乌鸦传媒

Homologous recombination deficiency (HRD) predicted most responses to the PARP inhibitor olaparib (Lynparza) in patients with triple-negative breast cancer (TNBC), including patients without germline (g)BRCA or PALB2 mutations, a small clinical trial showed.

Overall, 18 of 32 TNBCs responded to primary treatment with olaparib, and HRD was present in 16 of 18 responding tumors. A majority of responses occurred in tumors without germline mutations, in contrast to conventional wisdom about PARP inhibitors' activity in breast cancer.

"Olaparib monotherapy yielded a high response rate when administered to treatment-naïve, large TNBC, with germline or somatic HR deficiency," reported Hans Petter Eikesdal, MD, of the University of Bergen in Norway, and colleagues in the . "While the benefit of PARP inhibitor monotherapy in TNBC needs confirmation, it presents a potential sequential approach for TNBC downstaging prior to chemotherapy."

PARP inhibitors' have established antitumor activity in breast cancers harboring gBRCA1/2 mutations, for which olaparib has an . About 15% of unselected TNBCs harbor gBRCA1 mutations, but a majority of TNBCs have a gene expression signature similar to what was seen in carriers of gBRCA1 mutations, the authors noted.

Additionally, TNBCs may harbor somatic BRCA1 mutations, BRCA1 silencing through promoter hypermethylation, or somatic-germline alterations impacting other genes affecting homologous recombination, they continued. All told, as many as 80% of TNBCs might be associated with HRD.

"Of notice, BRCA1 methylated and gBRCA1-mutated TNBCs share gene expression and immune profiles, and seem to have a similar outcome after adjuvant chemotherapy, indicating that somatic HRD may promote the same biological phenotype and treatment response as germline HRD in TNBC," the authors stated.

On the basis of the evidence, Eikesdal and colleagues hypothesized that PARP inhibition would be effective in treatment-naïve TNBC beyond those tumors with gBRCA1/2 defects. To test the hypothesis they enrolled patients with untreated TNBC into a phase II trial evaluating neoadjuvant regimens for patients with stage II/III breast cancer. Patients in the TNBC cohort received olaparib monotherapy for a maximum of 10 weeks in an attempt to achieve tumor shrinkage prior to chemotherapy.

Tumor specimens analyses before and after olaparib treatment included DNA sequencing by a 360-gene panel, BRCA1 promoter methylation, and BRCAness.

As determined by clinical and MRI evaluation, olaparib achieved objective responses in 18 of 32 (56.3%) patients in the TNBC cohort, all but one of which were partial responses. Responses occurred across the range of tumor sizes. Exclusion of the five patients with gBRCA1/2 and gPALB2 mutations resulted in an objective response rate of 51.9% (14 of 27 patients).

Ten of 18 responding patients had germline or somatic mutations affecting HR, as compared with one of 14 patients who did not respond to olaparib (P=0.008). The difference remained significant when the patients with germline mutations were excluded (six of 14 vs none of 13, P=0.02). Six of the remaining eight patients who responded to olaparib had BRCA1 promoter methylation versus three of 13 patients who did not respond (P=0.03).

Collectively, HR mutations (germline or somatic) and BRCA1 promoter methylation accounted for all but two of the responses to olaparib. No tumor harbored both BRCA1 methylation and a germline or somatic BRCA1 mutation.

The 360-gene panel identified several other types of mutations associated with DNA damage repair, but only one (occurring in a patient who did not respond to olaparib) occurred in concert with an HR mutation, the authors reported. Additionally, TP53 mutations and tumor mutational burden did not predict response to olaparib. Treatment with the PARP inhibitor reduced the total number of mutations in responding tumors but not in nonresponding tumors (P=0.01).

Despite the study's small size, the results may have the potential to influence thinking about use of PARP inhibitors to treat breast cancer, said Charles Shapiro, MD, of Mount Sinai Health System in New York City.

"The germline (mutations) work with PARP, but it's not so clear about somatic mutations," he told 乌鸦传媒. "I think this study shows that somatic mutations, the right mutation, wherever the mutation may be, if it's sensitive to PARP, then (a PARP inhibitor) will work in the tumor, not necessarily the germline mutations."

"This suggests that you have to test not only for germline mutations but for somatic mutations in the tumor, by next generation sequencing or some other genomic test to uncover these targetable mutations," added Shapiro, who was not involved in the study.

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