Heather Parsons, MD, MPH
By Beth Dougherty
In 2020, data from a clinical trial of patients with metastatic HER2-positive breast cancer caught the attention of Dana-Farber breast oncologist Heather Parsons, MD, MPH. She noticed what she describes as a "long tail." Sixteen percent of patients who were taking the novel combination therapy shared one common trait: they were surviving for an unexpectedly long time.
While most patients on the trial saw their cancer progress after about a year, these patients were all still doing well after eight years with no disease progression. They are exceptional responders, and Dr. Parsons and her colleagues are taking a close look at them to understand what differentiates them from conventional responders. What they learn could help them improve treatment for patients with metastatic disease.
The idea of zooming in on exceptional responders is not new. A little over a decade ago, oncologists observed small numbers of people in trials with unexpectedly positive results from therapy. These observations provided clues about how medicines could zero in on vulnerabilities in cancer more precisely and achieve better results. Today, medicines that do just that are showing ripple effects of improvement for patients.
"We've learned that precision medicines that target a fundamental change in the cells that drives the development of cancer can be very effective," says Dr. Parsons. "Anti-HER2 therapy is a great example of a precision medicine success story."
The Long Journey to Notable Impact
HER2+ breast cancer growth is driven by an overabundance of a receptor, called human epidermal growth factor receptor 2 (HER2), that drives rapid cancer growth. Twenty-five years ago, HER2-positive breast cancer was one of the most lethal forms of breast cancer.
Then, in 1998, the first treatment to target HER2 and shut down that growth — a monoclonal antibody called trastuzumab — was approved. Trastuzumab reduced the risk of death by a third and cut the risk of relapse in half.
In 2012, another anti-HER2 therapy, called pertuzumab, gained approval. Pertuzumab is also a monoclonal antibody that blocks HER2, but in a different way. Trastuzumab blocks one channel cancer cells use to signal more growth, but it leaves open a backchannel. Pertuzumab shuts down that backchannel.
The exceptional responders in the "long tail" noted by Dr. Parsons were participants in the pivotal phase 3 trial that ushered in the approval of pertuzumab. The trial, called CLEOPATRA, led to the use of the current standard therapy combining trastuzumab, pertuzumab, and chemotherapy in patients with metastatic disease.
Today, many patients with early-stage disease are considered cured after taking therapy that targets the HER2 protein. Most patients with metastatic disease, however, show signs of cancer progression after one or two years on treatment. Their disease is considered incurable.
Given this backdrop, the exceptional responders who participated in CLEOPATRA stand out, in part because they have only become visible after many years of follow up.
"It is only recently that we've had these targeted anti-HER2 therapies in use for long enough to know that they are working as well as they are for some metastatic patients," says Dr. Parsons. "Now that we're able to see the duration of these responses, we are able to think about what we can learn from it to improve responses for more patients."
As a first next step, Dr. Parsons and her team wanted to see if the same phenomenon of exceptional responses had propagated to patients outside of the trial.
Results Ripple Across the Real World
Nancy Lin, MD
One source of real-world data is the EMBRACE metastatic breast cancer program led by Dana-Farber breast oncologist Nancy Lin, MD, MPH. EMBRACE (Ending Metastatic BReAst Cancer for Everyone) includes a longitudinal study of the same name examining outcomes for patients with metastatic breast cancer who were seen at Dana-Farber. Since the study began in 2010, thousands of patients have enrolled, enabling researchers to home in on a subset of patients and learn more about their similarities and differences over time.
Stefania Morganti, MD, is one of those researchers. Dr. Morganti, a clinical research fellow in the Parsons lab, searched EMBRACE for patients with HER2-positive metastatic breast cancer who had taken standard first-line anti-HER2 therapy. To differentiate exceptional responders from conventional responders, she defined exceptional responders as those who had survived without progression on first-line therapy for at least three years, three times the median duration.
"There isn't a formal definition for an exceptional responder," says Dr. Parsons. "But this was a definition everyone we consulted with was comfortable with."
Stefania Morganti, MD
Dr. Morganti found that 28% of patients in this real-world dataset were exceptional responders, with 147 exceptional responders and 370 conventional responders.
"It's impressive, because we think of metastatic disease as incurable, with a dismal prognosis," says Dr. Morganti.
Dr. Morganti's analysis revealed a few features that increased the chances that a patient would be an exceptional responder. One was having strong HER2 expression, meaning the HER2 receptor is rated as extremely abundant on the cancer cells. Another was having de novo metastatic disease, meaning the disease had already spread at the time of diagnosis. And a third was having therapy with the triplet regimen tested in CLEOPATRA, rather than the older regimen of trastuzumab and chemotherapy.
The findings were compelling, but the EMBRACE database, even with thousands of patients, is relatively small and limited to a regional population. So, Dr. Morganti approached Thomas Grinda, MD, a breast oncologist at Gustav Roussy Cancer Center in Paris. Dr. Grinda had access to the much larger database called the Épidémio-Stratégie Médico-Economique Programme, or ESME. This repository contains more than 32,600 metastatic breast cancer cases representing all patients treated in a comprehensive cancer center in France.
Thomas Grinda, MD
"We wanted to ask the same question, but in a larger and different real-world dataset to see if we could validate our findings," says Dr. Morganti.
Dr. Grinda's analysis, which included 3,291 conventional responders and 1,016 exceptional responders, yielded results similar to Dr. Morganti's, with 25% of patients being exceptional responders, and the same three features as predictors of an exceptional response.
"This second analysis validates the findings in EMBRACE, but in a population that represents the whole population of France," says Dr. Grinda, who has been working as a clinical research fellow with Dr. Parsons. "These are good predictive variables, and we need to use them."
The Role of Genetics and Circulating Tumor DNA
The ESME database has the advantage of being large and widely representative, but it is limited to clinical observations and pathology reports. In contrast, the EMBRACE repository contains genetic sequencing of some tumor samples, and tumor and blood samples from some patients. This additional data gave Dr. Morganti a chance to do analyses that were not possible with the ESME database.
For instance, she had tumor genetic sequencing data, in the form of results of Dana-Farber's OncoPanel test that is used to identify mutations in tumors, for more than half of the patients she'd studied earlier. In a preliminary analysis, this data revealed two key genetic mutations that are associated with poor response to therapy.
One marker, PIK3CA, was already known. Another, MYC, was new in this setting. It isn't yet clear how these findings might be used to guide treatment, but as a next step, Dr. Grinda hopes to collect tumor samples from a subset of patients in the ESME database and perform OncoPanel tests on them to validate these findings about genetic mutations in his population.
"The genomics plus the clinical variables could be a strong predictor of who is going to be an exceptional responder," says Dr. Grinda.
Dr. Morganti also is hoping to analyze blood samples from the EMBRACE population. The goal is to determine if a simple blood test that looks at circulating tumor DNA — fragments of DNA that have shed from tumors and float in the bloodstream — might help doctors identify exceptional responders and conventional responders early on during treatment.
The Role of Individual Differences
While these investigations have focused on the cancer, another possible influence on the effectiveness of therapy could be the patient's genetics. The patient's individual germline mutations — mutations found in all of the patient's cells, and not just in the tumor cells — could influence response to treatment.
There are several examples of this phenomenon. For instance, patients with BRCA1/2 mutations, which confer an inherited risk of breast or ovarian cancer, may be more likely to respond to PARP inhibitors.
Nolan Priedigkeit, MD, PhD
"If you see one or two examples of such mechanisms, there are probably other similar ones that we don't understand yet," says Dana-Farber physician-scientist Nolan Priedigkeit, MD, PhD. "This gives us a rationale for doing analyses that might help us find them."
Whole genome sequencing of a patient's genome is expensive and time-consuming. To address this, Dr. Priedigkeit is using a tool that can infer germline genomic information from tumor genomic data. Created by Dana-Farber researcher Alexander Gusev, PhD, the tool enables Dr. Priedigkeit to analyze OncoPanel data from a subset of HER2-positive metastatic breast cancer patients in the EMBRACE cohort. It can identify germline mutations and determine whether they might influence the likelihood of an exceptional response or a conventional one.
"I think it's a powerful approach to look at extreme phenotypes such as exceptional responders and determine if there is something we can learn about their biology that can be applied to a broader group of patients," says Dr. Priedigkeit.
More Waves to Come
One potential application of this emerging knowledge is to determine if more patients can become exceptional responders. Dr. Parsons is planning a clinical trial called SAPPHO that will identify a subset of patients who are predicted to be conventional responders and examine the effects of intensifying therapy.
Another is to address the question of whether some exceptional responders have been cured. Currently, HER2-positive metastatic breast cancer treatment is given indefinitely, but Parsons is leading a clinical trial called STOP-HER2 to explore the possibility that treatment can safely be stopped for some of these patients.
"There is this dogma that we can't cure metastatic disease," says Dr. Parsons. "But if we have these really effective therapies, maybe we can."
