September 16, 2022
Contributed by Dr. Muneeb Niazi, Medical Fellow at SurvivorNet.
For oncologists across the country, including community practices, the new developments around categorizing breast cancer patients as HER2-low is starting to play out in practice. The drug enhertu was approved for patients previously considered HER2 negative, but in an important breakthrough, the drug has been approved by the Food and Drug Administration for certain stage four breast cancer patients whose tumors are classified as HER2- low. So what does this mean for late stage breast cancer patients? Regardless if your tumor has been classified as HER2, you should seek out your original biopsy from your doctor and have it retested for HER2 low so you can find out if you now qualify for treatment with Enhertu.
Previous therapies targeting cancer tumors with HER2 (Human Epidermal Growth Factor 2)-low proteins, such as Herceptin, have largely failed to benefit the HER2 low population, representing a large fraction of the diagnosed breast cancers. The benefit of Enhertu for this population, as demonstrated in the recently published DESTINY-Breast04 trial, is so significant that it has already been incorporated into the National Comprehensive Cancer Network (NCCN) Guidelines for the treatment of HER2-low tumors, which have failed at least one prior line of chemotherapy, or HER2 positive tumors which have become immune to the traditional hormone therapies.
Dr. Elizabeth Comen, MD, an expert in breast cancer oncology at Memorial Sloan Kettering Cancer Center, terms this development groundbreaking. “It totally changes the treatment and outcomes for patients living with HER2 low metastatic breast cancer,” she tells SurvivorNet. “And we are all so excited about the new hope and promise of this medication for a large population of breast cancer patients.”
Enhertu is not exactly a debutante in the world of cancer treatment. It has heretofore been used to treat HER2-positive breast cancers with great success. “This drug has been around for a few years, and it’s very effective in the HER2-positive population,” Dr. Julie Gralow, MD, FACP, FASCO, the chief medical office and the executive vice president of the American Society of Clinical Oncology, tells SurvivorNet. “Now, however, we have a whole, huge group [HER2 low] of patients who have the potential for benefit, who we never even thought of giving HER2 targeted therapy to.” Dr Gralow tells us this represents yet another leap in using tumor characteristics to inform an individualized, targeted treatment for each patient, which usually begets improved patient outcomes.
HER2 Status and Treatment Options for Patients
Breast cancer is an exceedingly common diagnosis with a projected 290,000 new cases in the United States in 2022. Yet its treatment is extremely nuanced, particularly in the metastatic setting when cancer has spread outside the breast. There has been a trend in oncology toward customizing treatment for each patient based on the pathologic and genomic characteristics of their tumors. HER2 is one such characteristic. HER2 are receptors on the surface of cancer cells, not unlike hormone receptors, such as those for estrogen (ER) and progesterone (PR).
The HER2 status of a tumor is usually assessed via two laboratory assays, fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). FISH tests divide tumors into 3 categories: no, low, or high HER2 amplification. The latter separates the HER2 status numerically, with 0 representing no HER2 expression and 4+ representing maximal expression. 1+, 2+, 3+ describe those tumors with intermediate HER2 expression. Traditional classification groups IHC 3+ and 4+ as HER2 positive, and others as HER2 negative.
HER2-low is a nascent designation, encompassing tumors that her IHC 1+ or 2+ and FISH negative. This population was historically lumped together as HER2 negative. “But these assays were perfected to pick out HER2 positives… We did not design these assays to perfectly pick out the 1+ and 2+ tumors,” notes Dr. Gralow. This means that FISH and IHC assays are an imperfect solution for characterizing HER2-low tumors. In time, as the nuances in the HER2 status become increasingly important for treatment selection, these tests may need to be refined or replaced by a better test.
This new HER2 group, previously HER2 negative, has been traditionally treated with hormone therapy or chemotherapies with modest success. However, DESTINY-Breast04 Phase III trial, which used Enhertu as the investigational treatment for this group, may have changed the treatment approach for the better.
How Does Enhertu Work?
Enhertu is a HER2-directed antibody tethered to a chemotherapy drug. The antibody selectively binds to the HER2 proteins on the surface of breast cancer cells and infuses highly potent chemotherapy directly into those cancer cells. This selectivity allows for the sparing of normal cells and the consequent side effects. In the words of Dr. Comen, “essentially, Enhertu targets the HER2 receptor, goes into the cancer cell, and kills it. This in turn helps metastatic breast cancer patients live longer and better.”
This mechanism is separate from the way more established drugs like Herceptin operate. Herceptin targets the same HER2 receptors, thereby preventing them from binding to substances that may promote cancer cell growth. The distinct modus operandi of Enhertu is the reason that has succeeded in treating HER2-low patients while Herceptin failed to do so.
Findings Of The Trial
DESTINY-Breast04 was a phase III randomized trial, representing the highest level of scientific evidence available in medicine. 557 patients with unresectable or metastatic breast cancer who were also HER2 low were selected for the trial. The HER2 classification was based on the results of combined FISH and IHC testing, with those testing negative for the former and 1+ or 2+ for the latter categorized as HER20-low. These patients were spread across a wide variety of ages, hormone receptor statuses (ER and PR), and races including White, Asian, African American, and Hispanic and Latino. All in all, this translates to a trial whose results can veritably be used to inform the clinical decision-making process for the general population.
The results from this trial were game-changing. Across all the patients, those who received Enhertu had progression-free survival (PFS) of 9.9 months as compared to the group who received traditional chemotherapy, whose PFS was 5.1 months. PFS represents the time a patient is alive without a worsening of their disease. Overall survival (OS), the ultimate measure of a treatment’s efficacy, is defined as the length of time patients are alive after their initial diagnosis of cancer. In the DESTINY-Breast04 trial, the OS for the Enhertu and the chemotherapy treatment groups was 23.4 months and 16.8 months respectively, a very impressive difference.
Enhertu is not without its side effects. Its side-effect profile in this trial was like that reported in the study which used the drug for HER2-positive metastatic breast cancer. The most reported side effect was interstitial lung disease (ILD), which was noted in 12% of the patients, with most of these cases being mild to moderate and reasonably treatable. There were, however, 3 deaths attributed to ILD caused by Enhertu. This is a reminder that despite all the amazing benefits of such drugs, they are not without risk. A discussion of such risks should be part of a comprehensive discussion between physicians and patients considering Enhertu for their treatment. In the words of Dr. Gralow, “the antibody-drug conjugates carry real toxicities and are not benign treatments.”
Will Patients Need Additional Testing?
Most patients may not need additional invasive biopsies to determine the HER2 status of their disease. “You can go back to the original breast cancer tissue that has been stored in the pathology lab and test that for HER2,” says Dr. Gralow, “as was done for most of the patients in the study.” However, some caution is warranted when using such tissue, as the HER2 expression of the tumors can evolve with time and the treatments that the patients receive between the time of their biopsy and the present time. Especially patients who were initially classified as HER2 negative may need a new biopsy of one of their metastatic sites to re-evaluate their receptor status. When selecting a new biopsy site, it is prudent to use a location that will provide enough cancer tissue for satisfactory testing, such as a lymph node as opposed to a bony metastatic focus.
Dr. Comen concurs. “It is important that patients have their original pathology report to determine if they are HER2 low and be eligible for this drug,” she says. “If they do not have access to the original report, they may need another biopsy to determine the nature of their breast cancer and candidacy for the new treatment.”
Fortunately, since the FDA approval for Enhertu, the authoritative bodies in cancer have incorporated the drug into their treatment recommendations for HER2 low metastatic breast cancer, which has failed at least one line of chemotherapy or has recurred or progressed during or within six months of completing chemotherapy. “This means that the treatment will be offered to appropriately selected patients not just at large academic centers but across the country, including at community practices,” Dr. Comen tells SurvivorNet. This will afford a significant relief to patients for whom seeking care at large medical centers may be a significant inconvenience and impediment.
Looking to the Future
Given the exciting results of Enhertu within the metastatic breast cancer setting, future investigational studies may lead to the utilization of the drug for early-stage, non-metastatic breast cancers. Unlike metastatic cancers, early-stage cancers are curable with appropriate treatment. Should Enhertu find a use for the latter in the future, it could lead to higher cure rates for breast cancer patients.
The Main Takeaways, According to the Experts
The landscape of the treatment of breast cancer is rapidly evolving. Far from one size fits all, treatment of this cancer has become extremely nuanced and individualized. While these changes are exciting, the plethora of treatment options can also be confusing for the patients. When it comes to Enhertu, the patients should be aware of at least the following key points so that they can have an engaging, and informed discussion with their oncologists:
- Cancer treatment is becoming personalized. For metastatic breast cancer, we need to understand all the different proteins that contribute to cancer development. This includes the granular details of the HER2 status and other genes, such as BRCA1 and BRCA2. This information is of critical importance when deciding whether Enhertu or another drug is the best treatment option for them.
- Enhertu is very effective in extending the survival of metastatic breast cancer patients. It is, however, not currently a cure. It is important to be aware of the benefit and the limitations of Enhertu in order to achieve the best clinical outcomes.
- While revolutionary in the way they kill cancer cells, antibody-drug conjugates such as Enhertu have real toxicities. These toxicities are not necessarily better or worse than more traditional treatments. They are different. Hence, patients and physicians need to carefully evaluate their individual risk of such toxicities before starting treatment.