatments. Patient-specific chemoresistome maps disclosed tumors’ acquired resistance and exposed their vulnerabilities.Mapping the complexity of dysregulated pathways in individual patients revealed important insights on adaptive resistance mechanisms. To survive the toxic drug effect, tumor cells either sustain a drug-tolerant state or intensify it, specifically bypassing the drug’s interference. Depicting an individual road map to resistance can offer personalized therapeutic strategies.

BACKGROUND: Addition of veliparib to carboplatin-paclitaxel, with continuation of veliparib monotherapy if carboplatin-paclitaxel was discontinued, improved progression-free survival (PFS) in patients with germline BRCA-associated locally advanced/metastatic HER2- breast cancer and ≤2 lines of previous cytotoxic therapy for metastatic disease in BROCADE3. A pre-planned subgroup analysis evaluated efficacy and safety in patients without previous cytotoxic therapy for metastatic disease. METHODS: Patients were randomised 2:1 to receive veliparib (120 mg orally BID) or placebo on days -2 to 5. Carboplatin (AUC 6) was administered on day 1, and paclitaxel (80 mg/m2) on days 1, 8 and 15 (21-day cycles). Patients discontinuing carboplatin-paclitaxel for reasons besides progression could continue veliparib/placebo monotherapy (300 mg BID, increasing to 400 mg BID if tolerated) until progression. The primary end-point was PFS assessed by investigator. RESULTS: Of 509 patients in the intention-to-treat population (98.6% female; mean age 47, standard deviation 11), 413 (81%) had no previous cytotoxic therapy for metastatic disease (274, veliparib; 139, placebo). In the first-line subgroup, median PFS was 16.6 months (95% confidence interval [CI] 13.4-18.7) versus 13.1 months (95% CI 11.4-14.5) for the veliparib versus control groups (hazard ratio 0.70, 95% CI 0.54-0.89, P = .004). More patients were alive and progression-free at 2 years (36% versus 23.2%) and 3 years (27.9% versus 13.3%) in the veliparib versus control group. Adverse events unrelated to progression leading to study drug discontinuation occurred in 25 (9.1%) and 8 (5.8%) patients. CONCLUSIONS: Veliparib with carboplatin-paclitaxel led to durable disease control among first-line patients, suggesting a benefit of this treatment approach in early lines. CLINICAL TRIAL REGISTRATION: NCT02163694. ispartof: European Journal Of Cancer vol:154 pages:35-45 ispartof: location:England status: accepted

Background In the KATHERINE study (NCT01772472), patients with residual invasive early breast cancer (EBC) after neoadjuvant chemotherapy (NACT) plus human epidermal growth factor receptor 2 (HER2)-targeted therapy had a 50% reduction in risk of recurrence or death with adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab. Here, we present additional exploratory safety and efficacy analyses. Patients and methods KATHERINE enrolled HER2-positive EBC patients with residual invasive disease in the breast/axilla at surgery after NACT containing a taxane (± anthracycline, ± platinum) and trastuzumab (± pertuzumab). Patients were randomized to adjuvant T-DM1 (n = 743) or trastuzumab (n = 743) for 14 cycles. The primary endpoint was invasive disease-free survival (IDFS). Results The incidence of peripheral neuropathy (PN) was similar regardless of neoadjuvant taxane type. Irrespective of treatment arm, baseline PN was associated with longer PN duration (median, 105-109 days longer) and lower resolution rate (∼65% versus ∼82%). Prior platinum therapy was associated with more grade 3-4 thrombocytopenia in the T-DM1 arm (13.5% versus 3.8%), but there was no grade ≥3 hemorrhage in these patients. Risk of recurrence or death was decreased with T-DM1 versus trastuzumab in patients who received anthracycline-based NACT [hazard ratio (HR) = 0.51; 95% confidence interval (CI): 0.38-0.67], non-anthracycline-based NACT (HR = 0.43; 95% CI: 0.22-0.82), presented with cT1, cN0 tumors (0 versus 6 IDFS events), or had particularly high-risk tumors (HRs ranged from 0.43 to 0.72). The central nervous system (CNS) was more often the site of first recurrence in the T-DM1 arm (5.9% versus 4.3%), but T-DM1 was not associated with a difference in overall risk of CNS recurrence. Conclusions T-DM1 provides clinical benefit across patient subgroups, including small tumors and particularly high-risk tumors and does not increase the overall risk of CNS recurrence. NACT type had a minimal impact on safety.

BackgroundPoly(adenosine diphosphate-ribose) polymerase inhibitors target cancers with defects in homologous recombination repair by synthetic lethality. New therapies are needed to reduce recurrence in patients with BRCA1 or BRCA2 germline mutation-associated early breast cancer.MethodsWe conducted a phase 3, double-blind, randomized trial involving patients with human epidermal growth factor receptor 2 (HER2)-negative early breast cancer with BRCA1 or BRCA2 germline pathogenic or likely pathogenic variants and high-risk clinicopathological factors who had received local treatment and neoadjuvant or adjuvant chemotherapy. Patients were randomly assigned (in a 1:1 ratio) to 1 year of oral olaparib or placebo. The primary end point was invasive disease-free survival.ResultsA total of 1836 patients underwent randomization. At a prespecified event-driven interim analysis with a median follow-up of 2.5 years, the 3-year invasive disease-free survival was 85.9% in the olaparib group and 77.1% in the placebo group (difference, 8.8 percentage points; 95% confidence interval [CI], 4.5 to 13.0; hazard ratio for invasive disease or death, 0.58; 99.5% CI, 0.41 to 0.82; P

Purpose: Safety, efficacy, and exploratory biomarker analyses were evaluated in patients with advanced HER2-negative germline breast cancer susceptibility gene (gBRCA)-associated breast cancer enrolled in the BROCADE3 trial who received crossover veliparib monotherapy after disease progression on placebo plus carboplatin/paclitaxel. Patients and Methods: Eligible patients (N = 513) were randomized 2:1 to veliparib plus carboplatin/paclitaxel or placebo plus carboplatin/paclitaxel; patients had variable platinum-free intervals (PFI) at progression. In the placebo arm, patients were eligible to receive crossover veliparib monotherapy (300–400 mg twice daily continuous). Antitumor activity and adverse events were assessed during crossover veliparib treatment. BRCA reversion mutations at crossover were analyzed retrospectively using next-generation sequencing on plasma circulating tumor DNA (ctDNA). Results: Seventy-five patients in the placebo plus carboplatin/paclitaxel arm received ≥1 dose of crossover veliparib postprogression (mean treatment duration: 154 days). Eight of 50 (16%) patients with measurable disease had a RECIST v1.1 response. Activity was greater in patients with PFI ≥180 days compared with Conclusions: Crossover veliparib monotherapy demonstrated limited antitumor activity in patients who experienced disease progression on placebo plus carboplatin/paclitaxel. PFI appeared to affect veliparib activity. BRCA reversion mutations may promote cross-resistance and limit veliparib activity following progression on platinum.

Background Treatment with immune checkpoint inhibitors (ICI) has greatly improved survival for patients with a number of malignant diseases in recent years. Neurological immune-related adverse events (n-irAE) of varying severity have been reported in the literature. We aimed to identify the incidence of n-irAE, focusing on immune-related encephalitis (IRE), in patients treated with ICI for multiple non-hematological malignancies in our institution. Methods All patients with histologically verified cancer that received treatment with ICI at the Sheba Medical Center between January 2017 and August 2019 were surveyed. Medical records for each patient were reviewed and information regarding n-irAE was recorded. Results In total, 1993 patients were included. Eleven cases of IRE were recorded, affecting 0.55% of patients overall, eight had non-melanoma cancer. Eight patients had made a full recovery. Conclusions IRE is a n-irAE more frequent than previously reported, particularly in non-melanoma patients. The diagnostic criteria and optimal treatment needs to be determined. ICI re-challenge after IRE can be considered for selected patients.

There is a paucity of data on the rates of ipsilateral breast tumor recurrence (IBTR) in BRCA1/2-associated breast cancer (BC). Scarcer yet are outcomes data in BRCA1/2 mutation carriers in the setting of newer mastectomy techniques, such as skin-sparing mastectomies (SSM) and nipple-sparing mastectomies (NSM).Data were extracted from the medical records of BRCA1/2 carriers who were diagnosed with BC and treated at a single institution between 2006 and 2020. The data extracted included patient demographics, tumor characteristics, disease stage, surgical treatment, use of radiation therapy (RT), and disease outcome.Overall, 255 BC patients with BRCA1/2 germline mutations were identified. Of these, 128 (50.2%) underwent a mastectomy (SSM or NSM in 82% of them), 76 (59.4%) without postmastectomy RT (non-PMRT) and 52 (40.6%) with PMRT, whereas 127 (49.8%) elected for breast-conserving treatment (BCT). The non-PMRT group had earlier disease stages (82.3% were Tis and T1N0) compared with the PMRT and BCT groups (3.6% and 48.1%, respectively; P.05). The IBTR cumulative rate was 9 of 76 (11.8%) in the non-PMRT cohort compared with 0 of 52 in the PMRT group (P = .01) and 6 of 127 (4.7%) in the BCT group (P = .06). The cumulative incidences of IBTR at 5 and 10 years were 9.8% and 27.4%, respectively, in the non-PMRT group versus 2% and 11.3%, respectively, in the BCT group (P = .0183). No significant difference in overall survival was observed at the time of follow-up.BRCA1/2 mutation carriers treated with mastectomy without PMRT had higher rates of IBTR than those who underwent mastectomy and PMRT or BCT, despite earlier stages of disease. The safety of SSM/NSM should be evaluated in a prospective trial.

Advanced Breast Cancer; Efficacy; Margetuximab Cáncer de mama avanzado; Eficacia; Margetuximab Càncer de mama avançat; Eficàcia; Margetuximab Importance ERRB2 (formerly HER2)–positive advanced breast cancer (ABC) remains typically incurable with optimal treatment undefined in later lines of therapy. The chimeric antibody margetuximab shares ERBB2 specificity with trastuzumab but incorporates an engineered Fc region to increase immune activation. Objective To compare the clinical efficacy of margetuximab vs trastuzumab, each with chemotherapy, in patients with pretreated ERBB2-positive ABC. Design, Setting, and Participants The SOPHIA phase 3 randomized open-label trial of margetuximab plus chemotherapy vs trastuzumab plus chemotherapy enrolled 536 patients from August 26, 2015, to October 10, 2018, at 166 sites in 17 countries. Eligible patients had disease progression on 2 or more prior anti-ERBB2 therapies and 1 to 3 lines of therapy for metastatic disease. Data were analyzed from February 2019 to October 2019. Interventions Investigators selected chemotherapy before 1:1 randomization to margetuximab, 15 mg/kg, or trastuzumab, 6 mg/kg (loading dose, 8 mg/kg), each in 3-week cycles. Stratification factors were metastatic sites (≤2, >2), lines of therapy (≤2, >2), and chemotherapy choice. Main Outcomes and Measures Sequential primary end points were progression-free survival (PFS) by central blinded analysis and overall survival (OS). All α was allocated to PFS, followed by OS. Secondary end points were investigator-assessed PFS and objective response rate by central blinded analysis. Results A total of 536 patients were randomized to receive margetuximab (n = 266) or trastuzumab (n = 270). The median age was 56 (27-86) years; 266 (100%) women were in the margetuximab group, while 267 (98.9%) women were in the trastuzumab group. Groups were balanced. All but 1 patient had received prior pertuzumab, and 489 (91.2%) had received prior ado-trastuzumab emtansine. Margetuximab improved primary PFS over trastuzumab with 24% relative risk reduction (hazard ratio [HR], 0.76; 95% CI, 0.59-0.98; P = .03; median, 5.8 [95% CI, 5.5-7.0] months vs 4.9 [95% CI, 4.2-5.6] months; October 10, 2018). After the second planned interim analysis of 270 deaths, median OS was 21.6 months with margetuximab vs 19.8 months with trastuzumab (HR, 0.89; 95% CI, 0.69-1.13; P = .33; September 10, 2019), and investigator-assessed PFS showed 29% relative risk reduction favoring margetuximab (HR, 0.71; 95% CI, 0.58-0.86; P

Abnormal molecular processes occurring throughout the genome leave distinct somatic mutational patterns termed mutational signatures. Exploring the associations between mutational signatures and clinicopathological features can unravel potential mechanisms driving tumorigenic processes. We analyzed whole genome sequencing (WGS) data of tumor and peripheral blood samples from 37 primary breast cancer (BC) patients receiving neoadjuvant chemotherapy. Comprehensive clinico-pathologic features were correlated with genomic profiles and mutational signatures. Somatic mutational landscapes were highly concordant with known BC data sets. Remarkably, we observed a divergence of dominant mutational signatures in association with BC subtype. Signature 5 was overrepresented in hormone receptor positive (HR+) patients, whereas triple-negative tumors mostly lacked Signature 5, but expectedly overrepresented Signature 3. We validated these findings in a large WGS data set of BC, demonstrating dominance of Signature 5 in HR+ patients, mostly in luminal A subtype. We further investigated the association between Signature 5 and gene expression signatures, and identified potential networks, likely related to estrogen regulation. Our results suggest that the yet elusive Signature 5 represents an alternative mechanism for mutation accumulation in HR+ BC, independent of the homologous recombination repair machinery related to Signature 3. This study provides theoretical basis for further elucidating the processes promoting hormonal breast carcinogenesis.

BACKGROUND: Poly (ADP-ribose) polymerase inhibitors combined with immunotherapy have shown antitumour activity in preclinical studies. We aimed to assess the safety and activity of olaparib in combination with the PD-L1-inhibitor, durvalumab, in patients with germline BRCA1-mutated or BRCA2-mutated metastatic breast cancer.METHODS: The MEDIOLA trial is a multicentre, open-label, phase 1/2, basket trial of durvalumab and olaparib in solid tumours. Patients were enrolled into four initial cohorts: germline BRCA-mutated, metastatic breast cancer; germline BRCA-mutated, metastatic ovarian cancer; metastatic gastric cancer; and relapsed small-cell lung cancer. Here, we report on the cohort of patients with breast cancer. Patients who were aged 18 years or older (or aged 19 years or older in South Korea) with germline BRCA1-mutated or BRCA2-mutated or both and histologically confirmed, progressive, HER2-negative, metastatic breast cancer were enrolled from 14 health centres in the UK, the USA, Israel, France, Switzerland, and South Korea. Patients should not have received more than two previous lines of chemotherapy for metastatic breast cancer. Patients received 300 mg olaparib in tablet form orally twice daily for 4 weeks and thereafter a combination of olaparib 300 mg twice daily and durvalumab 1·5 g via intravenous infusion every 4 weeks until disease progression. Primary endpoints were safety and tolerability, and 12-week disease control rate. Safety was analysed in patients who received at least one dose of study treatment, and activity analyses were done in the full-analysis set (patients who received at least one dose of study treatment and were not excluded from the study). Recruitment has completed and the study is ongoing. This trial is registered with ClinicalTrials.gov, NCT02734004.FINDINGS: Between June 14, 2016, and May 2, 2017, 34 patients were enrolled and received both study drugs and were included in the safety analysis. 11 (32%) patients experienced grade 3 or worse adverse events, of which the most common were anaemia (four [12%]), neutropenia (three [9%]), and pancreatitis (two [6%]). Three (9%) patients discontinued due to adverse events and four (12%) patients experienced a total of six serious adverse events. There were no treatment-related deaths. 24 (80%; 90% CI 64·3-90·9) of 30 patients eligible for activity analysis had disease control at 12 weeks.INTERPRETATION: Combination of olaparib and durvalumab showed promising antitumour activity and safety similar to that previously observed in olaparib and durvalumab monotherapy studies. Further research in a randomised setting is needed to determine predictors of therapeutic benefit and whether addition of durvalumab improves long-term clinical outcomes compared with olaparib monotherapy.FUNDING: AstraZeneca.

In view of the relatively limited efficacy of immunotherapies targeting the PD-1–PD-L1 axis in triple-negative breast cancer (TNBC) and of published reports on tumor-promoting roles of TNFR2+ tumor-infiltrating lymphocytes (TNFR2+ TILs), we determined the incidence of TNFR2+ TILs in TNBC patient tumors, their association with disease outcome and relations with PD-1+ TILs. Using a cohort of treatment-naive TNBC patients with long follow-up (n = 70), we determined the presence of TNFR2+ TILs and PD-1+ TILs by immunohistochemistry. TILs (≥ 1% of cellular mass) and TNFR2+ TILs (≥ 1% of total TILs) were detected in 96% and 74% of tumors, respectively. The presence of TILs at > 5% of tumor cell mass (“Positive TILs”), as well as of positive TNFR2+ TILs (> 5%), was independently associated with good prognosis, and combination of both parameters demonstrated superior outcome relative to their lower levels. PD1+ TILs (> 5/hot spot) were detected in 63% of patients. High levels of PD-1+ TILs (> 20/hot spot) showed an unfavorable disease outcome, and in their presence, the favorable outcome of positive TNFR2+ TILs was ablated. Thus, TNFR2+ TILs are strongly connected to improved prognosis in TNBC; these findings suggest that TNFR2+ TILs have favorable effects in TNBC patients, unlike the tumor-promoting roles attributed to them in other cancer systems. Overall, our observations propose that the TNFR2+ TIL subset should not be targeted in the course of TNBC therapy; rather, its beneficial impacts may become into power when anti-PD-1 regimens—that may potentiate immune activities—are administered to TNBC patients.

Purpose: To investigate the activity of niraparib in patients with germline-mutated BRCA1/2 (gBRCAm) advanced breast cancer. Patients and Methods: BRAVO was a randomized, open-label phase III trial. Eligible patients had gBRCAm and HER2-negative advanced breast cancer previously treated with ≤2 prior lines of chemotherapy for advanced breast cancer or had relapsed within 12 months of adjuvant chemotherapy, and were randomized 2:1 between niraparib and physician’s choice chemotherapy (PC; monotherapy with eribulin, capecitabine, vinorelbine, or gemcitabine). Patients with hormone receptor–positive tumors had to have received ≥1 line of endocrine therapy and progressed during this treatment in the metastatic setting or relapsed within 1 year of (neo)adjuvant treatment. The primary endpoint was centrally assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), PFS by local assessment (local-PFS), objective response rate (ORR), and safety. Results: After the pre-planned interim analysis, recruitment was halted on the basis of futility, noting a high degree of discordance between local and central PFS assessment in the PC arm that resulted in informative censoring. At the final analysis (median follow-up, 19.9 months), median centrally assessed PFS was 4.1 months in the niraparib arm (n ¼ 141) versus 3.1 months in the PC arm [n ¼ 74; hazard ratio (HR), 0.96; 95% confidence interval (CI), 0.65–1.44; P ¼ 0.86]. HRs for OS and local-PFS were 0.95 (95% CI, 0.63–1.42) and 0.65 (95% CI, 0.46–0.93), respectively. ORR was 35% (95% CI, 26–45) with niraparib and 31% (95% CI, 19–46) in the PC arm. Conclusions: Informative censoring in the control arm prevented accurate assessment of the trial hypothesis, although there was clear evidence of niraparib’s activity in this patient population., SCOPUS: ar.j, info:eu-repo/semantics/published

Background: Veliparib (Vel) is a potent PARP1/2 inhibitor with demonstrated antitumor activity when administered alone or combined with carboplatin and paclitaxel (C/P). The phase 3 randomized, double-blind, multicenter BROCADE3 study (NCT02163694) evaluated the efficacy and safety of Vel + C/P treatment compared with placebo (Pbo) + C/P treatment in patients (pts) with germline BRCA1/2 mutations and HER2-negative metastatic or locally advanced breast cancer (BC). Vel + C/P significantly prolonged progression-free survival (PFS) compared with Pbo + C/P treatment (14.5 months [mo] vs 12.6 mo, hazard ratio [HR]=0.71 [95% CI: 0.57, 0.88]; P=0.002). Previous studies have identified increased acute hematologic toxicity in response to chemotherapy in pts with BC carrying BRCA1 mutations compared with BRCA2 mutations or wildtype BRCA1/2. Herein we report a subgroup analysis of the efficacy and safety of Vel + C/P treatment in pts with BRCA1- or BRCA2-positive BC. Methods: Pts ≥18 years of age who received ≤2 prior lines of cytotoxic chemotherapy for metastatic disease were randomized 2:1 to receive Vel + C/P or Pbo + C/P: Vel (120 mg PO BID) or Pbo on days -2 to 5, C (AUC 6 IV) on day 1, and P (80 mg/m2 IV) on days 1, 8, and 15 in 21-day cycles. Pts who discontinued C/P in the absence of disease progression could continue receiving Vel or Pbo monotherapy (300-400 mg BID continuous). Subgroup analysis of PFS stratified by BRCA1/2 status was preplanned. The primary endpoint was investigator-assessed PFS. Adverse events (AEs) were graded according to NCI CTCAE version 4.0. Ten pts with both BRCA1 and BRCA2 mutations were excluded from the analyses presented here. Results: In the intent-to-treat population, 256 pts had BRCA1 mutations and 243 pts had BRCA2 mutations. The proportion of as-treated pts with BRCA1 or BRCA2 mutations was comparable between the Vel + C/P (51.4% BRCA1, 48.6% BRCA2) and Pbo + C/P (50.9% BRCA1, 49.1% BRCA2) study arms. Investigator-assessed PFS for the Vel + C/P and Pbo + C/P arms was 14.2 mo vs 12.6 mo, respectively, in the BRCA1 subgroup (HR=0.75 [95% CI: 0.55, 1.03]; P=0.073) and 14.6 mo vs 12.6 mo, respectively, in the BRCA2 subgroup (HR=0.69 [95% CI: 0.50, 0.95]; P=0.021). Safety data in the as-treated population are presented in the Table. Regarding any grade AEs, thrombocytopenia and anemia were slightly more frequent in pts in the BRCA1 subgroup compared with the BRCA2 subgroup, whereas pts in the BRCA2 subgroup experienced slightly more frequent nausea, fatigue, and neuropathy. Conclusions: Globally, there was no clinically relevant difference in toxicity between BRCA1 and BRCA2 subgroups. Comparisons between treatment arms were generally consistent with findings in the overall study population, with more frequent thrombocytopenia and anemia of any grade reported in the Vel + C/P arm within both the BRCA1 and BRCA2 subgroups. Vel + C/P treatment improved PFS similarly in both BRCA1 and BRCA2 subgroups over C/P alone. BRCA1-Positive Subgroup (n=253)BRCA2-Positive Subgroup (n=241)Vel + C/P (n=168)Pbo + C/P (n=85)Vel + C/P (n=159)Pbo + C/P (n=82)Any grade AE [≥50% of pts], n (%)Any event167 (99.4)85 (100)158 (99.4)82 (100)Neutropenia151 (89.9)78 (91.8)140 (88.1)74 (90.2)Thrombocytopenia140 (83.3)66 (77.6)124 (78.0)54 (65.9)Anemia139 (82.7)64 (75.3)122 (76.7)52 (63.4)Nausea118 (70.2)49 (57.6)119 (74.8)58 (70.7)Alopecia89 (53.0)43 (50.6)89 (56.0)41 (50.0)Fatigue79 (47.0)37 (43.5)87 (54.7)48 (58.5)Peripheral sensory neuropathy69 (41.1)37 (43.5)82 (51.6)49 (59.8)Any grade ≥3 AE [≥30% of pts], n (%)Any event164 (97.6)82 (96.5)152 (95.6)77 (93.9)Anemia73 (43.5)31 (36.5)67 (42.1)35 (42.7)Leukopenia54 (32.1)20 (23.5)44 (27.7)25 (30.5)Neutropenia136 (81.0)72 (84.7)131 (82.4)67 (81.7)Thrombocytopenia72 (42.9)30 (35.3)59 (37.1)18 (22.0)Serious AEs, n (%)58 (34.5)26 (30.6)56 (35.2)22 (26.8)AEs of special interest, n (%)Infections within 14 days of neutropenia64 (38.1)34 (40.0)59 (37.1)25 (30.5)Hemorrhages within 14 days of thrombocytopenia14 (8.3)5 (5.9)17 (10.7)7 (8.5)Any AE leading to study drug discontinuation not due to disease progression, n (%)16 (9.5)5 (5.9)15 (9.4)4 (4.9)Any AE leading to study drug interruption, n (%)153 (91.1)77 (90.6)139 (87.4)67 (81.7)Any AE leading to study drug reduction, n (%)28 (16.7)6 (7.1)27 (17.0)7 (8.5)Any AE leading to death with reasonable possibility related to study drug, n (%)0 (0)0 (0)0 (0)0 (0)AE, adverse event; BRCA, breast cancer susceptibility gene; C/P, carboplatin plus paclitaxel; Pbo, placebo; pts, patients; Vel, veliparib. Citation Format: Hans Wildiers, Jean-Pierre Ayoub, Michael Friedlander, Bella Kaufman, Banu K. Arun, Hyo S. Han, Shannon L. Puhalla, David Maag, Dai Feng, Christine K. Ratajczak, Bruce A. Bach, Véronique Diéras. Safety and efficacy of veliparib plus carboplatin/paclitaxel in patients with HER2-negative metastatic or locally advanced breast cancer: A subgroup analysis of germline BRCA1 or BRCA2 mutations from the phase 3 BROCADE3 trial [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 PS11-03.

Background: Annual MRI screening is associated with a significant reduction in the incidence of advanced-stage breast cancer (BC) in BRCA1/2 mutation carriers. The purpose of our study was to assess stage at diagnosis and therapeutic approaches in BRCA1/2 carriers and compare these parameters in women who developed BC while adhering to the recommended surveillance scheme ("known carriers"), with BC cases who became aware of their BRCA carreirship after BC diagnosis ("latent carriers"). Methods: Retrospective data were collected on BRCA1/2 mutation carriers treated for BC at the Sheba medical center, both at the oncology institute and the high-risk clinic. The main variables evaluated were tumor characteristics, stage at diagnosis, and treatment decisions. Results: Overall, 529 BRCA1/2 carriers were identified. At the time of data summary, relevant clinical information was available for 297 patients. Median follow-up time was 77.4 months (range, 2.5-519). The group of known carriers included 95 women (median age at diagnosis 41.9 [range 27.8-80.3 years]), 70 (74%) were BRCA1 carriers, 23 (24%) BRCA2 carriers, and 2 (2.1%) carried mutations in both genes. The median age at diagnosis of 202 latent carriers was 43.7 (range 23.8-75 years), p=0.8284. Of latent carriers 117 (58%) were BRCA1 mutation carriers and 85 (42%) harbored a BRCA2 mutation. In the group of known carriers, 19% were diagnosed with carcinoma in situ (DCIS) vs. 5% in the group of latent carriers (p=00012). Stage T1N0 disease was diagnosed in 54/95 (56.8%) of known carriers vs. 59/202 (29.2%) of latent carriers (p Overall, in the group of known carriers (including all stages) 46/95 (48.4%) received neoadjuvant (n=12) or adjuvant (n=34) chemotherapy (71.7% of them for triple-negative disease), and 41/95 (43.2%) received radiotherapy. In the group of latent carriers, 162/202 (80.2%) received neoadjuvant (n=74) or adjuvant (n=88) chemotherapy (p Contralateral risk-reducing mastectomy (CRRM) was performed by 59/95 (62%) of the known carriers, 73% of them at the time of primary tumor resection and the rest – at a later stage. Among latent carriers, 82/202 (40.6%) underwent CRRM, 44% at the time of primary tumor resection (p=0.00054). Conclusions: As expected, diagnosis of early stage disease (DCIS or T1N0) was significantly higher in the group of known BRCA1/2 carriers - disease that was diagnosed in the course of tight surveillance. Yet, despite this early stage diagnosis, chemotherapy and radiotherapy treatments were employed in a substantial proportion of these cases. Healthy BRCA1/2 mutation carriers should be informed about these chemotherapy and radiotherapy rates while discussing risk-reducing surgical options. There is an urgent need for a more accurate ability to predict individual mutation carrier cancer risk, as well as tools for selection of patients with stage I triple-negative disease who will do well without chemotherapy. Citation Format: Rinat Bernstein Molho, Bella Kaufman, Merav A Ben David, Miri Sklair-Levy, Yael Laitman, Eitan Friedman. Surveillance for BRCA1/2 mutation carriers - Is "early detection" really early enough? [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 P5-08-10.

Background: The RS assay is widely used in ER+ HER2-negative BC to guide treatment decisions. In TAILORx, RS distribution was similar in blacks vs whites and in Hispanics vs non-Hispanics. Also, TAILORx analyses revealed similar results across ethnic groups with endocrine therapy being consistently noninferior to chemotherapy (CT) plus endocrine therapy in RS 11-25 pts. We investigated RS distribution among Jewish vs Arab/Druze pts who underwent RS testing through Clalit Health Services (CHS), the largest HMO in Israel, as well as differences in CT use and clinical outcomes between these 2 ethnic groups. Methods: The RS distribution analysis included all CHS pts (regardless of nodal status) who were tested between 1/2006 and 2/2019. For the clinical outcomes analysis, we employed a dataset used in prior analyses (Stemmer et al, poster# 249, SG-BCC 2019) of node-negative pts who were tested between 1/2006 and 12/2009, and as such, it is a subset of the cohort used for the RS distribution analysis. The study was approved by the IRB of the CHS Community Division and was granted a waiver for obtaining pt consent. Results: The RS distribution analysis involved 9054 pts who were tested in the evaluated timeframe and for whom RS results and ethnicity information were available. These included 8223 (91%) Jews and 831 (9%) Arabs/Druze, approximately reflecting the proportion of BC cases diagnosed in the respective ethnic groups. The 2 groups were similar in their baseline pt/tumor characteristics except for age and tumor size (Table). RS distribution was also similar between the 2 ethnic groups (Table). The subset of node-negative pts for whom treatment and clinical outcomes are known included 1274 (93%) Jewish pts and 91 (7%) Arab/Druze pts. In this subset, the only statistically significant difference in pt/tumor characteristics between the ethnic groups was age (median [interquartile range]) of 60 [53-66] yrs in the Jewish pts vs 55 [48-63] yrs in the Arab/Druze pts; P=.0004), similar to the complete cohort. The RS distribution was similar to that in the larger cohort, with no significant differences between the ethnic groups (P=.75). Also, CT use was consistent with the RS result in both ethnic groups, and was overall somewhat higher among Arab/Druze pts (25% vs 19%), due primarily to higher CT use among Arabs/Druze pts in the largest RS category (11-25), in which significant differences with respect to age were noted (median [interquartile range], 59 [52-66] yrs in Jewish pts vs 52 [46-61] yrs in Arab/Druze pts; P Conclusions: RS distribution and clinical outcomes were similar in Jewish and Arab/Druze BC pts. Arab/Druze pts undergoing RS testing were overall younger than the Jewish pts, which may suggest under-diagnosis and/or under-testing in the older Arab/Druze pt population. Also, CT use seemed higher in the Arab/Druze pt population, possibly reflecting the differences in the age distribution between these ethnic groups. Table: Patient/tumor characteristics by ethnicityJewsArabs/DruzeP valuen = 8223n = 831Female, n (%)8132 (98.9%)825 (99.3%).3Median (interquartile range) age, years62 (53-68)55 (48-64)1 - 2 cm4233 (51.5%)411 (49.5%)>22153 (26.2%)302 (36.3%)Unknown123 (1.5%)6 (0.7%)Tumor grade category, n (%).12Grade 11109 (13.4%)123 (14.8%)Grade 24192 (51.0%)443 (53.3%)Grade 31389 (16.9%)120 (14.4%)Not applicable/Unknown1533 (18.6%)145 (17.4%)Histology, n (%).92IDC6530 (79.4%)665 (80.0%)ILC1113 (13.5%)113 (13.6%)Papillary79 (1.0%)10 (1.2%)Mucinous/colloid144 (1.8%)16 (1.9%)Other/unknown357 (4.3%)27 (3.2%)Recurrence Score category, n (%).170-101612 (19.6%)176 (21.2%)11-255091 (61.9%)522 (62.8%)26-1001520 (18.5%)133 (16.0%) Citation Format: Gil Bar Sela, Yousef Samih, Rinat Yerushalmi, Michelle Leviov, Noa Efrat Ben-Baruch, Iryna Kuchuk, Margarita Tokar, Tamar Peretz, Amir L Sonnenblick, Lior Soussan-Gutman, Avital Bareket-Samish, Georgeta Fried, Shani Paluch-Shimon, Bella Kaufman, Ariel Hammerman, Nicky Liebermann, Salomon M Stemmer. Ethnicity, recurrence score (RS) distribution, and clinical outcomes in ER+ HER2-negative breast cancer (BC) patients (pts) in Israel [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 P1-10-16.

Background PIK3CA mutations occur in approximately 40% of patients with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer. The PI3Kα-sp...

Background Women who carry germ-line mutations in BRCA1/2 are at very high risk of developing breast and ovarian cancer. Breast conserving therapy is associated with a similar risk of ipsilateral cancer recurrence in BRCA carriers compared with non-carriers. However, the risk of subsequent contralateral breast cancer in carriers is markedly increased. Therefore, mastectomy of the diseased breast along with risk reducing mastectomy of the contralateral breast is often advocated for BRCA carriers who are treated for early breast cancer. Yet, many BRCA carriers forgo this option for fear of harmful effects and choose breast conserving treatment and observation instead. In Israel, BRCA-associated breast cancer is relatively common. Accordingly, a national protocol was devised for this enriched population. Patients and methods In this Institutional Review Board-approved phase II trial, the option of prophylactic irradiation to the contralateral breast, in addition to standard loco-regional treatment, was offered to BRCA carrier patients treated for early breast cancer who declined contralateral mastectomy. The primary end point was contralateral breast cancer. Results Between May 2007 and October 2017, 162 patients were enrolled. Eighty-one patients opted for standard loco-regional treatment including surgery and radiation to the involved side (control arm) and 81 patients chose additional contralateral breast irradiation (intervention arm). At a median follow-up of 58 months, 10 patients developed contralateral breast cancer in the control arm at a median of 32 months, as compared with 2 patients in the intervention arm who developed contralateral breast cancer 80 and 105 months after bilateral breast irradiation (log-rank P = 0.011). Conclusions Among BRCA carrier patients treated for early breast cancer, the addition of contralateral breast irradiation was associated with a significant reduction of subsequent contralateral breast cancers and a delay in their onset. Clinical trial Phase II, comparative two-arm trial (NCT00496288).

Background Activation of the phosphatidylinositol-3-kinase (PI3K) pathway via PIK3CA mutations occurs in 28%-46% of hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2−) advanced breast cancers (ABCs) and is associated with poor prognosis. The SOLAR-1 trial showed that the addition of alpelisib to fulvestrant treatment provided statistically significant and clinically meaningful progression-free survival (PFS) benefit in PIK3CA-mutated, HR+, HER2− ABC. Patients and methods Men and postmenopausal women with HR+, HER2− ABC whose disease progressed on or after aromatase inhibitor (AI) were randomized 1 : 1 to receive alpelisib (300 mg/day) plus fulvestrant (500 mg every 28 days and once on day 15) or placebo plus fulvestrant. Overall survival (OS) in the PIK3CA-mutant cohort was evaluated by Kaplan–Meier methodology and a one-sided stratified log-rank test was carried out with an O'Brien–Fleming efficacy boundary of P ≤ 0.0161. Results In the PIK3CA-mutated cohort (n = 341), median OS [95% confidence interval (CI)] was 39.3 months (34.1-44.9) for alpelisib-fulvestrant and 31.4 months (26.8-41.3) for placebo-fulvestrant [hazard ratio (HR) = 0.86 (95% CI, 0.64-1.15; P = 0.15)]. OS results did not cross the prespecified efficacy boundary. Median OS (95% CI) in patients with lung and/or liver metastases was 37.2 months (28.7-43.6) and 22.8 months (19.0-26.8) in the alpelisib-fulvestrant and placebo-fulvestrant arms, respectively [HR = 0.68 (0.46-1.00)]. Median times to chemotherapy (95% CI) for the alpelisib-fulvestrant and placebo-fulvestrant arms were 23.3 months (15.2-28.4) and 14.8 months (10.5-22.6), respectively [HR = 0.72 (0.54-0.95)]. No new safety signals were observed with longer follow-up. Conclusions Although the analysis did not cross the prespecified boundary for statistical significance, there was a 7.9-month numeric improvement in median OS when alpelisib was added to fulvestrant treatment of patients with PIK3CA-mutated, HR+, HER2− ABC. Overall, these results further support the statistically significant prolongation of PFS observed with alpelisib plus fulvestrant in this population, which has a poor prognosis due to a PIK3CA mutation. ClinicalTrials.gov Id NCT02437318.

BACKGROUND: BRCA1 or BRCA2-mutated breast cancers are sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors and platinum agents owing to deficiency in homologous recombination repair of DNA damage. In this trial, we compared veliparib versus placebo in combination with carboplatin and paclitaxel, and continued as monotherapy if carboplatin and paclitaxel were discontinued before progression, in patients with HER2-negative advanced breast cancer and a germline BRCA1 or BRCA2 mutation.METHODS: BROCADE3 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 147 hospitals in 36 countries. Eligible patients (aged ≥18 years) had deleterious germline BRCA1 or BRCA2 mutation-associated, histologically or cytologically confirmed advanced HER2-negative breast cancer, an Eastern Cooperative Oncology Group performance status of 0-2, and had received up to two previous lines of chemotherapy for metastatic disease. Patients were randomly assigned (2:1) by interactive response technology by means of permuted blocks within strata (block size of 3 or 6) to carboplatin (area under the concentration curve 6 mg/mL per min intravenously) on day 1 and paclitaxel (80 mg/m2 intravenously) on days 1, 8, and 15 of 21-day cycles combined with either veliparib (120 mg orally twice daily, on days -2 to 5) or matching placebo. If patients discontinued carboplatin and paclitaxel before progression, they could continue veliparib or placebo at an intensified dose (300 mg twice daily continuously, escalating to 400 mg twice daily if tolerated) until disease progression. Patients in the control group could receive open-label veliparib monotherapy after disease progression. Randomisation was stratified by previous platinum use, history of CNS metastases, and oestrogen and progesterone receptor status. The primary endpoint was investigator-assessed progression-free survival per Response Evaluation Criteria in Solid Tumors version 1.1. Efficacy analyses were done by intention to treat, which included all randomly assigned patients with a centrally confirmed BRCA mutation, and safety analyses included all patients who received at least one dose of velilparib or placebo. This study is ongoing and is registered with ClinicalTrials.gov, NCT02163694.FINDINGS: Between July 30, 2014, and Jan 17, 2018, 2202 patients were screened, of whom 513 eligible patients were enrolled and randomly assigned. In the intention-to-treat population (n=509), 337 patients were assigned to receive veliparib plus carboplatin-paclitaxel (veliparib group) and 172 were assigned to receive placebo plus carboplatin-paclitaxel (control group). Median follow-up at data cutoff (April 5, 2019) was 35·7 months (IQR 24·9-43·6) in the veliparib group and 35·5 months (23·1-45·9) in the control group. Median progression-free survival was 14·5 months (95% CI 12·5-17·7) in the veliparib group versus 12·6 months (10·6-14·4) in the control group (hazard ratio 0·71 [95% CI 0·57-0·88], p=0·0016). The most common grade 3 or worse adverse events were neutropenia (272 [81%] of 336 patients in the veliparib group vs 143 [84%] of 171 patients in the control group), anaemia (142 [42%] vs 68 [40%]), and thrombocytopenia (134 [40%] vs 48 [28%]). Serious adverse events occurred in 115 (34%) patients in the veliparib group versus 49 (29%) patients in the control group. There were no study drug-related deaths.INTERPRETATION: The addition of veliparib to a highly active platinum doublet, with continuation as monotherapy if the doublet were discontinued, resulted in significant and durable improvement in progression-free survival in patients with germline BRCA mutation-associated advanced breast cancer. These data indicate the utility of combining platinum and PARP inhibitors in this patient population.FUNDING: AbbVie.

Tumor relapse as a consequence of chemotherapy resistance is a major clinical challenge in advanced stage breast tumors. To identify processes associated with poor clinical outcome, we took a mass spectrometry‐based proteomic approach and analyzed a breast cancer cohort of 113 formalin‐fixed paraffin‐embedded samples. Proteomic profiling of matched tumors before and after chemotherapy, and tumor‐adjacent normal tissue, all from the same patients, allowed us to define eight patterns of protein level changes, two of which correlate to better chemotherapy response. Supervised analysis identified two proteins of proline biosynthesis pathway, PYCR1 and ALDH18A1, that were significantly associated with resistance to treatment based on pattern dominance. Weighted gene correlation network analysis of post‐treatment samples revealed that these proteins are associated with tumor relapse and affect patient survival. Functional analysis showed that knockdown of PYCR1 reduced invasion and migration capabilities of breast cancer cell lines. PYCR1 knockout significantly reduced tumor burden and increased drug sensitivity of orthotopically injected ER‐positive tumor in vivo, thus emphasizing the role of PYCR1 in resistance to chemotherapy., Proteomic profiling of matched tumor and normal samples, associates distinct proteomic patterns with patient prognosis in breast cancer. Functional studies in vivo support the effectiveness of PYCR1 suppression in combination with chemotherapeutics in clinical settings.

Background: Hyperactivation of the phosphatidylinositol-3-kinase (PI3K) pathway can occur due to PIK3CA mutations, present in ~40% of patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2—) ABC. SOLAR-1, a Phase 3 randomized, double-blind trial (NCT02437318), investigated efficacy and safety of ALP (α-specific PI3K inhibitor) + FUL in pts with HR+, HER2— ABC. ALP+FUL met the primary endpoint by significantly extending progression-free survival (PFS) vs placebo (PBO) + FUL in the PIK3CA-mutant cohort (hazard ratio [HR] 0.65; 95% CI 0.50—0.85; p=0.00065; median 11.0 vs 5.7 months). Here we report overall survival (OS), subgroup data and safety in the PIK3CA-mutant cohort, and PFS by circulating tumor (ct)DNA PIK3CA mutation status in the total population. Methods: Enrollment was open to men/postmenopausal women with PIK3CA-mutant HR+, HER2— ABC and 1 prior line of endocrine therapy. Pts were randomized (1:1) to ALP (300mg/day) + FUL (500mg every 28 days and Cycle 1 Day 15) or PBO+FUL. OS was the key secondary endpoint. PFS was analyzed by PIK3CA mutant status in ctDNA, and in important prognostic subgroups, including line of treatment in ABC and prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) use. Safety was analyzed in the PIK3CA-mutant cohort. Results: 341 pts in the PIK3CA-mutant cohort received ALP+FUL (n=169) or PBO+FUL (n=172). Median follow-up from randomization to data cut-off was 20.0 months. At data cut-off, 92 deaths had occurred (52% of the total 178 pts planned for final OS analysis); 40 for ALP+FUL (24%) and 52 for PBO+FUL (30%). OS results were immature at data cut-off (HR 0.73; 95% CI 0.48—1.10; p=0.06; median not estimable vs 26.9 months). There was a 45% risk reduction in PFS for pts with ctDNA PIK3CA mutations (HR 0.55; 95% CI 0.39—0.79; n=186); 20% for pts without (HR 0.80; 95% CI 0.60—1.06; n=363). PFS treatment effect for ALP+FUL vs PBO+FUL was generally consistent across subgroups of interest, with a risk reduction of 29% for pts receiving first-line (1L) treatment (HR 0.71; 95% CI 0.49—1.03; n=177), and 39% for 2L treatment (HR 0.61; 95% CI 0.42—0.89; n=161); 52% in pts with prior CDK4/6i (HR 0.48; 95% CI 0.17—1.36; n=20) and 33% in pts without (HR 0.67; 95% CI 0.51—0.87; n=321). Most frequent all-grade adverse events (AEs; ≥40% in either arm by single preferred term; ALP+FUL vs PBO+FUL) were hyperglycemia (65% vs 9%), diarrhea (54% vs 11%), nausea (46% vs 20%), and rash (40% vs 6%). Grade 3/4 AEs in ≥10% pts in either arm were hyperglycemia (fasting plasma glucose >250mg/dL; 37% for ALP+FUL vs Conclusions: ALP+FUL showed consistent clinically meaningful treatment benefit for pts with ctDNA PIK3CA mutant status, and across pt subgroups, including pts with/without prior treatment for ABC and prior CDK4/6i use. OS data were not yet mature at the data cut-off, but OS appeared numerically longer for ALP+FUL vs PBO+FUL after 52% of events. Key words: advanced breast cancer; PI3K; alpelisib; endocrine therapy Citation Format: Juric D, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo HS, Iwata H, Conte P, Mayer IA, Kaufman B, Yamashita T, Lu Y-S, Inoue K, Takahashi M, Pápai Z, Longin A-S, Mills D, Wilke C, Sellami D, Andre F. Alpelisib + fulvestrant for advanced breast cancer: Subgroup analyses from the phase III SOLAR-1 trial [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 GS3-08.

Current international guidelines, including the Choosing Wisely Initiative, recommends against the routine use of systemic imaging studies or tumor markers in early-stage breast cancer. Accumulating data suggests that adherence to these guidelines is low. We aimed to investigate the execution of unnecessary diagnostic tests among Israeli breast cancer patients and identify factors associated with their performance.A retrospective analysis was conducted involving a database of early breast cancer patients treated at Tel Aviv Sourasky Medical Center. A survey was distributed among Israeli surgeons and oncologists specializing in breast cancer treatment.The study included early breast cancer patients (n = 178), who have no indication for completing systemic evaluation. Nearly half of the patients (76, 42%) were referred to 128 unjustified diagnostic studies, with the most common referral comprising a PET-CT (n = 39 30.5%). As expected, none of the tests led to any change in either disease staging or alteration in clinical management. Variables associated with systemic evaluation included younger age (61.8% for 50 years vs 38.9% for 50 years, p = 0.02), diagnosis by palpable mass compared to screening mammography (26.9% vs 52.9% p = 0.043, respectively) and higher tumor grade (33.7% vs 52.2% p = 0.02, respectively). In concordance with the findings of the database, the physicians' survey revealed low adherence to guidelines and a role of the treating physicians' subjective feelings. Doctors were more likely to recommend unnecessary studies when presented with a clinical case as an image, than to an informative question.Our data indicate a high rate of non-adherence to guidelines, physicians recommending extensive systemic evaluation for women with early breast cancer. These deviations from the guidelines are associated with subjective factors, some of them being physician-dependent. Initiatives aimed at improving adherence to guidelines, and specifically to guidelines recommending "doing less" should therefore include not just knowledge-based education but also encourage conversation about what is appropriate and necessary.

Purpose In the Breast cancer trials of OraL EveROlimus-2 (BOLERO-2) trial, everolimus plus exemestane improved progression-free survival (PFS) in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC) recurring or progressing on/after prior endocrine therapy (ET), suggesting that dual blockade using targeted therapy and ET was an effective treatment option. Here, we investigated the clinical benefit of combining everolimus with different endocrine partner, letrozole, in a similar patient population. Methods In this phase II, open-label, single-arm, multicenter trial, postmenopausal women with HR+, HER2− ABC who had recurrence/progression on/after prior ET received everolimus 10 mg daily and letrozole 2.5 mg daily. The primary end point was objective response rate; key secondary end points included disease-control rate, PFS, overall survival, and safety. Results A total of 72 patients were enrolled and followed-up for a median duration of 11.4 months. Everolimus plus letrozole achieved an overall response rate of 23.3% (95% confidence interval [CI], 13.4%-36.0%). The median PFS was 8.8 months (95% CI, 6.6-11.0 months), and the overall survival was 22.9 months (95% CI, 18.5-28.9 months). Disease-control rate was achieved in 51 (85%) patients. The safety profile was consistent with previously published data: The most frequently reported any grade adverse events (AEs) were fatigue (61.1%), stomatitis (54.2%), and rash (33.4%). The most frequently reported grade 3 AEs were stomatitis and anemia (8.3% each), fatigue and diarrhea (5.6% each), and hyperglycemia (4.2%). Only 1 patient had grade 4 AE of anemia. Conclusions Everolimus plus letrozole demonstrated clinical benefit and could be a valid treatment option for postmenopausal women recurring/progressing on prior endocrine therapy.

Background Olaparib is a potent poly(ADP-ribose) polymerase (PARP) inhibitor, with first-in-class approval (400 mg capsules BID) for BRCA-mutated advanced ovarian cancer. Olaparib was recently found to be superior compared with chemotherapy in HER2-negative gBRCAm MBC in the Phase III OlympiAD trial. Olaparib induces DNA damage and genomic instability in gBRCAm tumors, which is hypothesized to result in enhanced immunogenicity. Here, we assess if a combination of olaparib and an anti-programmed cell death ligand-1 (PD-L1) agent, durvalumab, leads to enhanced antitumor activity in one of the four cohorts (NCT02734004). Methods Individuals with deleterious gBRCA1 or BRCA2 mutations and HER2-negative MBC were eligible. Patients with prior platinum therapy were allowed to enter if they had not experienced disease progression on platinum. No more than two prior lines of chemotherapy were allowed for metastatic disease, and patients with hormone receptor (HR) positive disease had to have at least one line of prior endocrine therapy. Concomitant use of endocrine therapy was not allowed. All patients received olaparib tablets 300 mg PO BID for a 4-week run-in, followed by a combination of olaparib 300 mg PO BID and durvalumab 1.5 g IV q 4 weeks. The combination was continued until progressive disease (PD) by RECIST 1.1 criteria. Tumor assessments were done at baseline, 4 weeks and every 8 weeks thereafter. The primary endpoint was disease control rate (DCR) at 12 weeks, and safety and tolerability of the combination. The secondary endpoints included DCR at 28 weeks, objective response rate, duration of response, progression-free survival (PFS) and overall survival. Biomarker endpoints included PD-L1 expression and evaluation of tumor infiltrating lymphocytes. Olaparib monotherapy has previously demonstrated a median PFS (mPFS) of 6 months in this patient population, and addition of durvalumab was predicted to increase the mPFS to 7.5 months, corresponding to a target DCR of 75% at 12 weeks. This was achievable by enrolling 30 patients using a Bayesian predictive probability design. Results of the first 25 patients are presented. Results Median age was 46 years (range 29−66); 11 and 14 patients had BRCA1 and BRCA2 mutations, respectively; 13 patients had HR positive disease, and nine had previously received platinum therapy. Median number of prior chemotherapy lines was 1 (range 0-4). Grade 3 or higher adverse events (AEs) were anemia (8%), neutropenia (8%), hemolysis (4%), dyspnea (4%), pancreatitis (4%), fatigue (4%), lymphopenia (4%) and leukopenia (4%). There was one grade 5 AE (dyspnea), which was attributed to disease progression. Observed DCR at 12 weeks was 80%. Eight confirmed responses and five unconfirmed responses were seen. The updated results from primary and secondary endpoints, including DCR at 28 weeks, as well as biomarker and PK data, will be presented. Conclusions The combination of olaparib and durvalumab was well tolerated, with no apparent overlapping toxicities. The efficacy of the combination at an early time point reached the target DCR in gBRCAm HER2-negative MBC, and warrants further investigation. Citation Format: Domchek SM, Postel-Vinay S, Bang Y-J, Park YH, Alexandre J, Delord J-P, Italiano A, You B, Bastian S, Krebs M, Wang D, Waqar S, Angell H, Learoyd M, Chang S-C, Gresty C, Herbolsheimer P, Kaufman B. An open-label, multitumor, phase II basket study of olaparib and durvalumab (MEDIOLA): Results in germline BRCA-mutated (gBRCAm) HER2-negative metastatic breast cancer (MBC) [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 PD6-11.

Population screening of three common BRCA1/BRCA2 mutations in Ashkenazi Jews (AJ) apparently fulfills screening criteria. We compared streamlined BRCA screening via self-referral with proactive recruitment in medical settings.Unaffected AJ, age ≥25 years without known familial mutations, were either self-referred or recruiter-enrolled. Before testing, participants received written information and self-reported family history (FH). After testing, both non-carriers with significant FH and carriers received in-person genetic counseling. Psychosocial questionnaires were self-administered 1 week and 6 months after enrollment.Of 1,771 participants, 58% were recruiter-enrolled and 42% were self-referred. Screening uptake was 67%. Recruited enrollees were older (mean age 54 vs. 48, P0.001) and had less suggestive FH (23 vs. 33%, P0.001). Of 32 (1.8%) carriers identified, 40% had no significant FH. Post-test counseling compliance was 100% for carriers and 89% for non-carrier women with FH. All groups expressed high satisfaction (90%). At 6 months, carriers had significantly increased distress and anxiety, greater knowledge, and similar satisfaction; 90% of participants would recommend general AJ BRCA screening.Streamlined BRCA screening results in high uptake, very high satisfaction, and no excess psychosocial harm. Proactive recruitment captured older women less selected for FH. Further research is necessary to target younger women and assess other populations.Genet Med advance online publication 08 December 2016.

Background: Olaparib (Lynparza®) is a PARP inhibitor that alters the repair of single-strand DNA breaks. Durvalumab (Imfinzi®) is a monoclonal antibody against programmed cell death ligand 1 (anti-PD-L1) that promotes antitumor immune responses. MEDIOLA (NCT02734004) is a Ph I/II open-label, multicenter study enrolling patients (pts) across several tumor types (small-cell lung cancer, gastric cancer, germline BRCA-mutated [gBRCAm] BC, or platinum sensitive relapsed gBRCAm ovarian cancer). 34 pts with gBRCAm BC received olaparib 300 mg po bid for a 4-wk run-in, followed by olaparib 300 mg po bid and durvalumab 1.5 g IV q4 wks. Encouraging preliminary results support an expansion cohort in a BRCAm popn. Evidence suggests that mutations in other homologous recombination repair (HRR) genes may confer a BRCA-like phenotype, warranting an expansion of the study population beyond BRCAm. Inhibition of vascular endothelial growth factor (VEGF) has been reported to enhance the efficacy of chemotherapy in TNBC. In addition, VEGF inhibition potentiates PARP inhibitor activity, particularly in pts who do not carry BRCAm. Combinations of immune checkpoint inhibitors and bevacizumab, an anti-VEGF-A antibody, have shown promising results in other tumor types. Thus, MEDIOLA will additionally explore the efficacy and safety of olaparib + durvalumab in combination with bevacizumab in TNBC pts. Trial design: Pts in the additional MBC cohorts will receive combination olaparib and durvalumab with no olaparib run-in. Pts in the TNBC cohort will also receive concurrent bevacizumab 10 mg/kg q 2 wks. Tumor assessments will be performed at baseline and every 8 wks thereafter. Eligibility criteria: Pts with histologically confirmed, locally advanced or metastatic HER2-neg BC, who are PARP-inhibitor and immunotherapy naïve. Prior anthracycline and/or taxane therapy in early or MBC is required. Prior platinum therapy is allowed, if there was no disease progression while receiving treatment and at least 12 mths has elapsed since the last dose. Pts will undergo BRCA and HRR mutation testing and will be assigned to a cohort based on their mutation status, as illustrated in Table 1. Specific aims: Cohort-specific primary efficacy endpoint targets were calculated aiming for superiority to standard of care treatment (Table 1). Other primary outcomes are safety and tolerability. Secondary endpoints are PK, DCR at 24 wks, objective response rate, duration of response, progression-free survival and overall survival. Exploratory endpoints include the analysis of tumor-infiltrating lymphocytes and PD-L1 expression. Statistical methods: The expansion cohort will have a single-stage statistical design. Bayesian predictive probability design will be used for the analysis of the HRRm and TNBC triplet cohorts. Accrual: Accrual targets are shown in Table 1. First subject will be enrolled in Nov 2018. New MEDIOLA BC cohortsCohort nameTarget accrualDrugsPopnPrimary endpointBreast BRCAm expansion80Olap+DurvHER2-neg, tBRCAmORR 70%Breast HRRm cohort29Olap+DurvHER2-neg, non BRCAm, HRRm-posDCR at 16 wks 80%TNBC triplet cohort30Olap+Durv+BevTNBC, non BRCAm, non HRRmDCR at 16 wks 80%Bev, bevacizumab; durv, durvalumab; olap, olaparib Citation Format: Domchek SM, Postel-Vinay S, Im S-A, Hee Park Y, Delord J-P, Italiano A, Alexandre J, You B, Bastian S, Krebs MG, Waqar S, Lanasa M, Angell HK, Tang M, Gresty C, Opincar L, Herbolsheimer P, Kaufman B. MEDIOLA: An open-label, phase I/II basket study of olaparib (PARP inhibitor) and durvalumab (anti-PD-L1 antibody)–Additional breast cancer cohorts [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 OT3-05-03.

Carriers of pathogenic variants (PVs) in moderate–high-penetrance cancer susceptibility genes are offered tailored surveillance schemes for early cancer diagnosis. The clinical implications of low-penetrance variant carriers are less clear. Clinical and demographic data were retrieved for a cohort of Israeli individuals who underwent oncogenetic testing by the 30-gene cancer panel at Color Genomics laboratory, between 04/2013 and 12/2018. Of 758 genotyped individuals, 504 had been diagnosed with cancer prior to testing: 283 (56%) had breast cancer and 106 (21%) colorectal cancer. Pathogenic or likely pathogenic (P/LP) variants were detected in 123 (16%) individuals. Overall, 44 different P/LP variants were detected in 18/30 cancer susceptibility genes; 20 of them were founder/recurrent mutations. Of the carriers, 39 (32%), 10 (8%), and 74 (60%) carried high-, moderate-, or low-penetrance variants, respectively. After excluding low-penetrance variants, 7% (33/504) of all cancer patients, 6% of breast or ovarian cancer patients were found to be carriers, as well as 7% (14/203) of individuals with colonic polyps, and 4% (11/254) of cancer-free individuals. The diagnostic yield of moderate- and high-penetrance PVs using multigene panel testing was 6%, with 3.7% carriers of non-recurrent PVs. This yield should be discussed during pre-test counseling, and emphasizes the need for harmonized recommendations regarding clinical implications of low-penetrance variants.