Erika Hamilton, MD
Nikhil Wagle, MD
Erika Hamilton, MD, Director of the Breast Cancer and Gynecologic Cancer Research Program, Sarah Cannon Research Institute at Tennessee Oncology, Nashville, who gave the Metastatic Breast Cancer Highlights presentation, and Nikhil Wagle, MD, Assistant Professor of Medicine, Harvard Medical School, a medical oncologist at Dana-Farber Cancer Institute, and the invited discussant of PADA-1, commented on the trial.
Dr. Hamilton pointed out ESR1 mutations are rare in primary breast cancer and in first metastatic recurrence, but they arise in as many as 40% of metastatic treatment-refractory hormonally driven tumors. Aromatase inhibitors in combination with CDK4/6 inhibitors have consistently yielded median progression-free survivals of between 25 and 28 months, but this prognosis appears to be worse for patients with ESR1 mutations.
In PADA-1, Dr. Hamilton said, it is “not surprising the 33 patients with mutations detected at the start of therapy fared significantly worse than those without these mutations. The mutations may hasten resistance to treatment with an aromatase inhibitor plus palbociclib…. Of note, however, in two-thirds of patients on PADA-1, ESR1 mutations cleared within 1 month of treatment on what we would traditionally consider an inadequate endocrine therapy backbone in the setting of an ESR1 mutation. They fared almost the same as those who did not have the ESR1 mutation at baseline. “The rules that previously held true—such as fulvestrant being more active than aromatase inhibitors and being needed for tumors with ESR1 mutations—may no longer be true when in combination with CDK4/6. Perhaps when CDK4/6 is in the mix, the endocrine backbone is no longer the driving force for benefit. It remains to be determined whether novel oral [selective estrogen receptor degraders] can change this.”
Negative Marker for Treatment Response
Dr. Wagle called PADA-1 “an innovative study that addresses the critical question of what clinical action can be taken with early detection of resistance mechanisms found with circulating tumor DNA.” The study may provide information that informs the question of whether this “near-universal” resistance to treatment is resistance to endocrine therapy, the CDK4/6 inhibitor, or both, he noted. “Underlying mechanisms of resistance may allow us to tailor our therapies to individual patients, including changing the endocrine therapy,” Dr. Wagle said.
The main message from PADA-1, according to Dr. Wagle, is “an ESR1 mutation at baseline, or perhaps more accurately one that persists over 4 weeks, is a negative marker for response to treatment with an aromatase inhibitor plus a CDK4/6 inhibitor.” It is possible that patients in whom the mutation is cleared early may be “more sensitive to palbociclib alone or may represent a small subclone or even a false-positive result,” he suggested. Short of a more complete understanding of ESR1 mutations and the patients they affect, the results so far have implications for the choice of endocrine therapy in the first-line metastatic setting for patients who received an aromatase inhibitor more than 12 months ago, Dr. Wagle said. These patients are often considered to be sensitive to aromatase inhibitors, but 7% had ESR1 mutations detected at baseline and had significantly worse progression-free survival.
DISCLOSURE: Dr. Hamilton has received consulting fees (paid to institution only) from -Pfizer, Genentech/Roche, Lilly, Puma Biotechnology, Daiichi Sankyo, Mersana Therapeutics, Boehringer Ingelheim, AstraZeneca, Novartis, Silverback Therapeutics, Black Diamond, and NanoString; and has received institutional research support from Seattle Genetics, Puma, AstraZeneca, Hutchinson MediPharma, OncoMed, MedImmune, StemCentrx, Genentech/Roche, Curis, Verastem, Zymeworks, Syndax, Lycera, Rgenix, Novartis, Mersana, Millenium, TapImmune, Lilly, BerGenBio, Medivation, Pfizer, Tesaro, Boehringer Ingelheim, Eisai, H3 Biomedicine, Radius Health, Acerta, Takeda, Macrogenics, AbbVie, Immunomedics, FujiFilm, Effector, Merus, Nucana, Regeneron, Leap Therapeutics, Taiho Pharmaceutical, EMD Serono, Daiichi Sankyo, ArQule, Syros, Clovis, Cytomx, InventisBio, Deciphera, Unum Therapeutics, Sermonix Pharmaceuticals, Sutro, Aravive, Zenith Epigenetics, Arvinas, Torque, Harpoon, Fochon, Black Diamond, Orinove, Molecular Templates, Silverback Therapeutics, Compugen, G1Therapeutics, Karyopharm Therapeutics, and Torque Therapeutics. Dr. Wagle has received honoraria from or has served as a consultant or advisor to Lilly, Novartis, and Relay Therapeutics; owns stock in Foundation Medicine and Relay Therapeutics; and has received research funding from Novartis and Puma Biotechnology.
ESR1 mutations are known to confer resistance to endocrine therapy in the metastatic breast cancer setting. These mutations herald a poor prognosis, so their clearance early in the treatment course may greatly reduce the risk of recurrence, according to the early results of the prospective phase...