scholarly journals Olaparib for metastatic breast cancer in a patient with a germline PALB2 variant

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Sherko Kuemmel ◽  
Hakima Harrach ◽  
Rita K. Schmutzler ◽  
Athina Kostara ◽  
Katja Ziegler-Löhr ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Parp Inhibitor ◽  
Metastatic Breast ◽  
Adenosine Diphosphate ◽  
Parp Inhibitors ◽  
Parp Inhibition ◽  
Sequence Variant ◽  
Wild Type ◽  
Genetic Changes

Abstract There is a strong biologic rationale that poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors may benefit a broader range of metastatic breast cancer (MBC) patients than covered by current approvals, which require a germline BRCA1/2 sequence variant affecting function. We report a patient with germline/somatic BRCA1/2 wild-type MBC, who had a dramatic response to the PARP inhibitor olaparib of at least 8 months’ duration. The patient is a 37-year-old woman with recurrent, hormone receptor-positive, HER2-negative MBC that had progressed despite hormonal therapy and palbociclib. Sensitivity to olaparib was likely conferred by a germline sequence variant affecting function in PALB2 (exon 1, c.18G>T, p.(=)). This case documenting activity of olaparib monotherapy in germline/somatic BRCA1/2 wild-type MBC illustrates that the clinical potential of PARP inhibition in MBC extends beyond currently approved indications to additional patients whose tumors have (epi)genetic changes affecting homologous recombination repair.

Measurement of gamma-H2AX in circulating tumor cells (CTC) from patients receiving ABT-888 (veliparib) in combination with carboplatin on a phase I dose-escalation study (OSU-10080/NCI8609).

2011 ◽  
Vol 29 (27_suppl) ◽  
pp. 58-58
Author(s):  
A. Garcia-Villa
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Metastatic Breast Cancer ◽  
Phase I ◽  
Parp Inhibitor ◽  
Metastatic Breast ◽  
Parp Inhibitors ◽  
Immunocytochemical Staining ◽  
Dose Escalation Study ◽  
Non Invasive

58 Background: Non-invasive methods to accurately measure DNA damage induced by PARP inhibitors in the tumors are crucial in identifying the optimal biological dose and schedule of these novel agents. With the use of an antibody that targets the histone H2AX, which becomes phosphorylated on serine residue 139 (γ-H2AX), it is possible to measure DNA DSB in the cell. But repeated biopsy in patients with metastatic breast cancer is not feasible. We propose here to quantify γ-H2AX in CTCs as a measurement of DNA damage in the tumor in patients receiving veliparib (ABT-888), an oral PARP inhibitor and carboplatin on a phase I study. Methods: CTCs were isolated in 10 mL of peripheral blood using negative selection with immunomagnetic tagging and removal of CD45 positive cells at 3 time points. Immunocytochemical staining for nucleus (DAPI), pan-cytokeratin CD45, and γ-H2AX was completed on available samples. Double staining for nucleus and cytokeratin with high nucleus to cytoplasm ratio defined a CTC. The γ-H2AX foci present in the nucleus of the CTCs will be counted by immunocytochemistry (ICC) analysis. Results: We negatively enriched blood sample from enrolled patients with metastatic breast cancer (n=6). CTCs were observed in all samples (55CTCs/mL of blood - 2000CTCs/mL of blood). Thus far 3 out of 6 patient samples have been analyzed. The number of CTCs per mL of blood after enrichment at baseline has a mean of 293, a median of 140 and a range of (684-140) At time point 1 the mean is 1071.33, the median is 1151 and the range is (1151-63). ICC analysis on the CTCs demonstrated the presence of γ-H2AX positive cells. Conclusions: Our novel negative depletion method for isolating CTCs allows for separation of a wider range of CTCs, since it does not assume presence of epithelial markers before separation. This leads to improved yield and purity allowing better ICC detection of various markers directly on CTCs. Development and validation of the above methodology to determine γ-H2AX foci in CTCs will help in identifying a novel, non-invasive biomarker that can be used to assess the effect of DNA damaging agents during therapy.

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 .

Phase II trial of a PARP inhibitor in somatic BRCA mutant metastatic breast cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS1113-TPS1113
Author(s):  
Neelima Vidula ◽  
Nora K. Horick ◽  
Erica Blouch ◽  
Amalia Rivera ◽  
Erin Basile ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Metastatic Breast Cancer ◽  
Phase Ii ◽  
Massachusetts General Hospital ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Metastatic Breast ◽  
Parp Inhibition ◽  
The Impact

TPS1113 Background: Poly(ADP-ribose) polymerase (PARP) inhibitors are now approved for patients with germline BRCA1/2 mutated HER2 negative metastatic breast cancer (MBC). However, germline BRCA1/2 mutations only account for 5-10% of breast cancer. We previously demonstrated that a subset of MBC may harbor somatic BRCA1/2 mutations detectable by cell-free DNA (cfDNA) (Vidula, SABCS, 2017). We hypothesize that somatic BRCA1/2 mutant MBC may also respond to PARP inhibition, similar to ovarian cancer, where PARP inhibition is efficacious in both somatic and germline tumors (Oza, 2017). Methods: This single arm, open label, phase II clinical trial is evaluating the efficacy of talazoparib, a PARP inhibitor, in 30 patients with somatic pathogenic BRCA1/2 mutant MBC identified by cfDNA. Patients may have triple-negative disease with receipt of at least 1 prior chemotherapy regimen, or hormone receptor positive, HER2 negative disease with at least 1 prior hormone therapy for MBC. Patients may have received a prior platinum, in the absence of progression on platinum chemotherapy. Patients must not have a known germline BRCA1/2 mutation. Patients will be treated with talazoparib 1 mg daily until progression, unacceptable toxicity, or withdrawal of consent, with clinical exams monthly, scans (CT chest, abdomen, and pelvis, and bone scan as appropriate) every 3 months, and serial cfDNA collected monthly. The primary endpoint is progression-free survival, as defined by RECIST 1.1. Subjects are enrolled in a 2-stage design, which provides 80% power to demonstrate that treatment is associated with “success” (PFS > 12 weeks) in ³ 53% patients (4% alpha). Additional endpoints include objective response rate and toxicity (per NCI CTCAE version 5.0). Correlative endpoints include determining changes in BRCA1/2 mutant allele fraction, genomic evolution including emergence of BRCA reversion mutations, and the impact of biomarker changes on outcomes. This trial is currently enrolling patients at the Massachusetts General Hospital. Successful completion of this study may help expand the patient population that is able to benefit from PARP inhibition. Clinical trial information: NCT03990896 .

scholarly journals Enrichment of kinase fusions in ESR1 wild-type, metastatic breast cancer revealed by a systematic analysis of 4854 patients

2020 ◽  
Vol 31 (8) ◽  
pp. 991-1000 ◽  
Author(s):  
D.S. Ross ◽  
B. Liu ◽  
A.M. Schram ◽  
P. Razavi ◽  
S.M. Lagana ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Metastatic Breast ◽  
Wild Type ◽  
Systematic Analysis

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.

scholarly journals Multiomics analysis of serial PARP inhibitor treated metastatic TNBC inform on rational combination therapies

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Marilyne Labrie ◽  
Allen Li ◽  
Allison Creason ◽  
Courtney Betts ◽  
Jamie Keck ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Parp Inhibition ◽  
Patient Specific ◽  
Combination Therapies ◽  
Breast Cancer Patients ◽  
Effector Cells ◽  
Basal Breast Cancer ◽  
Rational Combination

AbstractIn a pilot study, we evaluated the feasibility of real-time deep analysis of serial tumor samples from triple negative breast cancer patients to identify mechanisms of resistance and treatment opportunities as they emerge under therapeutic stress engendered by poly-ADP-ribose polymerase (PARP) inhibitors (PARPi). In a BRCA-mutant basal breast cancer exceptional long-term survivor, a striking tumor destruction was accompanied by a marked infiltration of immune cells containing CD8 effector cells, consistent with pre-clinical evidence for association between STING mediated immune activation and benefit from PARPi and immunotherapy. Tumor cells in the exceptional responder underwent extensive protein network rewiring in response to PARP inhibition. In contrast, there were minimal changes in the ecosystem of a luminal androgen receptor rapid progressor, likely due to indifference to the effects of PARP inhibition. Together, identification of PARPi-induced emergent changes could be used to select patient specific combination therapies, based on tumor and immune state changes.

scholarly journals Update Breast Cancer 2020 Part 2 – Advanced Breast Cancer: New Treatments and Implementation of Therapies with Companion Diagnostics

2020 ◽  
Vol 80 (04) ◽  
pp. 391-398
Author(s):  
Diana Lüftner ◽  
Andreas Schneeweiss ◽  
Andreas D. Hartkopf ◽  
Volkmar Müller ◽  
Achim Wöckel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Targeted Therapy ◽  
Locally Advanced ◽  
Metastatic Breast ◽  
Parp Inhibitors ◽  
Companion Diagnostics ◽  
Molecular Tests ◽  
New Treatments ◽  
First Time

AbstractFor patients with locally advanced or metastatic breast cancer, new and effective therapies such as CDK4/6 inhibitors, PARP inhibitors and a PD-L1 inhibitor have been introduced in recent years. This review presents an update on the available studies with their data. In addition, two innovative anti-HER2 therapies are presented (trastuzumab-deruxtecan and tucatinib) for which the results from new studies have been reported. Molecular tests offer the possibility of defining patient populations or also monitoring courses of therapy. This can help identify patients with specific characteristics in order to provide them with individually targeted therapy within the framework of studies. In a large study, the benefit of such a biomarker study was able to be described for the first time.

Sign in / Sign up

Export Citation Format

Share Document