Ongoing Trials Aim to Advance HER2-Negative Breast Cancer Treatment

Dr. Kevin Kalinsky covers the gamut of the treatment landscape for HER2-negative breast cancer. © - stock.adobe.com

The landscape of HER2-negative breast cancer treatment is evolving, with an increasing focus on precision medicine and individualized treatment strategies, according to Dr. Kevin Kalinsky, who added that ongoing clinical trials aim to clarify current questions across the treatment landscape.

“There are other things that are on the horizon… [This includes things like] new endocrine therapies and new targeted therapies that are more precise and are potentially better tolerated, so it's an active, ongoing area of research,” Kalinsky, a professor and director in the Division of Medical Oncology, the Department of Hematology and Medical Oncology, at Emory University School of Medicine, in Atlanta, emphasized in an interview with CURE, live from the 42nd Annual Miami Breast Cancer Conference.

In the interview, he sat down with CURE to discuss the treatment of patients with HER2-negative breast cancer. Our conversation covered the gamut of patients with the disease, highlighting women with premenopausal node-positive breast cancer, as well as individuals with previously treated HER2-negative disease.

Kalinsky also serves as the director of the Glenn Family Breast Center and the Louisa and Rand Glenn Family Chair in Breast Cancer Research at Winship Cancer Institute of Emory University.

CURE: If a premenopausal woman has node-positive breast cancer, how do you determine whether chemotherapy is the right option for them?

Kalinsky: It used to be that patients who had node-positive breast cancer, even a few decades ago, when I was in training, the conversation was that everybody got chemotherapy. However, we've moved away from that with the utilization of these tests that we call genomic assays that help us inform what a patient's risk is and whether there's a benefit for chemotherapy. It's really an individualized conversation.

For our patients who have one to three nodes involved, the common question is, “is there a role for [a] tumor test, like the 21-gene recurrence score or the 70-gene MammaPrint test?” Ultimately, I think for prognosis and to understand one's risk, that it can be very helpful. There is then an individualized conversation about the role of chemotherapy, because sometimes, if that risk is very low, the conversation of, “Should we think about suppressing the ovaries, either through medicine or through surgery, and foregoing chemotherapy?” comes [into play]. That's really an individualized conversation that we have [which focuses on] a risk-versus-benefit [situation].

What are the potential risks and benefits of skipping chemotherapy in certain patients who are premenopausal with node-positive breast cancer?

At the heart of the question about chemotherapy in premenopausal patients is that we don't want to be over-treating our patients, but we also don't want to be under-treating our patients. We have data [on this topic], for example, from the RxPONDER trial, which was a large study that was sponsored by the National Cancer Institute [NCI] of about 5,000 patients. Of the 1,600 or so patients [who were enrolled] and pre-menopausal, we saw that everybody seemed to benefit from chemotherapy. However, we know that things are more nuanced than that, and the question that really remains, asks, “Is the benefit that we're seeing due to the fact that chemotherapy is suppressing patients’ periods?”

There is another study that's ongoing that's also currently enrolling patient called the OFSET trial, that's also sponsored by the NCI, that's helping to prospectively answer this question. But until we have those data, it really is an individualized conversation because we're trying to move away from a one-size-fits all approach.

If a patient with breast cancer progresses after taking a CDK4/6 inhibitor, how do you decide whether to continue with another option or to switch treatment options altogether?

The field for patients with estrogen-driven HER2-negative breast cancer is really evolving. We are trying to increasingly move to precision medicine, where we make decisions based upon whatever the tumor is being driven by, [such as] mutations, for example. We do have data for patients who were previously on an aromatase inhibitor plus a CDK4/6 inhibitor, [which showed] that for patients who don't have a mutation, there is benefit for potentially switching the endocrine therapy and also switching the CDK4/6 inhibitor. This benefit is also seen for patients that do have mutations, like ESR1 mutations, or alterations in the PI3K pathway. However, this is an individualized conversation. This is because there are other drugs that also target ESR1 mutations, like Orserdu [elacestrant]. There are drugs that target the PI3K pathway, like Truqap [capivasertib]or Piqray [alpelisib].

There are different nuanced conversations that we have that help determine if there is a benefit for continuing a CDK4/6 inhibitor. [However], I would really think about it in the patients who have low volume of disease — maybe it's bone-only — and they were on their hormonal therapy and CDK4/6 inhibitor for a long period of time. Those are the sorts of patients that I talk about continuing with the CDK4/6 inhibitors after progression.

What is your key takeaway from today’s conversation for patients with HER2-negative breast cancer?

There are a few things [that make up] the big picture for patients with estrogen-driven HER2-negative metastatic breast cancer. One is that we've made some real advances. Currently, we are in 2025, and even in the last couple of months, there have been new drugs that have been approved, or there's been a change of how we use those drugs. [For example], there was a change in the FDA label, and that's just within the last couple months. And there are other things that are coming down the pike.

So, if there is a subtype of breast cancer where we're using targeted drugs, like with targeted pills — this is a good example — it is important to understand that there are other things that are on the horizon. [This includes things like] new endocrine therapies and new targeted therapies that are more precise and are potentially better tolerated, so it's an active, ongoing area of research.

Transcript has been edited for clarity and conciseness.

For more news on cancer updates, research and education, don’t forget to subscribe to CURE®’s newsletters here.