Neoadjuvant study of niraparib in patients with HER2-negative, BRCA-mutated, resectable breast cancer.
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SUBMITTER: Spring LM
PROVIDER: S-EPMC9402431 | biostudies-literature | 2022 Aug
REPOSITORIES: biostudies-literature
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Neoadjuvant study of niraparib in patients with HER2-negative, BRCA-mutated, resectable breast cancer.
Spring Laura M LM Han Hyo H Liu Minetta C MC Hamilton Erika E Irie Hanna H Santa-Maria Cesar A CA Reeves James J Pan Peng P Shan Ming M Tang Yongqiang Y Graham Julie R JR Hazard Sebastien S Ellisen Leif W LW Isakoff Steven J SJ
Nature cancer 20220704 8
This single-arm pilot study (NCT03329937) evaluated neoadjuvant niraparib antitumor activity and safety in patients with localized HER2-negative, BRCA-mutated breast cancer. Twenty-one patients received niraparib 200 mg once daily in 28-day cycles. After 2 cycles, tumor response (≥30% reduction from baseline) by MRI was 90.5% and 40.0% (6 of 15) of patients who received only niraparib (2-6 cycles) had pathological complete response; no new safety signals were identified. High niraparib intratumo ...[more]
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Project description:BackgroundTalazoparib is a poly (adenosine diphosphate-ribose) polymerase inhibitor approved for the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm), HER2-negative, locally advanced or metastatic breast cancer (LA/mBC), with approval based on the EMBRACA trial. To date, there are no published data on talazoparib use in the real-world United States (USA) setting.Patients and methodsCharacteristics, treatment patterns, and clinical outcomes of real-world US patients with gBRCAm HER2-negative LA/mBC treated with talazoparib monotherapy were collected via retrospective chart review and summarized using descriptive statistics.ResultsAmong 84 eligible patients, 35.7% had hormone receptor-positive tumors and 64.3% had triple-negative LA/mBC (TNBC). At talazoparib initiation, 29.8% had ECOG PS of ≥2 and 19.0% had brain metastasis. Mutations in gBRCA1 or 2 were detected among 64.3% and 35.7% of patients, respectively. Talazoparib was given as 1st-line therapy in 14.3% of patients, 2nd-line in 40.5%, and 3rd- or 4th-line in 45.2%. Median time to talazoparib treatment failure was 8.5 months (95% CI, 8.0-9.7), median progression-free survival was 8.7 months (95% CI, 8.0-9.9), the median time from initiation to chemotherapy was 12.2 months (95% CI, 10.5-20.1), and the overall response rate was 63.1%. No differences in clinical outcomes were observed between patients with HR-positive/HER2-negative LA/mBC and patients with TNBC by using unadjusted statistical comparisons. Brain metastasis and ECOG PS ≥2 at talazoparib initiation were associated with treatment failure and progression or mortality.ConclusionOverall, talazoparib clinical outcomes in this real-world population are consistent with findings from EMBRACA.
| S-EPMC10166159 | biostudies-literature
Project description:PURPOSE:As triple-negative breast cancers are associated with earlier recurrences and poorer survival, optimal treatment of early-stage breast cancer is essential. Several retrospective studies in triple-negative breast cancer have reported conflicting results in overall survival in patients receiving neoadjuvant or adjuvant systemic therapy. This study aims to analyze outcomes of adjuvant versus neoadjuvant in patients with early-stage triple-negative breast cancer with and without BRCA germline mutations. METHODS:Patients with stage I or II triple-negative breast cancer who had BRCA testing were identified from a prospective cohort study of 4027 patients. Clinical, demographic, genetic test results, chemotherapy, recurrence, and survival data were analyzed. Overall survival and disease-free survival were estimated using the Kaplan-Meier method. RESULTS:319 patients with stage I and II triple-negative breast cancer who met eligibility criteria were included in the analysis. 187 received adjuvant chemotherapy (58.6%) and 132 received neoadjuvant chemotherapy (41.4%). 135 were BRCA positive (42.3%) and 184 were BRCA negative (57.7%). There was no significant association between overall survival or disease-free survival and treatment with neoadjuvant versus adjuvant in the overall cohort. Furthermore, there were no significant differences between patient subgroups (neoadjuvant BRCA positive, neoadjuvant BRCA negative, adjuvant BRCA positive, and adjuvant BRCA negative) with respect to either overall survival or disease-free survival. CONCLUSIONS:Neoadjuvant versus adjuvant with standard anthracycline- and taxane-containing regimens results in similar disease-free survival and overall survival among patients with stage I and II triple-negative breast cancer regardless of BRCA status. Further studies are needed to evaluate whether similar results are observed with newer agents.
| S-EPMC5994186 | biostudies-literature
Project description:The optimal treatment regimen for breast cancer patients with gBRCA mutations remains controversial given the availability of numerous options, such as platinum-based agents, polymerase inhibitors (PARPis), and other agents. We included phase II or III RCTs and estimated the HR with 95% CI for OS, PFS, and DFS, in addition to the OR with 95% CI for ORR and pCR. We determined the treatment arm rankings by P-scores. Furthermore, we carried out a subgroup analysis in TNBC and HR-positive patients. We conducted this network meta-analysis using R 4.2.0 and a random-effects model. A total of 22 RCTs were eligible, involving 4253 patients. In the pairwise comparisons, PARPi + Platinum + Chemo was better than PARPi + Chemo for OS (in whole study group and in both subgroups) as well as PFS. The ranking tests demonstrated that PARPi + Platinum + Chemo ranked first in PFS, DFS, and ORR. Platinum + Chemo showed higher OS than PARPi + Chemo. The ranking tests for PFS, DFS, and pCR indicated that, except for the best treatment (PARPi + Platinum + Chemo) containing PARPi, the second and third treatments were platinum monotherapy or platinum-based chemotherapy. In conclusion, PARPi + Platinum + Chemo might be the best regime for gBRCA-mutated BC. Platinum drugs showed more favorable efficacy than PARPi in both combination and monotherapy.
| S-EPMC9966507 | biostudies-literature
Project description:Patients with triple-negative breast cancer (TNBC) who have residual disease after neoadjuvant therapy have a high risk of recurrence. We tested the impact of DNA-damaging chemotherapy alone or with PARP inhibition in this high-risk population. Patients with TNBC or deleterious BRCA mutation (TNBC/BRCAmut) who had >2 cm of invasive disease in the breast or persistent lymph node (LN) involvement after neoadjuvant therapy were assigned 1:1 to cisplatin alone or with rucaparib. Germline mutations were identified with BROCA analysis. The primary endpoint was 2-year disease-free survival (DFS) with 80% power to detect an HR 0.5. From Feb 2010 to May 2013, 128 patients were enrolled. Median tumor size at surgery was 1.9 cm (0-11.5 cm) with 1 (0-38) involved LN; median Residual Cancer Burden (RCB) score was 2.6. Six patients had known deleterious BRCA1 or BRCA2 mutations at study entry, but BROCA identified deleterious mutations in 22% of patients with available samples. Toxicity was similar in both arms. Despite frequent dose reductions (21% of patients) and delays (43.8% of patients), 73% of patients completed planned cisplatin. Rucaparib exposure was limited with median concentration 275 (82-4694) ng/mL post-infusion on day 3. The addition of rucaparib to cisplatin did not increase 2-year DFS (54.2% cisplatin vs. 64.1% cisplatin + rucaparib; P = 0.29). In the high-risk post preoperative TNBC/BRCAmut setting, the addition of low-dose rucaparib did not improve 2-year DFS or increase the toxicity of cisplatin. Genetic testing was underutilized in this high-risk population.
| S-EPMC7985189 | biostudies-literature
Project description:Ovarian cancer (OC) is the eighth most common cancer among the female population and the most lethal of all the female reproductive system malignancies. Poly (ADP-ribose) polymerase inhibitors (PARPis) have reshaped the treatment scenario of metastatic OC in the maintenance setting post platinum-based chemotherapy. Niraparib is the first Food and Drug Administration (FDA)- and European Medical Agency (EMA)-approved PARPi as maintenance therapy for platinum-sensitive OC, regardless of BReast CAncer gene (BRCA) status, in first-line patients, with a recent restriction to germline BRCA mutations in second-line patients. In this review, we comprehensively summarized the pharmacological properties of niraparib, alongside the efficacy and safety data of the main trials leading to the current approvals, and discussed the future development of this agent.
| S-EPMC10536506 | biostudies-literature
Project description:PurposeTo investigate real-world clinical outcomes in patients with BRCA-mutated (BRCAm), HER2-negative metastatic breast cancer (mBC) according to BRCA and hormone receptor (HR) status.MethodsPatients diagnosed with HER2-negative mBC between 01 January 2010 and 31 December 2018 were retrospectively identified from the American Society of Clinical Oncology's CancerLinQ Discovery® database. Time to first subsequent therapy or death (TFST) from date of mBC diagnosis and start of first-line treatment for mBC and overall survival (OS) from date of mBC diagnosis were investigated according to BRCA status (BRCAm, BRCA wild type [BRCAwt] or unknown BRCA [BRCAu]) and HR status (positive/triple negative breast cancer [TNBC]). Follow-up continued until 31 August 2019 (i.e. minimum of 8 months).Results3744 patients with HER2-negative mBC were identified (BRCAwt, n = 460; BRCAm, n = 83; BRCAu, n = 3201) (HR-positive, n = 2738). Median (Q1, Q3) age was 63.0 (54.0, 73.0) years. Median (95% confidence interval [CI]) TFST (months) from mBC diagnosis was as follows: HR-positive, 7.7 (5.0, 11.2), 8.3 (6.6, 10.2) and 9.4 (8.7, 10.1); TNBC, 5.4 (3.9, 12.4), 5.6 (4.7, 6.6) and 5.4 (5.0, 6.2) for BRCAm, BRCAwt and BRCAu, respectively. Median (95% CI) OS (months) was as follows: HR-positive, 41.1 (31.5, not calculable), 55.1 (43.5, 65.5) and 33.0 (31.3, 34.8); TNBC, 13.7 (11.1, not calculable), 14.4 (10.7, 17.0) and 11.7 (10.3, 12.8) for BRCAm, BRCAwt and BRCAu, respectively.ConclusionWhen stratified by HR status, TFST and OS were broadly similar for patients with HER2-negative mBC, irrespective of BRCA status. Further global real-world studies are needed to study outcomes of this patient population.
| S-EPMC8993712 | biostudies-literature
Project description:BackgroundDespite the poor prognosis of triple-negative breast cancer (TNBC) brain metastases, there are no approved systemic therapies. We explored the DNA-damaging poly(ADP-ribose) polymerase inhibitor (PARPi) niraparib in intracranial mouse models of breast cancer susceptibility protein (BRCA)-mutant TNBC.MethodsMice bearing intracranial human-derived TNBC cell lines (SUM149, MDA-MB-231Br, or MDA-MB-436) were treated with niraparib and monitored for survival; intracranial tissues were analyzed for PAR levels and niraparib concentration by mass spectrometry. RNASeq data of primary breast cancers using The Cancer Genome Atlas were analyzed for DNA damage signatures. Combined RAD51 and PARP inhibition in TNBC cell lines was assessed in vitro by colony-forming assays.ResultsDaily niraparib increased median survival and decreased tumor burden in the BRCA-mutant MDA-MB-436 model, but not in the BRCA-mutant SUM149 or BRCA-wild-type MDA-MB-231Br models despite high concentrations in intracranial tumors. RAD51 inhibitor B02 was shown to sensitize all cell lines to PARP inhibition (PARPi). In the analysis of BRCA-mutant primary human TNBCs, gene expression predictors of PARPi sensitivity and DNA repair signatures demonstrate widespread heterogeneity, which may explain the differential response to PARPi. Interestingly, these signatures are significantly correlated to RAD51 expression including PARPi sensitivity (R 2 = 0.602, R 2= 0.758).ConclusionsNiraparib penetrates intracranial tumor tissues in mouse models of TNBC with impressive single-agent efficacy in BRCA-mutant MDA-MB-436. Clinical evaluation of niraparib to treat TNBC brain metastases, an unmet clinical need desperate for improved therapies, is warranted. Further compromising DNA repair through RAD51 inhibition may further augment TNBC's response to PARPi.
| S-EPMC7212882 | biostudies-literature
Project description:We report a deep next-generation sequencing analysis of 13 sequentially obtained tumor samples, eight sequentially obtained circulating tumor DNA (ctDNA) samples and three germline DNA samples over the life history of 3 patients with triple-negative breast cancer (TNBC), 2 of whom had germline pathogenic BRCA1 mutation, to unravel tumor evolution. Tumor tissue from all timepoints and germline DNA was subjected to whole-exome sequencing (WES), custom amplicon deep sequencing (30,000X) of a WES-derived somatic mutation panel, and SNP arrays for copy-number variation (CNV), while whole transcriptome sequencing (RNA-seq) was performed only on somatic tumor.There was enrichment of homologous recombination deficiency signature in all tumors and widespread CNV, which remained largely stable over time. Somatic tumor mutation numbers varied between patients and within each patient (range: 70-216, one outlier). There was minimal mutational overlap between patients with TP53 being the sole commonly mutated gene, but there was substantial overlap in sequential samples in each patient. Each patient's tumor contained a founding ("stem") clone at diagnosis, which persisted over time, from which all other clones ("subclone") were derived ("branching evolution"), which contained mutations in well-characterized cancer-related genes like PDGFRB, ARID2, TP53 (Patient_02), TP53, BRAF, BRIP1, CSF3R (Patient_04), and TP53, APC, EZH2 (Patient_07). Including stem and subclones, tumors from all patients were polyclonal at diagnosis and during disease progression. ctDNA recapitulated most tissue-derived stem clonal and subclonal mutations while detecting some additional subclonal mutations. RNA-seq revealed a stable basal-like pattern, with most highly expressed variants belonging to stem clone.SignificanceIn germline BRCA1 mutated and BRCA wild-type patients, TNBC shows a branching evolutionary pattern of mutations with a single founding clone, are polyclonal throughout their disease course, and have widespread copy-number aberrations. This evolutionary pattern may be associated with treatment resistance or sensitivity and could be therapeutically exploited.
| S-EPMC10865976 | biostudies-literature
Project description:PurposeThe interim analysis of the phase IIIb LUCY trial demonstrated the clinical effectiveness of olaparib in patients with germline BRCA-mutated (gBRCAm), human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (mBC), with median progression-free survival (PFS) of 8.11 months, which was similar to that in the olaparib arm of the phase III OlympiAD trial (7.03 months). This prespecified analysis provides final overall survival (OS) and safety data.MethodsThe open-label, single-arm LUCY trial of olaparib (300 mg, twice daily) enrolled adults with gBRCAm or somatic BRCA-mutated (sBRCAm), HER2-negative mBC. Patients had previously received a taxane or anthracycline for neoadjuvant/adjuvant or metastatic disease and up to two lines of chemotherapy for mBC.ResultsOf 563 patients screened, 256 (gBRCAm, n = 253; sBRCAm, n = 3) were enrolled. In the gBRCAm cohort, median investigator-assessed PFS (primary endpoint) was 8.18 months and median OS was 24.94 months. Olaparib was clinically effective in all prespecified subgroups: hormone receptor status, previous chemotherapy for mBC, previous platinum-based chemotherapy (including by line of therapy), and previous cyclin-dependent kinase 4/6 inhibitor use. The most frequent treatment-emergent adverse events (TEAEs) were nausea (55.3%) and anemia (39.2%). Few patients (6.3%) discontinued olaparib owing to a TEAE. No deaths associated with AEs occurred during the study treatment or 30-day follow-up.ConclusionThe LUCY patient population reflects a real-world population in line with the licensed indication of olaparib in mBC. These findings support the clinical effectiveness and safety of olaparib in patients with gBRCAm, HER2-negative mBC.Clinical trial registrationClinical trials registration number: NCT03286842.
| S-EPMC10948524 | biostudies-literature
Project description:PurposePARP inhibitors (PARPi) have demonstrated efficacy in tumors with germline breast cancer susceptibility genes (gBRCA) 1 and 2 mutations, but further factors influencing response to PARPi are poorly understood.Experimental designBreast cancer tumor tissue from patients with gBRCA1/2 mutations from the phase III EMBRACA trial of the PARPi talazoparib versus chemotherapy was sequenced using FoundationOne CDx.ResultsIn the evaluable intent-to-treat population, 96.1% (296/308) had ≥1 tumor BRCA (tBRCA) mutation and there was strong concordance (95.3%) between tBRCA and gBRCA mutational status. Genetic/genomic characteristics including BRCA loss of heterozygosity (LOH; identified in 82.6% of evaluable patients), DNA damage response (DDR) gene mutational burden, and tumor homologous recombination deficiency [assessed by genomic LOH (gLOH)] demonstrated no association with talazoparib efficacy.ConclusionsOverall, BRCA LOH status, DDR gene mutational burden, and gLOH were not associated with talazoparib efficacy; however, these conclusions are qualified by population heterogeneity and low patient numbers in some subgroups. Further investigation in larger patient populations is warranted.
| S-EPMC9365365 | biostudies-literature