Acquired Mutations in Breast Cancer Can Explain Resistance to Palbociclib/Fulvestrant

A new analysis found that several different driver mutations acquired during treatment can help explain acquired resistance to the combination of palbociclib and fulvestrant. These results from an analysis of the PALOMA-3 trial (abstract 1001) were presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 1–5 in Chicago.

“Palbociclib is an oral selective inhibitor of CDK4/6 that, in combination with endocrine therapy, is a standard of care for patients with advanced [hormone receptor] HR-positive/HER2-negative breast cancer,” said Nicholas C. Turner, MD, PhD, of the Royal Marsden NHS Foundation Trust in London. He said that several mechanisms of acquired resistance have been identified in preclinical research, but their relevance to the clinic was unknown.

The study included 521 patients randomized to receive either palbociclib plus fulvestrant (347 patients) or placebo plus fulvestrant (174 patients). Turner’s group used paired baseline and end-of-treatment circulating tumor DNA (ctDNA) analysis to identify mutation profiles that differ between the groups and over time.

The analysis included 193 paired ctDNA samples, 125 from the palbociclib group and 68 from the placebo group. They also used amplicon error–corrected sequencing and exome sequencing in smaller numbers of patients.

Several acquired driver mutations were identified, including mutations to ESR1, PIK3CA, and others. The time on palbociclib was associated with the acquisition of mutations; those without acquired mutations at end of treatment had a median time on treatment of 7.4 months, compared with 13.6 months in those with acquired mutations (P = .0066).

RB1 mutations are also acquired on palbociclib; no such mutations were detected at baseline, and 4.8% of patients had an RB1 mutation at end of treatment, compared with none on fulvestrant alone. The PIK3CA mutations and ESR1 mutations, in contrast, were acquired in both groups.

“These findings suggest parallel evolution of resistance to fulvestrant and to CDK4/6 inhibitors that may inform future treatment strategies,” Turner said.

Angela DeMichele, MD, of the University of Pennsylvania in Philadelphia, was the discussant for the session. “The data we saw this morning go a long way to help us understand what is happening to patients while they are taking endocrine therapy and CDK4/6 inhibitors,” she said, noting that it is important to recognize that the resistance to the two agents is happening simultaneously.

“Emerging mutations can provide hints to how to modify therapy,” she said, adding that they probably do not tell the whole story. “There may be other gene and protein expression alterations that are important….We need to think about how we’d integrate this into practice.”