scholarly journals Single-agent PARP inhibitors for the treatment of patients with BRCA-mutated HER2-negative metastatic breast cancer: a systematic review and meta-analysis

ESMO Open ◽  
2018 ◽  
Vol 3 (4) ◽  
pp. e000361 ◽  
Author(s):  
Francesca Poggio ◽  
Marco Bruzzone ◽  
Marcello Ceppi ◽  
Benedetta Conte ◽  
Samuel Martel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Meta Analysis ◽  
Single Agent ◽  
Objective Response ◽  
Metastatic Breast ◽  
Parp Inhibitors ◽  
Treatment Discontinuation ◽  
Discontinuation Rate ◽  
Increased Risk

Single-agent poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have been approved as the first targeted therapy available for patients with BRCA-mutated HER2-negative metastatic breast cancer. This meta-analysis aimed to better evaluate activity, efficacy and safety of single-agent PARPi in this population. A systematic search of Medline, Embase and conference proceedings up to 31 January 2018 was conducted to identify randomised controlled trials (RCTs) investigating single-agent PARPi versus monochemotherapy in patients with BRCA-mutated HER2-negative metastatic breast cancer. Using the random-effect model, we calculated summary risk estimates (pooled HR and OR with 95% CI) for progression-free survival (PFS), overall survival (OS), objective response rate (ORR), any grade and grade 3–4 adverse events (AEs), treatment discontinuation rate and time to deterioration in quality of life (QoL). Two RCTs (n=733) were included. As compared with monochemotherapy, single-agent PARPi significantly improved PFS (HR 0.56(95% CI 0.45 to 0.70)) and ORR (OR 4.15 (95% CI 2.82 to 6.10)), with no difference in OS (HR 0.82 (95% CI 0.64 to 1.05)). Single-agent PARPi significantly increased risk of anaemia and any grade headache, but reduced risk of neutropenia and any grade palmar-plantar erythrodysesthesia syndrome as compared with monochemotherapy. No significant differences in other AEs and treatment discontinuation rate were observed. Patients treated with PARPi experienced a significant delayed time to QoL deterioration (HR 0.40 (95% CI 0.29 to 0.54)). Single-agent PARPi showed to be an effective, well tolerated and useful treatment in maintaining QoL of patients with BRCA-mutated HER2-negative metastatic breast cancer.

scholarly journals Rucaparib in patients presenting a metastatic breast cancer with Homologous Recombination Deficiency, without germline BRCA1/2 mutation

2020 ◽  
Author(s):  
Anne Patsouris ◽  
M'boyba Khadija DIOP ◽  
Olivier Tredan ◽  
Daniel Nenciu ◽  
Anthony Goncalves ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Homologous Recombination ◽  
Statistical Significance ◽  
Objective Response ◽  
Metastatic Breast ◽  
Parp Inhibitors ◽  
Small Subset ◽  
Durable Response ◽  
Homologous Recombination Deficiency

Abstract Breast cancer may present genomic alterations leading to homologous recombination deficiency. PARP inhibitors have proved their efficacy in patients with HER2-negative metastatic breast cancer (mBC) harboring germline (g) BRCA1/2 mutations. We conducted the phase 2 RUBY trial to assess the efficacy of rucaparib in HER2-negative mBC with high genomic loss of heterozygosity (LOH) score or somatic, without gBRCA1/2 mutation. 220 of 711 patients with mBC screened for LOH presented high LOH score which was associated with a higher likelihood of death (HR = 1.39, 95% CI: 1.11-1.75, p = 0.005). The primary objective was not reached with a clinical benefit rate (objective response or SD>16 weeks) of 13.5%. Two LOH-high patients, without somatic BRCA1/2 mutation, presented a complete and durable response (14 and 32 months). HRDetect tended to be associated with response to rucaparib, whithout reaching statistical significance (median HRDetect responders versus non responders: 0.465 versus, 0.040, p = 0.2135). Our data suggests that a small subset of patients with high LOH score could derive benefit from PARP inhibitors.

PARP inhibitors (PARPi) for the treatment of BRCA-mutated HER2-negative (HER2-) metastatic breast cancer (MBC) patients: A systematic review and meta-analysis.

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. e13098-e13098 ◽  
Author(s):  
Francesca Poggio ◽  
Marco Bruzzone ◽  
Marcello Ceppi ◽  
Benedetta Conte ◽  
Samuel Martel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Systematic Review ◽  
Metastatic Breast Cancer ◽  
Meta Analysis ◽  
Metastatic Breast ◽  
Parp Inhibitors

Capecitabine maintenance therapy after docetaxel/capecitabine combination chemotherapy in patients with metastatic breast cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e12018-e12018
Author(s):  
Pinar Gursoy ◽  
Zeki Gokhan Surmeli ◽  
Burcu Cakar ◽  
Cagatay Arslan ◽  
Baha Zengel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Maintenance Therapy ◽  
Single Agent ◽  
Objective Response ◽  
Metastatic Breast ◽  
Complete Response ◽  
Response To Treatment ◽  
Grade 3 ◽  
Metastatic Sites

e12018 Background: Addition of capecitabine to docetaxel improves survival outcomes compared with single agent docetaxel in metastatic breast cancer (MBC). In this study we analyzed efficacy of maintenance therapy with single agent capecitabine after six cycles of docetaxel/capecitabine chemotherapy in MBC patients. Methods: Patients with metastatic HER2 negative breast cancer were included. Six cycles of docetaxel (75mg/m2 q3wk) / capecitabine (1650mg/m2/day on days 1 to 14) followed by capecitabine (2000 mg/m2/day on days 1 to 14) were administered. Demographic features, progression free (PFS) and overall survival (OS) and response to treatment were recorded. Results: Fifty-four patients were included. Thirty-five patients (65%) were postmenopausal, and 40 (74%) were ER/PR positive. Median age was 53 (range 28 – 70). Number of metastatic sites was one in 23 patients, two in 21, three or more in 10 patients. Most common metastatic sites were bone (67%), lymph nodes (33%), lungs (30%), liver (13%); 13 patients (24%) had bone only disease. Forty-four (81.5%) patients received treatment in first-line, 10 (18.5%) received in second line setting. Median number of cycles applied (including docetaxel/capecitabine combination) was 9 (range 2 – 31, total 576). Median PFS was 9 months (10.4 for hormone receptor positive, 7.3 for negative patients) and median OS was 28 months. Objective response was assessable in 38 patients. Overall response rate (partial + complete response) was 42.6% (95% CI 29.6 – 55.6) with 1 complete response. Toxicities were evaluated in 41 patients; grade 3/4 neutropenia was observed in 10% and grade 3/4 hand-foot syndrome was observed in 24% of patients. Dose reduction was performed in capecitabine in 37%, and in docetaxel in 20% of patients. Conclusions: Maintenance with single agent capecitabine therapy after six cycles of docetaxel/capecitabine chemotherapy is an effective and tolerable treatment option for HER2 negative MBC patients.

Multinational Study of the Efficacy and Safety of Humanized Anti-HER2 Monoclonal Antibody in Women Who Have HER2-Overexpressing Metastatic Breast Cancer That Has Progressed After Chemotherapy for Metastatic Disease

1999 ◽  
Vol 17 (9) ◽  
pp. 2639-2639 ◽  
Author(s):  
Melody A. Cobleigh ◽  
Charles L. Vogel ◽  
Debu Tripathy ◽  
Nicholas J. Robert ◽  
Susy Scholl ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Monoclonal Antibody ◽  
Metastatic Breast Cancer ◽  
Adverse Events ◽  
Metastatic Disease ◽  
Median Duration ◽  
Single Agent ◽  
Objective Response ◽  
Metastatic Breast ◽  
Efficacy And Safety

PURPOSE: Overexpression of the HER2 protein occurs in 25% to 30% of human breast cancers and leads to a particularly aggressive form of the disease. Efficacy and safety of recombinant humanized anti-HER2 monoclonal antibody as a single agent was evaluated in women with HER2-overexpressing metastatic breast cancer that had progressed after chemotherapy for metastatic disease.PATIENTS AND METHODS: Two hundred twenty-two women, with HER2-overexpressing metastatic breast cancer that had progressed after one or two chemotherapy regimens, were enrolled. Patients received a loading dose of 4 mg/kg intravenously, followed by a 2-mg/kg maintenance dose at weekly intervals.RESULTS: Study patients had advanced metastatic disease and had received extensive prior therapy. A blinded, independent response evaluation committee identified eight complete and 26 partial responses, for an objective response rate of 15% in the intent-to-treat population (95% confidence interval, 11% to 21%). The median duration of response was 9.1 months; the median duration of survival was 13 months. The most common adverse events, which occurred in approximately 40% of patients, were infusion-associated fever and/or chills that usually occurred only during the first infusion, and were of mild to moderate severity. These symptoms were treated successfully with acetaminophen and/or diphenhydramine. The most clinically significant adverse event was cardiac dysfunction, which occurred in 4.7% of patients. Only 1% of patients discontinued the study because of treatment-related adverse events.CONCLUSION: Recombinant humanized anti-HER2 monoclonal antibody, administered as a single agent, produces durable objective responses and is well tolerated by women with HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. Side effects that are commonly observed with chemotherapy, such as alopecia, mucositis, and neutropenia, are rarely seen.

Phase II multicenter study of talazoparib for somatic BRCA1/2 mutant metastatic breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS1110-TPS1110
Author(s):  
Neelima Vidula ◽  
Erica Blouch ◽  
Nora K. Horick ◽  
Erin Basile ◽  
Senthil Damodaran ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Metastatic Breast Cancer ◽  
Phase Ii ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Metastatic Breast ◽  
Parp Inhibitors ◽  
Phase Iii ◽  
Patient Reported

TPS1110 Background: PARP inhibitors are approved for the treatment of HER2 negative metastatic breast cancer (MBC) with germline BRCA1/2 mutations, based on phase III studies demonstrating an improvement in progression-free survival (PFS) compared to chemotherapy in this population and better patient reported outcomes (Robson, NEJM, 2017; Litton, NEJM, 2018). However, germline BRCA1/2 mutations account for only 5-10% of breast cancer, limiting the current clinical applicability of PARP inhibitors. Somatic BRCA1/2 mutations are detectable in circulating cell-free DNA (cfDNA) in ̃13.5% of patients with MBC; in pre-clinical models, pathogenic somatic BRCA1/2 mutations have been shown to respond to PARP inhibition (Vidula, CCR, 2020). The purpose of this study is to evaluate the efficacy of talazoparib, a PARP inhibitor, in patients with MBC who have somatic BRCA1/2 mutations detectable in cfDNA, in the absence of a germline BRCA1/2 mutation, which we hypothesize will be effective in this setting. This study may help expand the population of patients with MBC who benefit from PARP inhibitors. Methods: This is an investigator initiated multicenter, single arm, phase II clinical trial studying the efficacy of talazoparib in 30 patients with MBC who have pathogenic somatic BRCA1/2 mutations detected in cfDNA. Patients with MBC who are found to have pathogenic somatic BRCA1/2 mutations detected in cfDNA in the absence of a germline BRCA1/2 mutation are eligible. Patients may have triple negative (with ≥ 1 prior chemotherapy), or hormone receptor positive/HER2 negative breast cancer (with ≥ 1 prior hormone therapy). Patients may have received any number of prior lines of chemotherapy, including a prior platinum (in the absence of progression). They must have adequate organ function and ECOG performance status ≤2, and should not have previously received a PARP inhibitor. Patients are treated with talazoparib 1 mg daily until disease progression or intolerability, with serial imaging using CT chest/abdomen/pelvis and bone scan performed at baseline and every 12 weeks, and cfDNA collection every 4 weeks. Primary endpoint is PFS by RECIST 1.1. Patients are being enrolled in a two-stage design with 80% power to demonstrate that the treatment is associated with “success” (PFS > 12 weeks) in ≥53% patients (4% alpha). Secondary endpoints include objective response rate and safety (NCI CTCAE v 5.0). Exploratory analyses include studying serial changes in cfDNA BRCA1/2 mutant allelic frequency and comparing pre-and post-treatment cfDNA for the emergence of BRCA1/2 reversion and resistance mutations. This study is activated and open at Massachusetts General Hospital, where 2 patients are completing screening. It is also opening soon at 6 other academic centers (NCT03990896). Grant support includes a Pfizer ASPIRE award and 2020 Conquer Cancer Foundation of ASCO – Breast Cancer Research Foundation – Career Development Award. Clinical trial information: NCT03990896 .

scholarly journals A Meta-Analysis Study of Polychemotherapy versus Monochemotherapy in Patients of Metastatic Breast Cancer

2016 ◽  
Vol 8 (03) ◽  
Author(s):  
Amal Kumar ◽  
Bhaswat Chakraborty
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Response Rate ◽  
Meta Analysis ◽  
Single Agent ◽  
Metastatic Breast ◽  
Nausea And Vomiting ◽  
Tumor Control ◽  
Randomized Controlled Studies ◽  
Significant Difference

Polychemotherapy and intermittent monochemotherapy regimens in metastatic breast cancer were examined in a meta analysis that included both tumor response rate and toxicities. Randomized controlled studies (conducted during 1990-2008) comparing monochemotherapy and poly-chemotherapy in advanced breast cancer patients were selected from electronic databases. Meta-analysis for response rate and toxicities [nausea and vomiting, toxic death, alopecia and reduced white cell count (WCC)] was performed using the MantelHaenszel method. The heterogeneity among the trials was assessed through a χ2 statistic, I2 and visual inspection of the forest plots. Analysis of eligible studies reveals statistical significant difference in response rate (OR 0.72, 95% CI 0.65-0.79), nausea and vomiting (OR 0.80, 95% CI 0.67-0.59), Alopecia (OR 0.75, 95% CI 0.640.88) and reduced WCC (OR 0.55, 95% CI 0.48-0.62) which favours polychemotherapy except toxic death (OR 0.87, 95% CI 0.58-1.29). There was marked evidence of heterogeneity in all end points except toxic death. This meta analysis shows the superiority of efficacy but not of safety of polychemotherapy over that of a single agent. However, the choice of treatment should be based on the response to the therapy, toxicity, patient preference, presence of metastases or imminent complications requiring aggressive and rapid tumor control.

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