The evolving treatment landscape for HR+/HER2- advanced breast cancer

In this video Dr Elisa Agostinetto, medical oncologist at the Institut Jules Bordet in Brussels and Prof Dr Virginia Kaklamani (UT Health San Antonio, TX, USA) discuss the contemporary treatment landscape for patients with hormone-receptor positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC).

Anno 2024, the combination of endocrine therapy (ET) with a CDK4/6 inhibitor is the undisputed standard of care in the first line treatment of patients with HR+/HER2- ABC. Only in very selected cases (e.g., patients with very indolent disease) one could still opt for ET monotherapy. With ribociclib, abemaciclib and palbociclib physicians now have the choice between 3 different CDK4/6 inhibitors in this setting. Across their respective clinical trials, the benefit in progression-free survival (PFS) that was obtained with these three agents was fairly similar. However, for Prof Kaklamani, the significant overall survival (OS) benefit that was demonstrated with ribociclib in the MONALEESA-2 trial is a reason to prefer this agent over the other two at the time of treatment initiation.¹ However, if a patient is doing well on abemaciclib or palbociclib there is no reason for her to switch to ribociclib based on these OS data.

On average, the median PFS obtained with these ET-CDK4/6 combinations is about 2 years. When progression occurs, Prof Kaklamani bases the treatment choice on the genetic make-up of the cancer. In about 30-40% of patients a PIK3CA mutation is found and for them alpelisib is the logical 2^nd line treatment. If an ESR1 mutation is present elacestrant is the preferred treatment. With respect to the latter, Prof Kaklamani underscored that ESR1 mutations develop over time and are almost never present in the primary tumor. Therefore, mutation testing on a liquid biopsy at the time of progression is warranted to detect these mutations. If no PIK3CA or ESR1 mutation is found, everolimus is often considered to be the most suitable treatment option, with single agent ET as a (suboptimal) alternative.

Following the results of the MonarchE trial, abemaciclib was incorporated in the adjuvant treatment for patients with high-risk HR+/HER2- early breast cancer.² The latter complicates the management of patients who progress during or shortly after (i.e., within 12 months) the end of this adjuvant treatment. For the moment there is a lack of data on the optimal treatment strategy for these patients but is to be expected that the clinical benefit of a CDK4/6 inhibitor in HR+/HER2- ABC patients with a rapid progression following a CDK4/6-based adjuvant therapy will be limited. For patients who progress beyond 12 months, re-challenge with (the same) CDK4/6 inhibitor is likely not a problem.

A final issue that was addressed in the interview relates to the management of men with HR+/HER2- ABC. Also for these patients there is a lack of data, largely because men were traditionally excluded from clinical trials in breast cancer. In clinical practice, Prof Kaklamani treats these men in the same way as their female counterparts with the exception that she always adds a luteinizing hormone-releasing hormone (LHRH) agonist to the treatment to counter the effects of testosterone.