NEARLY 20% OF BREAST CANCER PATIENTS have HER2-positive cancer, meaning their tumors have high levels of human epidermal growth factor receptor 2 protein. This cancer can grow quickly and generally requires treatment with aggressive chemotherapy and HER2-targeting drugs. But updated data from the PHERGain trial indicate that it may be possible to reduce the amount of chemotherapy used in patients with early-stage HER2-positive breast cancer. It also raises the possibility that some patients could be treated with anti-HER2 drugs, without chemotherapy.
“It is reassuring to see that chemotherapy provided excellent invasive disease-free survival [iDFS] when it was tailored to a patient’s progress as well as the fact that some patients did quite well when chemotherapy was omitted entirely,” says study co-author Javier Cortés, an oncologist at the International Breast Cancer Center in Barcelona, Spain.
In PHERGain, patients with early-stage HER2-positive breast cancer were given HER2-targeted therapy with Herceptin (trastuzumab) and Perjeta (pertuzumab) and randomly assigned to get a combination of two chemotherapy drugs or no chemotherapy to start. If a patient given targeted therapy alone responded to their treatment after two cycles, they continued without chemotherapy. Non-responders had chemotherapy added to their pre-surgical treatment regimen.
Patients in the targeted therapy group who were responsive to their treatment and had a pathologic complete response (the absence of cancer as assessed by an oncologist) at surgery continued on these drugs without chemotherapy. Patients who did not achieve a pathologic complete response (pCR) after surgery were given chemotherapy in addition to continued targeted therapy.
In the 267 participants who initially received just targeted therapy, 95.4% lived three years without signs of invasive cancer returning, which was similar to the rate in patients who received standard chemotherapy plus anti-HER2 drugs. Among the 86 patients with highly responsive disease who never received chemotherapy, 99% went without cancer returning in the study period, with one disease relapse after three years of follow-up.
Cortés says that the standard of care treatment for most early-stage HER2-positive breast cancer is the Herceptin and Perjeta combination followed by surgery and chemotherapy. He explained that right now there is no reliable way to know which patients will respond to treatment with HER2-targeted therapy alone, and omitting chemotherapy outside of clinical trials would put patients at an unnecessary risk. But Cortés adds that he could “foresee a future where we can reliably identify early-stage HER2-positive cancer patients that would be receptive to treatment without chemotherapy.”
One tool that could make this future a reality is the HER2DX assay, an algorithm that helps doctors predict the success of treatment strategies based on a tumor’s features. Although Cortés says he sees promise in this approach, he cautions that HER2DX is not covered by most insurances and still needs to be further validated before it could be relied on to predict which patients would likely achieve remission with a chemo-free regimen.
Lisa A. Carey, a breast cancer researcher at the University of North Carolina in Chapel Hill, who was not part of the PHERGain trial, says the study has established that there is a group of HER2-positive patients who “might safely avoid chemotherapy, but we are likely five years away from any chemo-free regimen being standard of care for HER2-positive cancer.”
She explains that the biggest risk to a woman’s health after being treated for HER2-positive breast cancer is disease recurrence. Although avoiding chemotherapy reduces the risk of negative side effects, not giving a patient standard of care therapy puts them at greater risk of relapse and metastatic cancer (a more difficult-to-treat stage of disease where tumors spread outside of breast tissue).
Currently, Carey says she advocates for an approach that includes de-escalating chemotherapy and anti-HER2 drugs based on a cancer’s responsiveness to treatment. She is a researcher for the ongoing EA1181 trial, which is trying to de-escalate treatment of HER2-positive cancer patients, including some who are at high risk, by only giving one chemotherapy drug plus two anti-HER2 drugs. Patients whose cancers respond with a pathologically complete response to de-escalated therapy do not get further chemotherapy. If the study meets its endpoint, it could change the standard of care for HER2-positive breast cancer to a regimen with fewer side effects.
“We can’t identify yet a group where my fear of the cancer is ameliorated enough that I would say here’s a good way to avoid chemotherapy, but there are definitely cases where less chemotherapy can be used. EA1181 is attempting to prove this,” Carey says.
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