A customized cure for ERBB2-positive metastatic breast cancer

Paolo Tarantino, MD

“Since the introduction of anti-HER2 agents in clinical practice roughly 20 years ago, the prognosis of metastatic HER2+ breast cancer has greatly improved,” said senior author Paolo Tarantino, MD, an advanced research fellow in breast medical oncology at the Dana-Farber Cancer Institute in Boston. “Once the most aggressive breast cancer subtype, HER2+ is now the one with the highest number of highly active treatment options.”

Interestingly, some patients have derived a long-lasting benefit from HER2-targeted therapies, with tumor responses lasting for several years after treatment initiation, according to Tarantino. “Metastatic breast cancer is traditionally considered incurable,” he said. “However, many clinicians are now starting to believe that some of these patients may have been cured from their metastatic disease.”

Because of clinical trials conducted in the 1990s, where the intensification of systemic treatment like high-dose chemotherapy failed to achieve long-term benefits for patients, “the aim of current treatments in the metastatic setting is not the eradication of the disease, but rather the prolongation of overall survival and preservation of quality of life,” Tarantino told Contemporary OB/GYN®.

The word ‘cure’ is, therefore, still used with extreme caution in this setting. “It is not established if long-term responses can be considered cures,” Tarantino said.

The HER2-targeted antibodies trastuzumab and pertuzumab are the 2 current standard first-line treatments for metastatic HER2+ breast cancer.

In the phase 3 CLEOPATRA trial conducted about a decade ago, in which the efficacy and safety of pertuzumab, trastuzumab and docetaxel were compared to placebo, “nearly 1/5 of the patients receiving these antibodies, combined with chemotherapy, had not experienced progression 8 years after treatment initiation,” Tarantino said.

In addition, it can be hypothesized that an escalation of first-line treatment among patients with appropriate features could further increase this rate of long-responders, according to Tarantino.

“A particularly promising agent is the antibody-drug conjugate trastuzumab deruxtecan, which has shown unprecedented activity in trastuzumab-refractory patients, and is currently being tested in the first-line setting,” he said.

Still, any attempt to escalate first-line treatment should be pursued with caution, to avoid overtreating incurable patients. “For this reason, patient selection remains the main challenge in seeking a cure for metastatic breast cancer,” Tarantino said.

The current review describes a number of clinical and pathologic features which have been consistently associated with a higher likelihood of experiencing long-lasting responses, and which may guide these types of curative attempts.

The ‘de-novo’ diagnosis of metastatic breast cancer will be used to select patients for the intensification trial being planned at the Dana-Farber Cancer Institute.

“Long-term responders tend to be de novo metastatic, have a reduced disease burden and likely show deep responses to systemic treatment,” Tarantino said.

On the other hand, 3 pathologic features linked to long-term response are high ERBB2 expression, lack of detrimental genomic aberrations and antitumor immune activation.

Tarantino is encouraged that today childhood leukemia is considered a highly curable disease, “with 90% of the cases being eradicated by chemotherapy. Several other tumors can also be cured with intensive systemic treatment, such as lymphomas and testicular cancer.”

Although breast cancer represents a vastly different entity, “we have relevantly deepened our understanding of the disease, including identifying subsets of patients who can derive long-term responses from cancer treatment,” Tarantino said.

Carefully implementing novel, highly potent treatment options in these subgroups of patients might result in a larger fraction of patients experiencing long-term responses and “hopefully a tailored cure for metastatic HER2-positive breast cancer,” he concluded.

Disclosure

Tarantino has been an advisor and speaker for AstraZeneca.

Reference

1. Tarantino P, Curigliano G, Parsons HA, et al. Aiming at a tailored cure for ERBB2-positive metastatic breast cancer: a review. JAMA Oncol. Published online January 13, 2022. doi:10.1001/jamaoncol.2021.6597