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Separate clinical trial presentation by Carey connects tumor subtype with survival benefit in hormone receptor-positive and HER2-negative advanced breast cancer treatment.

Headshot of Lisa Carey
UNC Lineberger’s Lisa Carey, MD, FASCO, the Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research.

At the recent San Antonio Breast Cancer Symposium, Lisa A. Carey, MD, ScM, FASCO, deputy director of Clinical Science and the Richardson and Marilyn Jacobs Preyer Distinguished Professor in Breast Cancer Research at UNC Lineberger, presented a plenary talk on the latest developments in triple negative breast cancer (TNBC).

Women diagnosed in the earliest stages of breast cancer have cure rates over 90%. However, for women diagnosed with triple negative disease the prognosis is less positive. Triple negative breast cancers lack receptors for the hormones estrogen and progesterone as well as the HER2 protein; therefore, this form of breast cancer, even when caught early, is often not responsive to conventional and targeted treatments that are designed to home in on receptors on a cancer cell.

“Cure rates in triple negative breast cancer, while still much lower than we’d like them to be, have clearly improved over the past several years thanks to new combinations of standard chemotherapy drugs. The addition of an immunotherapy drug increases this benefit even more,” Carey said. “Combination treatments that attach chemotherapy drugs to antibodies that target cancer cells, in one sense a form of “smart” chemo, are already delivering improved outcomes for metastatic TNBC. Moving ahead quickly to test these therapies in curable TNBC is crucial. All of these advances are important because TNBC particularly affects young women and women of color.”

Much of the current understanding of the reasons for poorer breast cancer outcomes in Black and younger women comes from the Carolina Breast Cancer Study (CBCS), which has provided insights into the biology and diversity of TNBC for many years and is considered a key contributor to knowledge about breast cancer. Indeed, Carey is working with CBCS investigators to open phase 4 of the study, which will have a special focus on TNBC.

The molecular subtypes underlying breast cancer, including the dominant biology in TNBC, were first defined and characterized in 2000 by Charles Perou, PhD, the May Goldman Shaw Distinguished Professor of Molecular Oncology and co-leader of the UNC Lineberger Breast Cancer Research Program. In a seminal paper in Nature, Perou published findings that demonstrated breast cancer was not one disease but a collection of molecularly distinct diseases with different biology as well as different prognoses.

Carey said while many of the molecular subtypes of breast cancer have therapeutic relevance, scientists are still struggling to find a molecular basis to tailor therapy in TNBC. Most TNBCs have “basal-like” biology; but recently, studies have identified subtypes within that subtype. The problem, she noted, is that no one has yet figured out how to leverage that information for better treatment.

“Beyond molecular subtyping and understanding the tumor itself, we now have an emerging understanding of how the tissue environment around the tumor is particularly relevant in TNBC,” Carey said. “We know that, to some degree, regardless of a tumor’s features, there can be immune activation in the area surrounding the tumor that has a large effect on response to conventional therapy in addition to response to immunotherapy.”

Recently, a large study in newly diagnosed patients with TNBC found that adding an immunotherapy drug to multiple chemotherapy drugs increased response to therapy as well as decreased relapse. Many initiatives are ongoing to try to optimize this treatment, including whether the full year of immunotherapy or all four chemotherapy drugs are needed, whether other drugs might be better combination partners, and whether there might be an even better solution using new technologies that are under development.

It is Carey’s hope that as the understanding of TNBC’s complexity continues to come into focus, the simplistic term “triple negative” will become a relic of the past.

Study confirms prognostic and predictive value of breast tumor subtypes for combination therapy

In a separate talk at the symposium, Carey presented findings from a study that assessed the correlation between tumor molecular subtype and overall survival benefit when using a combination therapy to treat postmenopausal women who have hormone receptor-positive and HER2-negative advanced breast cancer.

The researchers conducted a pooled analysis of data from the MONALEESA-2, MONALEESA-3 and MONALEESA-7 trials. These studies previously had demonstrated that treating hormone receptor-positive and HER2-negative advanced breast cancer with the enzyme inhibitor ribociclib, together with hormone therapy, produced a significant overall survival benefit compared to women treated with ribociclib and a placebo.

Carey and her colleagues looked at the molecular subtype of nearly 1,000 tumors and then assessed whether there was a correlation between tumor subtype and survival outcomes. They determined the combination therapy produced an overall survival benefit for the luminal A, luminal B, and, in particular, the HER2-enriched tumor subtypes, but not for the basal-like subtype. As noted in the TNBC findings, cancers that are basal-like may be resistant to known targeted therapies of the type used in the MONALEESA trials, so this combination therapy would be of nominal benefit in that subtype.

The researchers wrote that their study confirmed the prognostic and predictive value of tumor subtypes for overall survival. They also noted that “[t]he consistent survival benefit in the HER2-enriched subtype, which is associated with endocrine resistance and a very poor prognosis compared with luminal disease, warrants further investigation.” This finding will be further studied in an upcoming trial called HARMONIA.