Aditya Bardia, MD, MPH: Let’s talk about a patient with metastatic breast cancer. Let me give a common example of what we see in clinics. A 65-year-old woman who had received adjuvant endocrine therapy, stopped adjuvant endocrine therapy 2 years ago. She now has disease recurrence, has metastatic hormone receptive–positive HER2 [human epidermal growth factor receptor 2]–nonamplified or -negative breast cancer. The patient has a biopsy for confirmation of diagnosis. Michelle, what additional tests should the oncologist think about in terms of diagnosis, receptors, and genotyping? What’s your recommendation?

S. Michelle Shiller, DO, AP/CP, MGP: When a patient has progressed, especially on prior therapy, we like to do broad genomic profiling. NCCN [National Comprehensive Cancer Network] Guidelines support the use of broad genomic profiling in advanced metastatic disease. There was a paper released in the JCO [Journal of Clinical Oncology] in 2022. It was a collaborative paper between ASCO [American Society of Clinical Oncology] and the Association for Molecular Pathology. The provisional clinical opinion, not a guideline, was that broad genomic profiling should be considered in any advanced or metastatic disease setting. In the past year, we’ve seen at least 2 additional pan-tumor biomarkers with BRAF and RET gene fusion. I realize those are not as common in breast cancer. But as we see more pan-tumor biomarkers come to the forefront with clinical practice, it becomes a more…compassionate use. Also, there are other things that we expect to see, such as an AR [androgen receptor] mutation or a PIK3CA mutation. You’ll see HER2 status change post-therapy as well. It’s important to repeat some questions and to see what happened under selective pressure to that molecular milieu of the tumor.

Aditya Bardia, MD, MPH: Absolutely. Tumor evolves over time, and receptors can change, so it makes sense to get receptors and genotyping that are actionable. To that point, for this patient, let’s say we get the results, and the tumor is still ER [estrogen receptor]–positive and HER2-negative nonamplified and the patient has PIK3CA wild type tumor. Sara, what’s your first-line recommendation for this patient? Review some of the first-line trials with CDK4/6 inhibitors.

Sara A. Hurvitz, MD: I’ll give a broad overview of how the field has evolved in recent years. In the last 7 years, we’ve seen dramatic changes in the expected outcomes for patients with ER+ HER2- disease. Prior to CDK4/6 inhibitors, the median progression-free survival [PFS] that could be expected with single-agent endocrine therapy or single-agent chemotherapy was 9 to 12 months. If you look at a variety of clinical trials and endocrine therapy, it was of course preferred to do chemotherapy due to its better therapeutic index. There were a couple of studies looking at a combination of anastrozole with fulvestrant. One was a positive study published in the New England Journal of Medicine that showed an improved PFS and OS [overall survival]. Another was a negative study. The differences in outcomes for these 2 trials were probably related to the percentage of patients who had previously received tamoxifen, which works similarly to fulvestrant.

Then along came the CDK4/6 inhibitors. In 2015, Richard Finn presented the PALOMA-1 clinical trial, which was a phase 2 randomized study looking at the addition of palbociclib to letrozole compared with letrozole alone in postmenopausal ER+ HER2- first-line metastatic breast cancer. It showed a doubling in the median PFS. For the first time, the median PFS in the combination arm was 20 months, which was unheard of previously. The toxicity profile outside asymptomatic neutropenia was pretty darn good. That was confirmed in the PALOMA-2 large, randomized placebo-controlled clinical trial, which ended up securing full approval of this agent.

Two other agents were developed clinically: ribociclib and abemaciclib. Both demonstrated strikingly similar hazard ratios in favor of endocrine therapy plus CDK4/6 inhibitor. In each study, with palbociclib, ribociclib, and abemaciclib, when you add that CDK4/6 inhibitor to endocrine therapy, the hazard ratio is around 0.5 to 0.55—very similar. Then overall survival results began to emerge. That’s where we see some differences that may be attributable to study design, patient population, length of follow-up, or differences among the agents. The point is, this therapy allows patients to see a progression-free survival in excess of 2 years—in 1 study, it’s up to 3 years—in the frontline setting. So there are very different outcomes for women now.

Aditya Bardia, MD, MPH: It’s remarkable. It’s paradigm changing and great news for patients in the field to have access to this active class of drugs.

Transcript edited for clarity.