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SABCS Clinicogenomic Study Sheds Light on HER2-Targeted Therapy Resistance

NEW YORK – Alterations in the MAPK pathway could be playing a role in resistance to anti-HER2 therapies, according to a genomic analysis of 733 tumor samples from HER2-positive breast cancer patients presented Thursday during the San Antonio Breast Cancer Symposium.

Emanuela Ferraro, a clinical research fellow at Memorial Sloan Kettering, presented the results of the analysis as well as subsequent preclinical research aimed at overcoming these resistance mechanisms using existing targeted therapies.

Zeroing in on the reasons for HER2-targeted therapy resistance and potential mitigation strategies is particularly important given that, as Ciara O'Sullivan, assistant director of Medical Oncology at the Mayo Clinic, noted in a discussion of Ferraro's findings, up to a fifth of early-stage HER2-positive breast cancer patients and a quarter of metastatic HER2-positive patients have tumors that do not respond, or relapse after HER2-targeted therapy.

To conduct their study, Ferraro and colleagues analyzed the genomic profiles of HER2-positive breast cancer patients who had undergone tumor sequencing with Memorial Sloan Kettering's MSK-IMPACT panel. From 664 patients, they sequenced 733 samples total, 385 of which were primary tumor sites and 348 of which were metastases.

Analyzing the sequencing results, the researchers found concurrent PIK3CA mutations in 30 percent of tumors, and activating MAPK pathway alterations in 12.8 percent of tumors. Of these pathogenic activating alterations in the MAPK pathway, the most common alterations were NF1 loss, ERBB2, and RAS activating mutations. Relative to the primary tumors, the metastatic samples were more likely to have these MAPK alterations; 15.6 percent of metastatic tumors had MAPK alterations, compared with 9.8 percent of the primary tumors.

Pairing these data with integrated clinical information, the researchers homed in on associations between patients' genomic alterations and their progression-free survival outcomes on first-line trastuzumab (Genentech's Herceptin), pertuzumab (Genentech's Perjeta) and taxane-based chemotherapy. For this part of the study, they included just the 145 patients who had undergone sequencing before beginning treatment with first-line traszumab-pertuzumab-chemo.

Of the samples they analyzed from these patients, one-fifth did not have genomic ERBB2 amplification as detected by next-generation sequencing, and experienced significantly shorter median progression-free survival times — that is, they lived for 9.4 months without their cancers progressing versus 22.8 months among patients who did have ERBB2 amplification.

As Ferraro and colleagues expected might be the case, patients with PIK3CA mutations also had worse progression-free survival times than those with wildtype PIK3CA; they lived for a median of 13 months versus 23.4 months, respectively, without their tumors progressing. Prior research had already suggested that targeting PI3K could help overcome HER2 targeted therapy resistance, and indeed, Ferraro acknowledged that several clinical trials are ongoing evaluating this, including the EPIK-B2 study using apelisib (Novartis' Piqray) in the first-line treatment setting.

The aspect of their findings that was more novel, however, was that the same effect on outcomes was true of MAPK-altered tumors, which were associated with median progression-free survival times of 9.9 months, versus 21 months in the MAPK-wildtype patients.

"Our data showed that MAP kinase alteration is a new and intriguing mechanism of resistance [to anti-HER2 therapies] and is potentially targetable," she said. "For the very first time, genomic alteration of MAPK pathway genes are [shown to be] involved in the resistance to [trastuzumab and pertuzumab] in metastatic HER2-positive breast cancer."

Although there were not enough samples from both time points to confirm whether these mutations were required over time, the fact that the full analysis of genomic profiling showed that these alterations were significantly enriched in the metastatic samples versus the primary tumors did seem to suggest this may be the case. According to Ferraro, additional research is ongoing to answer whether these alterations develop as acquired resistance mutations following HER2-targeted therapy.

Looping all of these genomic characteristics into a multivariable analysis, the researchers found that MAPK pathway alterations had an independent association with worse outcomes on the first-line treatment regimen. This suggested to Ferraro and colleagues that the MAPK alterations played a causal role in resistance to anti-HER2 treatment — a role that they then sought to validate in the lab.

Testing treatment strategies in the lab

In cell lines, Ferraro and colleagues either depleted NF1 expression or expressed mutant KRAS or BRAF, and then treated them with approved HER2 inhibitors in vitro and in vivo using xenografts. Here, they found that time after time, the cell lines with the MAPK alterations resisted the therapies, further validating the role that MAPK alterations play in resistance to HER2-targeted therapy and suggesting that inhibiting this pathway may improve outcomes on trastuzumab-pertuzumab.

To test out the idea that treating the MAPK-altered tumors with targeted therapy is a means to overcome anti-HER2 therapy resistance, the researchers experimented in the lab with using ERK or MEK inhibitors on these cancer cells, and found that, indeed, these therapies did inhibit the cell replication that they were otherwise seeing. They conducted these experiments both in cell lines and in xenografts using trametinib (Novartis' Mekinist), both alone and in combination with trastuzumab, to reduce tumor growth in a model with NF1 loss. Given these in vitro and in vivo lab findings, Ferraro underscored a "huge need" to conduct clinical trials evaluating this approach.

"At this point, the question [entered] our minds, 'what about antibody-drug conjugates?'" Ferraro said. She and her colleagues wondered whether this new and promising class of drugs may be successful when used to treat tumors carrying MAPK alterations. Accordingly, they tried out trastuzumab deruxtecan (T-DXd, AstraZeneca/Daiichi Sankyo's Enhertu) in their lines and models, and found that they worked, too.

The reason for this, she suggested, might be related to the "multiple mechanisms of action of these agents, which are not limited to the blockade of HER2 signaling." Here, too, Ferraro doubled down on the need for clinical research to validate these preclinical findings.

"The genomic analysis highlights that targeting the PI3K or MAPK pathway could extend the benefit or [trastuzumab-pertuzumab]-based treatments," O'Sullivan said, acknowledging that although the field is largely still using trastuzumab-pertuzumab and chemo in the frontline setting, trials are ongoing — including the Phase III DESTINY-Breast09 trial and the HER2CLIMB-05 trial incorporating T-DXd and tucatinib (Seagen's Tukysa), respectively — which may someday change this.