Deleterious BRCA1/2 mutation is an independent risk factor for carboplatin hypersensitivity reactions

Dh, Moon; Lee, Jang-Ming; Noonan, Anne; Cm, Annunziata; Minasian, Lori M.; Houston, Nicole; Jl, Hays; Ec, Kohn

doi:10.1038/bjc.2013.389

Cited by 61 publications

(63 citation statements)

References 30 publications

(37 reference statements)

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“…The average prevalence of this mutation in tubo-ovarian cancer population is 13 to 17% (3), but when considering only allergic patients to carboplatin enrolled in the RDD program we identified a prevalence of 34%. This corroborates the finding of the BRCA mutation as an independent risk factor for HSR to carboplatin (1), since its prevalence is notably increased in our population.…”

Section: To the Editorsupporting

confidence: 92%

“…The studied population was composed of 87 patients with ovarian, fallopian tube or primary peritoneal cancer. This study also found that patients with BRCA1/2 mutations developed a HSR to carboplatin with a lower cumulative dose (1). …”

Section: To the Editormentioning

confidence: 63%

“…Deleterious germline BRCA 1/2 mutation was described as an independent risk factor for carboplatin hypersensitivity reactions (HSR) (1). In 2013, Moon et al observed in a retrospective study that most patients who developed carboplatin HSR had deleterious BRCA1/2 mutations (93%, 27/29), versus 50% (29/58) in patients without HSR (p<0.0001).…”

Section: To the Editormentioning

confidence: 99%

See 2 more Smart Citations

Carboplatin-allergic patients undergoing desensitization: prevalence and impact of the BRCA 1/2 mutation

Galvão

Phillips

Giavina‐Bianchi

et al. 2017

The Journal of Allergy and Clinical Immunology: In Practice

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Section: To the Editorsupporting

confidence: 92%

Section: To the Editormentioning

confidence: 63%

Section: To the Editormentioning

confidence: 99%

See 1 more Smart Citation

Carboplatin-allergic patients undergoing desensitization: prevalence and impact of the BRCA 1/2 mutation

Galvão

Phillips

Giavina‐Bianchi

et al. 2017

The Journal of Allergy and Clinical Immunology: In Practice

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“…However, retreatment with platinum-based chemotherapy poses certain risks, including exacerbation of residual neuropathy from initial treatment, enhanced myelosuppression, or onset of hypersensitivity reactions to platinum. Moon and colleagues identified a higher frequency of platinum hypersensitivity reactions at a lower net exposure in g BRCA m patients (30). Use of the cediranib/olaparib combination in lieu of platinum-containing chemotherapy would potentially reduce this risk while prolonging the platinum-free interval.…”

Section: Discussionmentioning

confidence: 99%

Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study

Liu

Barry

Birrer

et al. 2014

The Lancet Oncology

538

368

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Background Olaparib is an oral poly(ADP-ribose) polymerase inhibitor and cediranib is an oral anti-angiogenic with activity against VEGFR-1, 2, and 3. Both agents have antitumor activity in women with recurrent ovarian cancer, and the combination of these agents was active and had manageable toxicities in a Phase 1 trial. We asked whether the combination of cediranib and olaparib could improve progression-free survival compared to olaparib monotherapy in women with recurrent platinum-sensitive ovarian cancer. Methods We conducted a randomized, open-label, phase 2 study to evaluate the activity of olaparib monotherapy compared with combination cediranib and olaparib in women with ovarian cancer with measurable platinum-sensitive, relapsed, high-grade serous or endometrioid disease or those with deleterious germline BRCA1/2 mutations (gBRCAm). Patients were randomized using permuted blocks within stratum defined by gBRCA status and prior anti-angiogenic therapy to receive olaparib capsules 400mg twice daily or the combination at the recommended phase 2 dose of cediranib 30mg daily and olaparib capsules 200mg twice daily. The primary endpoint was progression-free survival (PFS) analyzed under intention to treat. The trial is registered with ClinicalTrials.gov, NCT01116648. The Phase 2 portion of the trial reported here is no longer accruing patients. Findings Forty-six of 90 randomized patients received olaparib alone, and 44 received cediranib/olaparib. Median PFS was significantly longer with cediranib/olaparib (17.7 vs. 9.0 mos, HR 0.42; p = 0.005). Grade 3 and 4 adverse events were more common with cediranib/olaparib, including fatigue (12 vs. 5), diarrhea (10 vs. 0), and hypertension (18 vs. 0). Subset analysis within stratum defined by BRCA1/2 status demonstrated activity of cediranib/olaparib in both gBRCAm and gBRCAwt/u (wild-type/unknown) patients. Significant improvement in PFS occurred in gBRCAwt/u women receiving cediranib/olaparib (16.5 vs. 5.7 mos, p = 0.008) with a smaller trend towards increased PFS in gBRCAm patients (19.4 vs. 16.5 mos, p = 0.16). Interpretation The combination of cediranib and olaparib significantly extended PFS by 8.7 months compared to olaparib alone in recurrent platinum-sensitive ovarian cancer. The activity observed with this oral combinaton in both gBRCAmt and gBRCAwt/u patients is encouraging and should be further explored as a potential alternative to cytotoxic chemotherapy. Given the side effect profile, such explorations should include assessments on quality of life and patient-reported outcomes to understand the effects of an ongoing oral regimen to that of intermittent chemotherapy.

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“…In contrast to the high dose of veliparib attained with cisplatin based therapy in this phase I study, myelosuppression has limited the dose of veliparib that can be combined with carboplatin as a single agent (50) or with carboplatin and paclitaxel doublet (51). Data from ovarian cancer literature demonstrate that patients with a BRCA1/2 mutation have increased susceptibility and shortened time to carboplatin hypersensitivity reactions, independent of other risk factors for hypersensitivity reactions (52). Therefore, cisplatin compared to carboplatin may improve the tolerability and durability of the platinum based combination regimens in BRCA mutation carriers in the metastatic setting where patients receive multiple cycles of chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Phase I Study of Veliparib (ABT-888) Combined with Cisplatin and Vinorelbine in Advanced Triple-Negative Breast Cancer and/orBRCAMutation–Associated Breast Cancer

Rodler

Kurland

Griffin

et al. 2016

Clinical Cancer Research

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PURPOSE Cisplatin is synergistic with vinorelbine and the poly(ADP-ribose) polymerase (PARP) inhibitor veliparib, and has anti-neoplastic activity in TNBC and BRCA mutation-associated breast cancer. This phase I study assessed veliparib with cisplatin and vinorelbine. PATIENTS AND METHODS A 3+3 dose escalation design evaluated veliparib administered BID for 14 days with cisplatin (75 mg/m2 day 1) and vinorelbine (25 mg/m2 days 1,8) every 21 days, for six to ten cycles, followed by veliparib monotherapy. Pharmacokinetics, measurement of poly(ADP-ribose) in peripheral blood mononuclear cells, and preliminary efficacy were assessed. Immunohistochemistry and gene expression profiling were evaluated as potential predictors of response. RESULTS Forty-five patients enrolled in nine dose cohorts plus five in an expansion cohort at the highest dose level and recommended phase II dose, 300 mg BID. Maximum tolerated dose of veliparib was not reached. Neutropenia (36%), anemia (30%), and thrombocytopenia (12%) were the most common grade 3/4 adverse events. Best overall response for 48 patients was radiologic response with 9-week confirmation for 17 (35%; 2 complete, 15 partial), and stable disease for 21 (44%). Germline BRCA mutation presence versus absence was associated with 6-month progression-free survival (10 of 14 (71%) vs 8 of 27 (30%), mid-p=0.01). Median progression-free survival for all 50 patients was 5.5 months (95% confidence interval 4.1–6.7). CONCLUSION Veliparib at 300 mg BID combined with cisplatin and vinorelbine is well tolerated with encouraging response rates. A phase II randomized trial is planned to assess veliparib’s contribution to cisplatin chemotherapy in metastatic TNBC and BRCA mutation-associated breast cancer. Translational Relevance We hypothesize that TNBC tumors have defects in homologous recombination DNA repair similar to BRCA mutation associated tumors, which will render them sensitive to platinum therapy and PARP inhibition. This report describes a phase I study that explored the safety and efficacy of cisplatin, vinorelbine and veliparib. This combination was tolerable and reached the highest dose of veliparib in combination with chemotherapy used in breast cancer to date. Antineoplastic activity was observed both in BRCA mutation associated breast cancer and in BRCA wild-type TNBC. We measured changes in PARP activity and performed gene expression profiling and immunohistochemistry studies. Based on promising results from this study, a randomized phase II study has been developed to evaluate the addition of veliparib to cisplatin chemotherapy for patients with advanced TNBC. This study will incorporate a multi-pronged biomarker approach to identify a homologous recombination repair deficiency (HRD) phenotype that derives benefit from PARP inhibition.

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Deleterious BRCA1/2 mutation is an independent risk factor for carboplatin hypersensitivity reactions

Cited by 61 publications

References 30 publications

Carboplatin-allergic patients undergoing desensitization: prevalence and impact of the BRCA 1/2 mutation

Carboplatin-allergic patients undergoing desensitization: prevalence and impact of the BRCA 1/2 mutation

Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study

Phase I Study of Veliparib (ABT-888) Combined with Cisplatin and Vinorelbine in Advanced Triple-Negative Breast Cancer and/orBRCAMutation–Associated Breast Cancer

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