HER2+ Breast Cancer Treatment Future May Lie in Adjuvant Therapies

HER2+ Breast Cancer Treatment

Mohammad Jahanzeb, MD

Therapies in the adjuvant setting like trastuzumab (Herceptin) and neratinib have shown more durable responses in patients with HER2+ breast cancer, as opposed to long-term treatment, said Mohammad Jahanzeb, MD, in an interview withTargeted Oncology.

"It is wonderful to have trastuzumab in the adjuvant space, which is the current standard treatment. It is standard of care to administer 12 months of trastuzumab-based therapy in addition to chemotherapy, ideally concurrently," said Jahanzeb, medical director, Sylvester Comprehensive Cancer Center at Deerfield Beach.

"However, we still have upwards room because we do not cure everybody. Therefore, there have been several attempts made to improve the cure rate of HER2-positive breast cancer by adding things to trastuzumab, or extending its duration. We found that giving patients trastuzumab for 2 years instead of 1 does not matter. There is no additional benefit to extend the duration."

Data from the phase III ExteNET study showed patients with early-stage, HER2-positive breast cancer who were treated with neratinib immediately following adjuvant trastuzumab plus chemotherapy resulted in a 33% reduction in the risk of disease recurrence.1 In a 2-year analysis, it was shown that the invasive disease-free survival was 93.9% in the neratinib arm versus 91.6% in the placebo arm (HR, 0.67; 95% CI, 0.50-0.91;P= .009).

"[The trial] was a placebo-controlled trial that, so far, has shown a 2% absolute benefit at the 2-year mark. In the hormone receptor—positive population, there was a 4% absolute benefit. There was an unplanned analysis, and if you looked at those patients who had centrally confirmed HER2-positivity by FISH and with hormone receptor positivity, their benefit was actually 9%," said Jahanzeb.

"The main problem was diarrhea. In the 95.4% who experienced the toxicity, 39.9% were grade 3/4 diarrhea, which can be managed by tapering down from 16 mg in the first month to 6 mg. Grade 3/4 diarrhea does not need to occur in nearly 40% of patients."

Trastuzumab also shows efficacy in the adjuvant setting. In a meta-analysis of data from the HERA, N9831, NSABP-B31, PACS-04, and FinHER trials published in the Journal of Clinical Oncology,²patients with HER2-positive breast cancer that was ≤2 cm experienced an improvement in disease-free and overall survival (OS) when treated with adjuvant trastuzumab.

In these trials, the 8-year disease-free survival was improved by 9.4% for patients with HER2-positive and HR-negative tumors &le;2 cm treated with trastuzumab compared with those who did not receive HER2 inhibition (HR, 0.66; 95% CI, 0.49-0.88;P<.001). Also, OS at 8 years was increased by 8.8% with trastuzumab versus without (HR, 0.59; 95% CI, 0.47-0.74;P<.001).

Jahanzeb also touches on current standard of care methods, saying oncologists should question what the "norm" is and possibly step into other therapies for their patients.

"Historically, when we look at things we don&rsquo;t question anymore after they become standard of care, such as use of taxanes after anthracyclines in node-positive patients, the benefit, in terms of survival benefit, has been 3% to 5% by those maneuvers," said Jahanzeb. "It does not hit double digits. If you look at some of the pivotal trastuzumab-based trials, the benefit, in terms of lives saved or additional patients cured at the end of a 10-year follow-up, is 4% to 9%. Single-digit survival improvement has been the ballpark, and neratinib falls right into that ballpark."

Looking toward the future of treatments for HER2+ breast cancer, Jahanzeb says the neoadjuvant setting is where studies should be digging for answers.

"Relapses are fewer and fewer, now that our therapies are more effective, and it takes a very long time to get to the event number, and you need to have lots of events to detect small differences," he said. "Perhaps, the neoadjuvant setting is where we ought to be testing more things to get those treatments to patients faster. The prime example with this is pertuzumab being proven effective in the neoadjuvant setting. Now, an expert panel is endorsing it for use in the adjuvant setting."

References

1. Chan A, Delaloge S, Holmes FA, et al. Neratinib after adjuvant chemotherapy and trastuzumab in HER2-positive early breast cancer: primary analysis at 2 years of a phase 3, randomized, placebo-controlled trial (ExteNET).J Clin Oncol. 2015;33 (suppl; abstr 508).
2. O'Sullivan CC, Bradbury I, Campbell C, et al. Efficacy of adjuvant trastuzumab for patients with human epidermal growth factor receptor 2—positive early breast cancer and tumors &le;2 cm: A meta-analysis of the randomized trastuzumab Trials.J Clin Oncol. 2015;33(24):2600-2608.