Predictive biomarkers identified through next-generation sequencing play an important role in treatment decision making for patients with HR+/HER2- breast cancer. Several presentations at the recent 2024 ASCO Annual Meeting reported data from clinical trials using predictive biomarkers.

Following these proceedings, featured expert Sara M. Tolaney, MD, MPH, was interviewed by Conference Reporter Associate Editor-in-Chief Christopher Ontiveros, PhD. Dr Tolaney’s clinical perspectives on these findings are presented here.

The idea with using predictive biomarkers is to try to tailor therapy to each patient and to figure out how much treatment each patient needs and which therapy may be appropriate for them. An example would be the 21-gene assay, which can determine a prognostic recurrence score for patients who have early-stage HR+/HER2- disease. It also provides predictive information about whether the patient could benefit from adjuvant chemotherapy, as shown in the TAILORx and the RxPONDER studies. We know that the majority of patients with HR+ breast cancer do not benefit from adjuvant chemotherapy, so selecting those individuals who really need it is critical so that we can spare patients who would not benefit from the unneeded toxicity.

Although most patients who have recurrence scores of 25 or less do not benefit from chemotherapy, premenopausal patients in both the TAILORx and the RxPONDER trials did seem to benefit even when they had these recurrence scores. So, whether premenopausal patients derive benefit from chemotherapy has been questioned, and we saw some really important data come out at ASCO 2024 that refine this further. Kevin Kalinsky, MD, MS, presented an analysis of RxPONDER correlating AMH levels and benefit from chemotherapy (abstract 505). There was benefit reported in patients whose AMH levels were more consistent with being premenopausal, but there was not benefit in patients whose AMH levels were in the menopausal range. In my mind, these data support the hypothesis that the impact of chemotherapy is not cytotoxic but rather is more of an effect on ovarian function.

There are many uses for biomarker testing in HR+ disease in the metastatic setting. Traditionally, when someone develops metastatic disease, there is tissue available for genomic testing. The issue is that it is difficult to perform invasive biopsies when someone develops progression. Sometimes patients do not have a spot that is accessible for a tissue biopsy. So, the liquid biopsy has become very practical in terms of being able to make decisions in a real-time manner, as discussed in abstract 1042 at ASCO 2024.

We use genomic testing to help us determine what therapy may be appropriate. It is very critical to perform a genomic assay at the time of progression on a CDK4/6 inhibitor, because approximately 30% to 40% of patients will have developed an ESR1 mutation. If a patient has developed an ESR1 mutation, an oral SERD such as elacestrant becomes an option. At least 40% of patients have an alteration in the PI3K pathway with a mutation in PIK3CA or AKT1 or have PTEN loss. In these patients, we know that the oral AKT inhibitor capivasertib and the oral PI3K inhibitor inavolisib improve progression-free survival.

At ASCO 2024, an abstract reported an association between DNA damage response (DDR) gene alterations and sacituzumab govitecan efficacy from the TROPICS-02 trial (abstract 1075). It was interesting, but I do not think that looking for DDR variants is ready for prime time, and it is definitely not something that I would do right now.

I think that genomic information is critical and that we will move toward using it even earlier. This is based on data from the INAVO120 trial, results of which were presented at ASCO 2024, because patients who relapse on or within 1 year of adjuvant endocrine therapy and have a PIK3CA mutation could be candidates for inavolisib in combination with palbociclib and fulvestrant (abstract 1003).