
Pictured above: Patient Yvonne Fantaci and Heather Parsons, MD, MPH
Dana-Farber Researchers Challenge Long-Held Beliefs About HER2-Positive Metastatic Breast Cancer
January 31, 2025
Breast Cancer
Chemotherapy
Metastic Breast Cancer
By Beth Dougherty
When Yvonne Fantaci discovered she had breast cancer at age 60, it had already spread to her lungs, liver, and elsewhere. Fantaci felt blindsided. She was otherwise completely healthy. She never expected such a shocking diagnosis.
"I remember it was 11 lesions, and the breast wasn’t even the largest one," says Fantaci, now 67 and working from home in Danvers, Mass., as a professional services manager for a large data company.
Fantaci sprang into action and sought care at Dana-Farber. She received standard treatment for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. During her treatment, her tumors began to shrink until they were, according to her regular computed tomography (CT) scans, all but gone. At that point, she began maintenance therapy — IV infusions of trastuzumab and pertuzumab every three weeks indefinitely — to keep the cancer at bay. Seven years have passed, and remarkably, the cancer has not returned.

HER2-positive breast cancer accounts for about 20% of all breast cancer cases. Thanks to advances in anti-HER2 medicines, about 16% of patients with HER2-positive metastatic breast cancer are surviving with undetectable levels of cancer for many years after treatment.
Fantaci is one of them. Dana-Farber breast oncologist Heather Parsons, MD, MPH, wants to know if patients like her are, essentially, cured and if it is safe for them stop treatment altogether. She also wants to know if there is a way, using medicines available right now, to dramatically increase the number of patients with metastatic cancer who live cancer-free for a long time after treatment.
"People are sometimes hesitant to use the word cure," says Parsons. "But we want to know if we can help people control their cancer and live for a long time without being on constant therapy."
People are sometimes hesitant to use the word cure. But we want to know if we can help people control their cancer and live for a long time without being on constant therapy.
Parsons is pursuing a goal that goes against the conventional wisdom that metastatic disease cannot be cured. Her observations of patients like Fantaci and others who are living free of disease for a long time after taking these modern medicines inspired her to ask a bold question: Could a cure for metastatic HER2+ breast cancer be possible — not only for patients like Fantaci, but potentially for more patients as well? The answer could fundamentally change how some metastatic breast cancer is thought of and treated.
To gather the evidence needed to answer these questions, Parsons has initiated a trial called STOP-HER2, to learn more about how to monitor and guide patients like Fantaci. She also designed a complementary trial, called SAPPHO, for patients with newly diagnosed disease to see if a novel regimen of approved medicines yields more exceptional responses.

Yvonne Fantaci (third from right) shares a moment with her family in Dana-Farber's healing garden. An "exceptional responder" to anti-HER2 medicines, she has enjoyed years of survival with undetectable cancer levels.
Evaluating Treatment Success
Prior to her diagnosis, Fantaci was looking forward to her 60th birthday. It was three weeks away and she happened to look at Facebook. A childhood friend had announced that she had breast cancer, so Fantaci naturally did a self-check. She found a lump on her left breast.
"Everyone asks me if I had symptoms, but I did not," says Fantaci. "I felt fine."
Fantaci followed up with her health care provider right away. After her diagnosis, friends urged her to transfer to Dana-Farber. She did, and her Dana-Farber doctor confirmed the HER2-positive diagnosis and identified the lesions.
Fantaci received standard first-line treatment, a combination of chemotherapy paired with anti-HER2 therapy in the form of two monoclonal antibodies, trastuzumab and pertuzumab, that kill cancer cells by blocking the receptor. Fantaci then transitioned to maintenance therapy — which calls for trastuzumab and pertuzumab, infused every three weeks, indefinitely.
This regimen has proven in clinical trials to be extremely effective. Trastuzumab, also known by the brand name Herceptin, emerged 25 years ago as the first targeted treatment for HER2-positive disease and revolutionized treatment for HER2-positive breast cancer. Pertuzumab built on that success with a slightly different approach to blocking the receptor. Anti-HER2 innovations have continued since.
The use of these and other more recently developed HER2-directed therapies have made a dramatic impact on our ability to prolong survival for patients with advanced disease and to cure patients with early-stage disease. It's been a wonderful story of progress.

"The use of these and other more recently developed HER2-directed therapies have made a dramatic impact on our ability to prolong survival for patients with advanced disease and to cure patients with early-stage disease," says Erica Mayer, MD, MPH, director of clinical research in Dana-Farber's breast oncology program. "It's been a wonderful story of progress."
Fantaci followed doctor's orders. Every few months, she reported for her regular CT scans, which are used to monitor the size of the lesions during and after treatment. She recalls wanting to know exactly how much her lesions had shrunk during every visit. When that number hit 98%, she was ready to celebrate, certain that the next scan would be clear.
It wasn't. The number stopped at 98% and stayed there.
"[My doctors] explained that CT scans just aren't that definitive," Fantaci says.
The scans can show shadows of cancer, possibly dead cancer cells, but there is no way to tell from a scan exactly what remains. Ultimately, 98% disappearance for a prolonged period is an excellent result. But for patients, the notion that there may still be cancer cells lurking is unsettling.
Fantaci later learned of the STOP-HER2 study, which wasn't up and running yet but was potentially a good fit for her. One of the more intriguing parts of the study for Fantaci was inclusion of an investigation of a blood test that measures circulating tumor DNA to assess if the cancer is gone or returning. In the trial, the blood tests would not guide treatment, but they held the possibility that in the future, patients might get a clearer view of their cancer status after treatment.
Those tests detect fragments of DNA shed by remaining cancer cells and could potentially help patients get an additional read on their cancer status, complementing the CT scan. Parsons, who also is intrigued by the potential for ctDNA tests to improve patient monitoring and decision-making, designed the study to assess its value as a clinical test.
Assessing Long-Term Remission
The STOP-HER2 study offers patients like Fantaci a way to safely stop taking trastuzumab and pertuzumab. Only patients who are deemed exceptional responders — those whose cancer has not progressed after three years of maintenance therapy — are eligible to enroll.
Fantaci joined and opted to stop treatment. Another group of patients in the trial will continue with maintenance treatment. When starting the trial and every nine weeks thereafter, patients receive a CT scan to make sure the cancer has not returned.
Blood is drawn and ctDNA tests performed, but not to detect disease progression or guide trial decisions. Rather, this trial is collecting the evidence needed to determine how they can be used to monitor patients.
When Fantaci stopped treatment, she was able to stop going to Dana-Farber every three weeks for infusions of the two drugs. She also stopped having gastrointestinal issues, which has made leaving the house much less stressful.
"STOP-HER2 has been very popular for patients," says Mayer. "We look forward to presenting data from this study, to determine if the approach is feasible, though long term follow-up will be needed to determine if this is a strategy that can be applied widely to patients."
The trial, which was designed and is led by Parsons, is open throughout the Translational Breast Cancer Consortium and available across the nation. Patients will be followed for 10 years.
Toward More Exceptional Responses
When Parsons observed that some patients were doing extremely well after treatment for HER2-positive breast cancer, she also observed that most patients were still experiencing relapses. There, she saw an opportunity.
"Since the advent of Herceptin, there have been many new agents for HER2-positive metastatic breast cancer," says Parsons. "We wondered if we could use all of them as an intensive form of treatment up front and see better results."
Specifically, the SAPPHO trial is testing a regimen of medicines taken back-to-back, each for a specific duration, with no delay in between. This differs from standard treatment, which administers one medicine, then does not apply the next one until the patient's cancer has started to grow again. Could this intensified regimen prevent the cancer from developing resistance and surging back?
"These medicines are hitting the same target, but not in the same way, which we think can address some heterogeneity," says Parsons.
That is, one drug might kill a large percentage of the cancer, but the cells remaining might be different and can surge back. On SAPPHO, rather than giving those resistant cancer cells time to surge back, the next medicine is given right away to shut them down.
The trial is enrolling only patients with newly diagnosed disease that is metastatic. This way, the patients have not ever received cancer therapy before, and their cancers have not had a chance to develop any resistance to therapy.
Treatment begins with the standard chemotherapy plus trastuzumab and pertuzumab. That is immediately followed by an antibody-drug conjugate called trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate that has been shown to work in HER2-positive, HER2-low, and possibly even some HER2-negative cancers. The next therapy is tucatinib, which is paired with another antibody-drug conjugate called T-DM1. These last two medicines have helped reduce recurrences in the brain, which is a high risk for patients with HER2-positive metastatic breast cancer.
"It is almost two years of treatment," says Parsons. "We want to make sure it's a long enough duration that you're really treating all of the disease."
Once treatment is complete, patients complete one year of maintenance therapy with trastuzumab, pertuzumab, and tucatinib, after which, patients stop treatment but are followed with clinical visits and scans. The current plan is to follow patients closely for ten years. Parsons' primary focus is to measure and report four-year progression-free survival.
The team knows from previous research that about 16% of HER2-postitive metastatic breast cancer patients are exceptional responders to standard therapy, but that trial included different, older regimens and patients who had been previously treated and recurred. In SAPPHO, they are assuming that 24% of patients would likely become exceptional responders with standard treatment because all patients are newly diagnosed and will receive newer medicines.
Their hypothesis, however, is that this intensive regimen will improve upon that. Parsons has seen the power of these medicines to melt away this extremely aggressive and advanced disease and, while she is cautious, she is also optimistic.
"We're shooting for more. We hope many more patients will be progression free four years after treatment is complete," says Parsons.
Gratitude for the Possibility
Parsons' optimism is fueled by the vision that more people could be where Fantaci is today, enjoying life and adjusting to the idea that she is no longer tethered to treatments and their limitations.
Fantaci, who was extremely cautious during the COVID-19 pandemic due to her treatments, is now remembering her love of travel and considering what might be possible. She is also enjoying time with her children and grandchildren and the freedom to do more with them with fewer concerns about her health.
"I am just so grateful," says Fantaci. "There are some days where it's an overwhelming sense of gratitude that I am here. Ten or 15 years ago, it might have been a different story."