New Studies Expand the BRCA Equation in Breast Cancer

Judy E. Garber, MD

Although BRCA1/2 mutations have been intensely studied in breast cancer for more than a decade, researchers are still seeking to determine which patient populations should be screened for abnormalities and how best to integrate that information into treatment protocols.

Two abstracts presented at the 2015 ASCO Annual Meeting explored those questions. In one study, researchers found evidence to support mutation testing of women 45 years or younger who have been diagnosed with any type of breast cancer.¹ In another study, investigators correlated clinical outcomes among patients with triplenegative breast cancer (TNBC) with an assay that offers a more comprehensive DNA repair pathway analysis than BRCA1/2 testing alone.²

Screening Younger Women

Platinum agents and PARP inhibitors are increasingly under study in women with TNBC, particularly among patients who harbor BRCA1/2 mutations. Yet focusing mutation testing on that population may bypass other patients who also might benefit from these therapies, according to Judy E. Garber, MD.

In a small study, Garber and colleagues found that BRCA and other mutations occurred in more than 10% of estrogen-receptor (ER)—positive/ HER2-negative invasive breast cancers in a cohort of women younger than 50 years.¹

Overall, 11 of 106 patients (10.4%) had a deleterious mutation. These included seven patients (6.6%) with BRCA1 or BRCA2 mutations. Other genes related to breast cancer identified through the analysis were ATM, CHEK2, and PALB2. One patient had a mutation in both BRCA2 and ATM.

“Neither age at diagnosis nor family history distinguished carriers in this relatively small cohort of women diagnosed before age 50,” said Garber, director of the Cancer Risk and Prevention Clinic at Dana-Farber Cancer Institute in Boston. “National Comprehensive Cancer Network [NCCN] guidelines call for testing women with breast cancer diagnosed at age 45 years or younger, regardless of subtype. These data are a reminder to extend testing beyond patients with triple-negative breast cancer.”

Among women with newly diagnosed TNBC, BRCA1/2 mutations typically occur in about 25% of tumors diagnosed at age 50 years or earlier and in 10% to 15% of tumors diagnosed at age 60 years or earlier. Epidemiologic data have shown that BRCA mutation carriers who are younger than 50 years at diagnosis are more likely to have higher-grade ER-positive tumors.

Given the NCCN recommendation for genetic testing of women 45 years or younger, “We wondered whether we are missing patients who might benefit from targeted therapies if only those with triple-negative breast cancer are tested,” said Garber. “We looked beyond BRCA to begin to contribute to that epidemiology.”

Investigators obtained blood samples from consenting patients with invasive breast cancer. All patients were younger than 50 years at diagnosis, had ER-positive/HER2-negative breast cancer, grade 3 (poorly differentiated) disease, and invasive cancer only. After exclusions for incorrect grade, insufficient DNA, and other factors, 106 patients remained for testing and data analysis.

The patient specimens were assessed by means of a next-generation sequence-based panel that identified mutations in 25 cancer predisposition genes. Investigators classified germline sequence variations and large rearrangements for pathogenicity.

The test panel identified deleterious mutations in 11 patients. BRCA1 mutations were detected in four patients and BRCA2 in three patients. Other cancer-predisposition genes identified in the study were ATM in two patients (including one BRCA2 carrier), CHEK2 in one patient, and PALB2 in two patients.

Gunter von Minckwitz, MD

Investigators found one or more variants of unknown significance (VUS) in any gene in 47 of 106 patients. The VUS occurred alone in 39 cases and with a mutation in eight cases. Mutation frequencies were higher among women of Ashkenazi Jewish ethnicity (3 of 11 mutations, 27.3%; P = .02), progesterone-receptor— negative tumors (27.3% vs 5.3% of women without mutations; P <.01), and women who previously had undergone genetic testing (81.8% vs 42.1% of women without mutations; P = .01).

“Panel testing identified mutations beyond BRCA1 and BRCA2 in women with high-grade ER-positive/HER2-negative tumors diagnosed before age 50. Further research to assess the mutation rate in women diagnosed after age 50 years with grade III, ER-positive/HER2-negative cancers is warranted,” Garber concluded.

James M. Ford, MD, who served as the discussant on Garber’s research, agreed with her conclusions. He said healthcare practitioners are well aware that NCCN guidelines recommend genetic testing for women 60 years or younger with TNBC but are not as cognizant that those guidelines extend to women diagnosed at 45 years or younger regardless of tumor histology.

“This study reinforces the NCCN guidelines, it shows interesting results from panel testing with similar distributions of genes in this population, and it certainly suggests further studies and results might lead to modifications of those guidelines to be more inclusive depending on risks,” said Ford, who is director of the Program for Clinical Cancer Genetics at Stanford University School of Medicine in California.

HRD and BRCA Mutations in TNBC Study2

HR indicates homologous recombination; HRD, homologous recombination deficiency; tmBRCA, a deleterious mutation of BRCA1 or BRCA2 in the primary tumor.

HRD Assay Correlates With Outcomes

While tumors with decreased DNA repair capacity due to BRCA1/2 mutations are expected to show high sensitivity to DNA-damaging agents, Gunter von Minckwitz, MD, and colleagues sought to develop an assay that goes beyond that genetic abnormality in TNBC.²

The investigators found that homologous recombination deficiency (HRD) or a high HRD score (derived from 3 HRD markers) identified TNBCs that had an increased likelihood of pathologic complete response (pCR) to chemotherapy.

To evaluate the assay, the researchers correlated outcomes among a subset of patients with TNBC who participated in the GeparSixto trial with their HRD score.

The GeparSixto trial involved patients with HER2-positive or TNBC, randomized to paclitaxel and liposomal doxorubicin with or without carboplatin.

Patients with TNBC also received bevacizumab. The primary analysis showed a higher pCR rate among patients treated with carboplatin, but the greater activity came at a price of increased toxicity.

The ability to predict responsiveness to carboplatin prior to treatment would spare patients unlikely to achieve pCR the toxicity of the third drug.

In the TNBC analysis, the pCR rate increased from 45.2% to 64.9%, respectively, in patients with HR-deficient tumors treated with the carboplatin combination compared with those who received the chemotherapy doublet. BRCA-negative primary tumors that had high HRD scores had a significantly higher pCR rate with the carboplatin regimen than did BRCA-negative tumors treated with the doublet.

However, patients with primary tumors containing mutant BRCA did not derive statistically significant benefit from carboplatin by the primary definition of pCR used in the study, but ironically, did benefit significantly when a more stringent definition of pCR was applied.

“HR deficiency in TNBC is an independent predictor of high pCR rates to neoadjuvant chemotherapy with paclitaxel and liposomal doxorubicin with or without carboplatin,” said von Minckwitz, who is managing director of the German Breast Group Research Institute. “However, results using pCR [as defined in this study] as an endpoint are inconsistent, and a formal interaction between HR deficiency and carboplatin could not be shown.

“Results have to be confirmed by other studies and set into context with survival data,” he said.

The study of HRD focused on 315 patients from GeparSixto with TNBC. Investigators determined the HRD score on the basis of the cumulative total of loss-of-heterozygosity score, telomeric allelic imbalance score, and largescale state transitions score.

The HRD score has a range of 0 to 100, and von Minckwitz et al defined a high HRD score as 42 or greater. The investigators defined HR deficiency as a high HRD score or the presence of a BRCA mutation in the primary tumor.

The study’s primary endpoint was pCR, defined as ypT0/is ypN0 (residual in situ disease).

The secondary endpoint was pCR more stringently defined as ypT0 ypN0 (no residual invasive or in situ disease).

HR deficiency could be adequately assessed in 193 of the 315 triple-negative tumors. Of those, 136 proved to be HR deficient, 82 of which had high HRD scores despite the absence of mutant BRCA in the primary tumor.

Using the primary endpoint definition of pCR, von Minckwitz et al found a pCR rate of 29.8% in the 57 HR nondeficient tumors and 55.9% in the 136 HR-deficient tumors (odds ratio [OR], 2.98; P <.001). Use of the more stringent definition of pCR resulted in response rates of 24.6% and 50.0% in HR nondeficient and deficient tumors, respectively. The data showed that 30 HR-nondeficient and 62 HR-deficient tumors were assigned to doublet therapy, which resulted in pCR rates of 20.0% and 45.2%, respectively (OR, 3.29; P = .016).

In the carboplatin arm, the pCR rate was 40.7% in 27 HR-nondeficient tumors and 64.9% in 74 HR-deficient tumors (OR, 2.68; P = .03).

For the secondary endpoint, pCR rates were 20.0% and 33.9% in the HR-nondeficient and deficient tumors assigned to doublet therapy (P = .162), increasing to 29.6% and 63.5% in the carboplatin arm (P = .002).

Investigators analyzed pCR rates by treatment and according to different definitions of HR deficiency. Tumors that were HR deficient by HRD score had pCR rates of 36.6% with the chemotherapy doublet and 63.2% with carboplatin (P = .018). A smaller, nonsignificant difference emerged from analysis of tumors containing mutant BRCA (61.9% vs 72.7%; P = .406).

Use of the more stringent pCR criteria resulted in pCR rates of 31.7% and 63.2%, respectively, for the doublet and carboplatin arms in tumors with high HRD scores (OR, 3.69; P = .005). Tumors containing mutant BRCA also had significantly higher pCR rates with carboplatin (69.7% vs 38.1%; OR, 3.74; P = .022).

In discussing the results of the trial, Pamela N. Munster, MD, of the University of California, San Francisco, indicated that the HRD assay has immediate clinical utility. “HRD assessment in triple-negative tumor should be used to select chemotherapy and platinum-based regimen,” she said.

At the same time, she added, “We really need an intense focus on biomarker refinement to move forward.”

References

1. Garber JE, Tung NM, Elkin EP, et al. Predisposing germline mutations in high grade ER+HER2- breast cancer patients diagnosed age <50. Presented at: 2015 ASCO Annual Meeting; May 29-June 2, 2015; Chicago, IL. Abstract 1503.
2. von Minckwitz G, Timms K, l Untch M, et al. Prediction of pathological complete response (pCR) by Homologous Recombination Deficiency (HRD) after carboplatin-containing neoadjuvant chemotherapy in patients with TNBC - Results from GeparSixto. Presented at: 2015 ASCO Annual Meeting; May 29-June 2, 2015; Chicago, IL. Abstract 1004.