New treatment regimens improve outlook for patients with HER2-positive breast cancer
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Key takeaways:
- The treatment landscape for HER2-positive disease appears “optimistic.”
- Continued research is needed to understand the mechanisms of resistance to HER2-directed therapies.
Tremendous progress has been made in the treatment landscape for HER2-positive breast cancer that has significantly altered and improved the outlook for this patient population.
“I am encouraged and optimistic about the ongoing research in this space,” Hatem Soliman, MD, medical director of the clinical trials office at H. Lee Moffitt Cancer Center and Research Institute, told Healio. “Patients with HER2-positive disease will have even better treatment options in the years to come. We now have hope to be optimistic that women will have excellent outcomes when diagnosed with HER2-positive disease.”
Charting treatment course
Tumor stage and sensitivity to therapy are used to determine the best treatment course for patients with HER2-positive disease, according to Soliman.
“We first determine how large the tumor appears on breast imaging and physical exam, which is a large driver of treatment sequencing,” he said. “Once that is determined, HER2-positive stage II to stage III breast cancers are now almost uniformly treated preoperatively with anti-HER2 agents plus chemotherapy to assess how sensitive their response is to therapy.”
Preoperative treatment then dictates the type of postoperative therapy patients receive, Soliman continued.
“Patients with early-stage breast cancer may sometimes undergo surgery first, followed by postoperative chemotherapy and anti-HER2 therapy,” he said.
Less is more
Due to the significant improvements in outcomes with new HER2-positive breast cancer targeted therapies, experts are now able to assess different treatment approaches.
“Ongoing work in the HER2-positive breast cancer space is focused on the use of HER2-directed therapy to reduce toxicity and maintain high cure rates that improve the quality of life for this patient population,” Soliman said. “Most research is now looking at the possibility of de-escalating treatment based on patients’ response to treatment — less therapy to achieve similar outcomes with less toxicity.”
For the prospective, multicenter ADAPT trial, researchers aimed to compare pathologic complete response (pCR) among patients assigned a de-escalated, 12-week neoadjuvant treatment regimen of dual HER2 blockade with trastuzumab (Herceptin, Genentech) plus pertuzumab (Perjeta, Genentech) combined with weekly paclitaxel vs. pertuzumab-trastuzumab alone.
As Healio previously reported, the de-escalated treatment regimen demonstrated high efficacy, and the trial stopped early due to the superiority of pathologic complete response rates observed in the paclitaxel group (ypT0/is ypN0, 90.5% vs. 34.4%; ypT0 ypN0, 78.6% vs. 24.4%).
The results are being validated in the ongoing, phase 3, COMPASS HER2 trial in which researchers are examining the use of trastuzumab emtansine (T-DM1) plus tucatinib vs. T-DM1 alone to prevent recurrence. Median follow-up is 10 years.
“In addition to these trials, other ongoing trials are looking to use alternative HER2 agents to see if they can better treat women who do not completely respond to current therapies,” Soliman said. “Other research is being done at Moffitt Cancer Center where we’re using HER2-directed immunotherapy vaccines to try and sensitize the body to HER2 proteins and utilize immune response to achieve better outcomes for patients while sparing them the toxicities of chemotherapy agents.”
In other research presented during the most recent ASCO Annual Meeting, researchers found that a chemotherapy de-escalation strategy, consisting of dual HER2 blockade, led to high rates of 3-year invasive DFS among patients with HER2-positive breast cancer.
For the phase 2 PHERGain trial, investigators randomly assigned patients with centrally confirmed, stage I to stage IIIA HER2-positive breast cancer to chemotherapy plus trastuzumab and pertuzumab (group A) or two cycles of trastuzumab and pertuzumab with or without endocrine therapy (group B). Those in group B who achieved a PET response could go on to receive another six cycles of trastuzumab and pertuzumab, whereas patients who did not achieve a PET response went on to receive six cycles of chemotherapy plus trastuzumab and pertuzumab.
Patients who achieved a postoperative pCR could remain on the chemotherapy-free regimen and those who did not could receive chemotherapy plus trastuzumab and pertuzumab.
According to study results, the group of PET responders who achieved a pCR who did not receive chemotherapy showed a 3-year invasive DFS rate of 98.8% (95% CI, 96.3-100), with only one invasive event (locoregional ipsilateral recurrence) compared with a DFS rate of 95.4% among those who received the chemotherapy regimen.
“This strategy might identify 30% of patients who may be cured without the need for chemotherapy and only be treated with the combination of trastuzumab, pertuzumab and endocrine therapy, if appropriate,” Javier Cortés, MD, PhD, of the International Breast Cancer Center in Madrid and the faculty of biomedical and health sciences in the department of medicine at Universidad Europea de Madrid, said during his presentation.
Research needs
Despite the surplus of ongoing research, more research is needed to fully understand the mechanisms of resistance to HER2-directed therapies, according to Soliman.
“We want to figure out why certain tumors may not completely respond to some of these newer treatments,” he said. “We also want to continue research to find new ways to leverage HER2-positive disease as far as the ability to develop new targeted therapies with improved or better payloads to gain even better responses from patients treated in the metastatic setting but also the early-stage disease setting. We are increasingly looking at ways to move these drugs from the metastatic setting into the early curative setting where we think they’ll make the biggest difference in terms of improving survival.”
Additionally, there is the potential for HER2-positive disease to respond to immunotherapy in various ways, he added.
“We need to look at ways to combine cancer immunotherapy drugs and integrate them with anti-HER2 therapy to be able to improve cure rates while trying to de-escalate the use of chemotherapy in these patients,” Soliman said. “Those are the additional areas of unmet need that we will continue to work on.”
References:
- Cortes J, et al. Abstract LBA506. Presented at: ASCO Annual Meeting; June 2-6, 2023; Chicago.
- Nitz U, et al. Lancet Oncol. 2022;doi:10.1016/S1470-2045(22)00159-0.
For more information:
Hatem Soliman, MD, can be reached at hatem.soliman@moffitt.org.
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