Joyce A. O'Shaughnessy, MD, discusses the importance of research regarding the application of DNA repair deficiency in breast cancer, even though it's still in early stages.
Joyce A. O’Shaughnessy, MD
Research regarding the application of DNA repair deficiency in breast cancer is still in its early stages, but its importance should not be understated, said Joyce A. O'Shaughnessy, MD, co-chair of Breast Cancer Research and the Celebrating Women Chair in Breast Cancer at Baylor-Sammons Cancer Center, Texas Oncology.
“What kind of DNA damage repair deficiency a cancer has is as important as the proliferative status and the invasiveness status. It’s going to be one of these fundamental properties that’s going to drive biology, and ultimately, therapy,” O’Shaughnessy, who is also chair of The US Oncology Network, and a 2016 Giant of Cancer Care® in Community Outreach, said in a presentation during the 19th Annual International Congress of the Future of Breast Cancer® West, a virtual program by Physician Education Resource® (PER®).
Current mutation signatures of importance which can be tested for with next-generation sequencing include homologous recombination deficiency (HRD) and APOBEC. Regarding treatment implications, HRD-positive cancers are thought to be more responsive to DNA-damaging agents, such as PARP inhibitors and platinum-based chemotherapy, said O’Shaughnessy.
One of the first trials to evaluate the value of testing for HRD was the GeparSixto trial.1 In the trial, 315 patients with early-stage triple-negative breast cancer (TNBC) received anthracycline and taxane chemotherapy with or without carboplatin. Approximately 70% of patients had HRD; of these patients, about 40% were BRCA1/2 positive. Patients with HRD tumors were more likely to have a pathologic complete response (pCR; 55.9%) than those with HR-proficient tumors, regardless of the use of carboplatin (29.8%; P= .001). Notably, the addition of carboplatin increased the pCR rate from 45.2% to 64.9% in HRD tumors (P= 0.025), whereas the addition of carboplatin in HR-proficient tumors was not statistically significant.
“The results of the trial suggested that we should be ordering an HRD assessment for patients with TNBC to see whether they need carboplatin,” said O’Shaughnessy.
However, subsequent results from the M14-011 BrighTNess study2 failed to confirm the utility of HRD as a biomarker of response to carboplatin. Instead, the results showed a significant improvement in pCR with the addition of carboplatin, irrespective of HRD status.
In order to understand the potential nuances of HRD status, investigators of the I-SPY 2 trial3 evaluated the MammaPrint 70-gene High1 (MP1) and High2 (MP2) risk score as a biomarker of response to carboplatin and veliparib. Among 986 patients in the trial, 49% had high-risk disease and 51% had ultra–high-risk disease.
When investigators separated patient responses to carboplatin and veliparib by MP1 and MP2 score, they found that patients with an MP2 score experienced more than a 30% improvement in pCR versus those with an MP1 score.
“It’s very interesting that MP1 versus MP2 may be a way to identify HRD in TNBC. It would be interesting to see this analysis applied to the BrighTNess study,” said O’Shaughnessy, who added that similar results were seen in an analysis of the I-SPY 2 trial with the combination of durvalumab (Imfinzi), olaparib (Lynparza), and cisplatin in patients with hormone receptor–positive, HER2-negative breast cancer.4
In the SWOG 1416 trial,5 patients with predominantly metastatic TNBC were randomized to receive cisplatin plus veliparib versus cisplatin plus placebo. Patients were stratified into 1 of 3 cohorts: germline BRCAgroup, BRCA-like group, and a non–BRCA-like group.
Only 50% of patients in the germline BRCA group had a high HRD score, unlike in the GeparSixto trial, said O’Shaughnessy, wherein almost all patients with a germline BRCA mutation had a high HRD score. In SWOG 1416, no benefit in progression-free survival (PFS) or overall survival (OS) was seen with the addition of veliparib in patients who harbored germline BRCA mutations (HR, 0.66; HR, 1.27, respectively).
However, in the BRCA-like group, investigators reported a benefit in PFS and OS with the addition of veliparib (HR, 0.53 and HR, 0.60, respectively).
“This is the first time we’ve seen an improvement in PFS and OS with a PARP inhibitor in a non-germline BRCA group,” said O’Shaughnessy. “These results suggest that we’re going to be able to perhaps sort out the heterogeneity of TNBC in the metastatic setting [and direct] platinum agents and PARP inhibitors toward patients with BRCA likeness and high HRD.”
In addition to measuring HRD by germline BRCA status, high HRD scores, and MP2, O’Shaughnessy cited estrogen receptor (ER)–positive basal status as another candidate marker.
The notion can be traced back to the NBRST Registry trial,6 in which 1072 patients were treated with neoadjuvant chemotherapy. A total of 694 patients had ER-positive disease by immunohistochemistry. However, 13% of these cancers were reclassified as basal cancers rather than luminal cancers with the 80-gene signature assay. Results showed that these patients experienced similar pCR rates and early recurrence rates as those with TNBC.
“It turned out that many of these ER-positive basal cancers had a non-functional ER ,” said O’Shaughnessy. “They had a spliced variant in the ER that rendered it nonfunctional, so it was a wolf in sheep’s clothing.
These results suggest that it’s not the ER status that drives chemotherapy sensitivity but rather DNA damage repair deficiency, said O’Shaughnessy.
Finally, O’Shaughnessy pointed to APOBEC3B, which is overexpressed in approximately 50% of all breast cancer and drives estrogen-related mutagenesis. Although the therapeutic implications of the ABOBEC mutation signature is unknown in breast cancer, early evidence suggests that exploiting DNA repair deficiency through inhibition of the ER may increase the cancer’s susceptibility to DNA-damaging agents.