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| Ref Type | Journal Article | ||||||||||||
| PMID | (33119476) | ||||||||||||
| Authors | Tung NM, Robson ME, Ventz S, Santa-Maria CA, Nanda R, Marcom PK, Shah PD, Ballinger TJ, Yang ES, Vinayak S, Melisko M, Brufsky A, DeMeo M, Jenkins C, Domchek S, D'Andrea A, Lin NU, Hughes ME, Carey LA, Wagle N, Wulf GM, Krop IE, Wolff AC, Winer EP, Garber JE | ||||||||||||
| Title | TBCRC 048: Phase II Study of Olaparib for Metastatic Breast Cancer and Mutations in Homologous Recombination-Related Genes. | ||||||||||||
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| Abstract Text | Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) in germline (g)BRCA1/2 mutation carriers. Olaparib Expanded, an investigator-initiated, phase II study, assessed olaparib response in patients with MBC with somatic (s)BRCA1/2 mutations or g/s mutations in homologous recombination (HR)-related genes other than BRCA1/2.Eligible patients had MBC with measurable disease and germline mutations in non-BRCA1/2 HR-related genes (cohort 1) or somatic mutations in these genes or BRCA1/2 (cohort 2). Prior PARPi, platinum-refractory disease, or progression on more than two chemotherapy regimens (metastatic setting) was not allowed. Patients received olaparib 300 mg orally twice a day until progression. A single-arm, two-stage design was used. The primary endpoint was objective response rate (ORR); the null hypothesis (≤ 5% ORR) would be rejected within each cohort if there were four or more responses in 27 patients. Secondary endpoints included clinical benefit rate and progression-free survival (PFS).Fifty-four patients enrolled. Seventy-six percent had estrogen receptor-positive HER2-negative disease. Eighty-seven percent had mutations in PALB2, sBRCA1/2, ATM, or CHEK2. In cohort 1, ORR was 33% (90% CI, 19% to 51%) and in cohort 2, 31% (90% CI, 15% to 49%). Confirmed responses were seen only with gPALB2 (ORR, 82%) and sBRCA1/2 (ORR, 50%) mutations. Median PFS was 13.3 months (90% CI, 12 months to not available/computable [NA]) for gPALB2 and 6.3 months (90% CI, 4.4 months to NA) for sBRCA1/2 mutation carriers. No responses were observed with ATM or CHEK2 mutations alone.PARP inhibition is an effective treatment for patients with MBC and gPALB2 or sBRCA1/2 mutations, significantly expanding the population of patients with breast cancer likely to benefit from PARPi beyond gBRCA1/2 mutation carriers. These results emphasize the value of molecular characterization for treatment decisions in MBC. | ||||||||||||
| Molecular Profile | Treatment Approach |
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| Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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| Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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| Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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| Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
|---|---|---|---|---|---|
| CDK12 | S1236fs | frameshift | unknown | CDK12 S1236fs results in a change in the amino acid sequence of the Cdk12 protein beginning at aa 1236 of 1490, likely resulting in premature truncation of the functional protein (UniProt.org). S1236fs has been identified in the scientific literature (PMID: 33119476), but has not been biochemically characterized and therefore, its effect on Cdk12 protein function is unknown (PubMed, Dec 2023). |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| CHEK2 mutant | breast cancer | no benefit | Olaparib | Case Reports/Case Series | Actionable | In a Phase II trial (TBCRC 048), Lynparza (olaparib) treatment did not result in an objective response in 7 patients with metastatic breast cancer harboring only germline mutations in CHEK2 (PMID: 33119476; NCT03344965). | 33119476 |
| ATM mutant | breast cancer | no benefit | Olaparib | Case Reports/Case Series | Actionable | In a Phase II trial (TBCRC 048), Lynparza (olaparib) treatment did not result in an objective response in 4 patients with metastatic breast cancer harboring only germline mutations in ATM (PMID: 33119476; NCT03344965). | 33119476 |
| PALB2 inact mut | breast cancer | predicted - sensitive | Olaparib | Phase II | Actionable | In a Phase II trial (TBCRC 048), Lynparza (olaparib) treatment resulted in an objective response rate (ORR) of 33% (9/27) and a clinical benefit rate (CBR) at 18 weeks of 50% in patients with metastatic breast cancer harboring germline mutations in homologous recombination-related genes other than BRCA1/2, all responders harbored germline PALB2 inactivating mutations, ORR and CBR in PALB2-mutant patients (n=11) were 82% and 100%, respectively (PMID: 33119476; NCT03344965). | 33119476 |
| BARD1 mutant | breast cancer | no benefit | Olaparib | Case Reports/Case Series | Actionable | In a Phase II trial (TBCRC 048), Lynparza (olaparib) treatment did not result in an objective response in a patient with metastatic breast cancer harboring a germline mutation in BARD1 (PMID: 33119476; NCT03344965). | 33119476 |
| CDK12 S1236fs | triple-receptor negative breast cancer | predicted - sensitive | Olaparib | Case Reports/Case Series | Actionable | In a Phase II trial (TBCRC 048), Lynparza (olaparib) treatment resulted in an unconfirmed partial response with a 33% tumor size reduction in a patient with metastatic triple negative breast cancer harboring a somatic CDK12 S1236fs mutation (PMID: 33119476; NCT03344965). | 33119476 |