Clinical Challenges: HR

by Mark L. Fuerst, Contributing Writer, MedPage Today December 19, 2022

Hormone receptor (HR)-positive breast cancers expressing both estrogen receptors (ERs) and progesterone receptors account for the majority of all breast cancers. Hormone-dependent cancers can often be treated successfully with a variety of drugs that modulate ER or reduce estrogen. Although HER2-positive breast cancers tend to be associated with a worse prognosis than HER2-negative breast cancers, the emergence of targeted anti-HER2 therapies, such as trastuzumab (Herceptin) and pertuzumab (Perjeta), has improved outcomes for patients with HER2-positive disease.

About 10% of all breast cancer tumors are both HR-positive and HER2-positive. These cancers have a complex interaction between the endocrine and HER2 pathways linked to these receptors. Traditionally, there are three main treatment options for this subgroup of breast tumors:

"The classes of treatments are growing for patients with HR-positive/HER2-positive breast cancer," said Sibel Blau, MD, of the Quality Cancer Care Alliance Network of independent community oncology practices. "In general, these patients undergo systemic anti-HER2 treatment for up to 1 year, and then may receive neratinib [Nerlynx], an orally targeted tyrosine kinase inhibitor anti-HER2 therapy. At the same time, we always offer anti-estrogen therapy to target estrogen in tumors."

First-line therapy for early-stage, small breast tumors is surgery followed by anti-HER2 systemic treatment with trastuzumab combined with chemotherapy or anti-estrogen therapy. For patients with node-positive, large tumors, patients receive upfront chemotherapy plus anti-HER2 therapy, and possibly a referral to a clinical trial to incorporate other treatments.

Frontline treatment for advanced disease in these patients is chemotherapy, such as docetaxel, combined with the monoclonal antibodies trastuzumab and pertuzumab.

"The choice of chemotherapy changes from patient to patient depending on the size of disease and how far it has locally advanced," said Blau. If the patient still has residual disease after surgery and treatment, they typically receive ado-trastuzumab emtansine (T-DM1; Kadcyla), and an offer of neratinib.

"In almost all regimens, trastuzumab for 1 year is standard treatment," she said. "The exception is residual disease, where T-DM1 takes the place of Herceptin."

Stage IV patients are prescribed antibody-drug conjugates (ADCs) that bind to HER2. "These targeted therapies, such as trastuzumab deruxtecan [T-DXd, Enhertu], incorporate a toxic payload to kill cancer cells," explained Deborah Patt, MD, PhD, MBA, of Texas Oncology in Austin. ADCs are also being incorporated into treatment of stage II/III disease in clinical trials.

Fulvestrant (Faslodex) has proven useful in the treatment of HR-positive/HER2-positive patients with multiple metastases who have received prior anti-HER2 therapy in combination with chemotherapy or an aromatase inhibitor. A combination of abemaciclib (Verzenio), fulvestrant, and trastuzumab in the monarcHER phase II trial in advanced HR-positive/HER2-positive breast cancer improved progression free-survival (PFS) compared with standard-of-care trastuzumab plus chemotherapy.

Another triplet in the ALTERNATIVE phase III trial -- dual HER2 blockade with lapatinib (Tykerb) and trastuzumab plus an aromatase inhibitor -- showed a PFS benefit in the treatment of postmenopausal women with HR-positive/HER2-positive metastatic breast cancer.

Estrogen therapy-containing first-line regimens may be associated with benefits among the subgroup of patients with HR-positive/HER2-positive metastatic breast cancer. Patients treated with maintenance estrogen therapy after anti-HER2 therapy with chemotherapy had significantly better survival outcomes than those who did not receive maintenance estrogen therapy.

As with all breast cancer patients, this group of patients should be evaluated on a case-by-case basis, Blau emphasized. "We need to understand comorbidities and choose the right treatment in the first place. Sequencing strategy is important. In the middle of Herceptin treatment, I will talk about future oral therapy. We need to share information with the patient and pull her into the treatment strategy."

One of the complications of treating the HR-positive/HER2-positive subgroup is the development of treatment resistance. In the cohort of patients with HER2-amplified cancers, about 50% will develop brain metastasis.

"Patients develop mechanisms of resistance to standard therapy, and we need to explore other strategies to control disease," said Patt. As a small molecule, neratinib has the benefit of passing through the blood-brain barrier and therefore has the ability to handle brain metastases more easily.

Precision medicine can help to strategize treatment and assess what leads to resistance. For example, a better understanding of the disease has led to neoadjuvant therapies. "We are more likely to find out if the patient achieves complete response or not and can avoid certain treatments and the resulting side effects," Blau explained.

Cardiotoxicity is usually reversible and transient if intervention occurs early. Most physicians who treat breast cancer know to monitor their patients with echocardiograms, and to be careful with those who have shortness of breath on trastuzumab, said Blau.

Another issue with newer agents is a high risk of diarrhea. This needs to be managed before it becomes dose limiting, but can usually be controlled. In addition, a small percentage of patients on ADCs may develop interstitial lung disease, so clinicians should be wary, she said.

New therapeutic strategies are emerging for this subgroup of patients, Patt noted. "We are evaluating ADCs such as T-DXd, moving them to earlier lines of therapy and high-risk adjuvant settings. I am excited about getting a better understanding of who needs less and who needs more treatment."

Blau noted that immunotherapy is an area of interest, with some patients showing benefit in clinical trials. Immunotherapy plus ADC combinations are being tried at different levels to try to lessen the harsh effects of chemotherapy combined with anti-HER2 therapies. The focus is on which patients will derive the most benefit from which drugs and how to minimize side effects. "If a patient receives neoadjuvant anti-HER2 therapy and achieves a complete response by the time of surgery, we can avoid chemotherapy and customize the therapeutic approach," she said.

Besides neratinib, other small molecules such as tucatinib (Tukysa) are being used, Patt said, and CDK4/6 inhibition also shows a great deal of promise but is not yet FDA-approved for the HER2-amplified population. "We have many advancements in the HR-positive, HER2-positive space, and initiating and managing our non-chemotherapy options as early-line choices will improve the care of patients in communities."

Disclosures

Blau and Patt reported no relevant conflicts of interest.