HER2-Low: What Patients Need To Know, Including How Low is Too Low?
- Breast cancer patients are being urged to ask their doctor about their HER2 status because it could change their treatment, but there is still much for the entire field to learn about this new classification.
- HER2-low is a new classification of breast cancer. More than 50% of all breast cancers may fall within this category.
- Current testing for HER2 protein, which is present on the surface of all breast cancer cells, is not entirely adequate for identifying HER2-low cancers.
- HER2-low cancers stand to significantly benefit from new drugs that are highly precise and targeted.
- The minimum level of HER2 expression required for benefit from these drugs is unknown. “How low is too low?” is a critical question that needs answers.
This excitement stems from the fact that “HER2-low [breast cancers] are targetable with the new FDA-approved [Enhertu (Fam-trastuzumab deruxtecan-nxki)],” remarks Dr. Yuan Yuan, MD, Ph.D., director of breast oncology at Cedars-Sinai Cancer and a breast medical oncologist and physician-scientist who specializes in triple-negative breast cancer and breast cancer immunotherapy.Read More
Breast CancerBreast cancer is a common diagnosis. An average woman has a 1 in 8 chance of developing it and it’s also the second leading cause of cancer-related death in females. Fortunately, because of better screening and improved therapeutics, the rates of breast cancer deaths have been steadily decreasing. Better treatments are now making it possible for even metastatic patients to live for many years, a feat that was not possible in even the recent past.
These treatments include targeted therapies that exploit specific cancer characteristics. These therapies come with their own challenges. Do we need better testing to select appropriate patients for these drugs? Do we need to better train community oncologists to manage drug side effects?… these are all questions physicians must consider with any new cancer classification and treatment, such as HER2-low breast cancers.
What Is HER2-Low Breast Cancer?
Human epidermal growth factor 2 (HER2) is a protein found on the surface of most breast cancer cells. The levels of this protein, however, can significantly vary from one patient to another. For many decades, these levels have been measured using tests such as immunohistochemistry (IHC) and in situ hybridization (ISH).
IHC assigns numeric scores that correspond to the level of HER2 expression. 0, the lowest possible score, represents no HER2 expression, while 4+, the highest score, represents maximal expression. 1+, 2+, and 3+ signal intermediate levels of expression. ISH, on the other hand, detects whether the HER2 gene is amplified within the cancer cells or not. Tumors that are IHC 3+ and 4+ with or without ISH amplification or IHC 2+ with ISH amplification are traditionally called HER2-positive and the others, HER2-negative.
Despite the traditional HER2-negative moniker, such tumors may express varying levels of the HER2 protein. And while these levels are not sufficient to make them eligible for older drugs (reserved for HER2-positive tumors), they could be enough for these patients to derive great benefits from the newer drugs as shown in recent trials. This has led to a more nuanced reclassification of tumors expressing low levels of HER2 protein as HER2-low. Tumors without any of the HER2 proteins (IHC 0) continue to be labeled HER2-negative or HER2-zero.
Dr. Kalliopi P Siziopikou, professor of pathology and medicine (hematology and oncology) and director of breast pathology at the Department of Pathology at Northwestern University Feinberg School of Medicine, summarises the HER2-low designation in the following words: “While there is no formally accepted definition of what HER2-low breast cancer is, some investigators are proposing we should be using a 3 tier system: Breast cancer cases with an IHC HER2 score of 3+ or IHC score 2+ and amplified by FISH should be called HER2-positive breast cancer cases. This group constitutes about 15% of all breast cancer cases. Breast cancer cases with an IHC HER2 score of 0 should be called HER2-negative breast cancer cases. This group constitutes about 30-40% of all breast cancer cases.”
She continues, “And finally, breast cancer cases with an IHC HER2 score of 1+ or 2+ and non-amplified/negative by FISH should be called HER2-low breast cancer cases. This group is the largest group and constitutes about 45-55% of all breast cancer cases. This is the group for which the new ADC therapies are now considered.”
Dr. Siziopikou co-moderated a special session titled “HER2-Low: A Separate Entity?” at SABCS 2022.
Current Testing For HER2 Testing Is Imperfect
Traditional HER2 tests were perfected to detect HER2-positive tumors as this was the only class of breast cancers that benefited from older HER2-directed drugs, such as Herceptin. Till now, there was no practical use for teasing apart HER2-low tumors.
Dr. Julie Gralow, MD, FACP, FASCO, the chief medical office and the executive vice president of the American Society of Clinical Oncology, told SurvivorNet: "These assays were perfected to pick out HER2 positivesâ€¦ We did not design these assays to perfectly pick out the 1+ and 2+ tumors."
IHC is imperfect and perhaps wholly inappropriate for detecting HER2-low tumors. "It would be like using a weighbridge calibrated for weighing elephants when you are trying to accurately weigh mice," claimed a recent paper on the topic. Additionally, this test is semi-quantitative, and the results depend on the judgment of the pathologist reading the test. This makes it vulnerable to human error. Consequently, it is not uncommon for pathologists to disagree about the IHC level of breast cancers, especially when they are in the HER2-low range.
The increasing therapeutic importance of the HER2-low classification and the shortfalls of current testing warrant more accurate testing for low levels of HER2 proteins. Potential candidate tests are already in development at leading institutions. These tests have not yet been adopted by leading scientific bodies, such as the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines, which unfortunately limits their perceived legitimacy at this time.
How Low is Too Low To Benefit From Targeted Therapies?
Targeted drugs like Enhertu are antibody-drug conjugates (ADCs). The antibody portion latches onto whatever HER2 proteins it can find on cancer cells. It then injects its partner drug, a potent toxin (chemotherapy), directly into the cells, killing them and their neighbors. Even though ADCs can function with low levels of HER2 expression, the minimum level of HER2 required for them to benefit patients is not known at this time.
This is due to many factors. As mentioned before, HER2-low is a new entity without a suitable test. Once such a test has been developed and standardized, it will need to be tested in rigorous scientific studies to establish the minimum threshold required for benefit from ADCs. This is especially important since ADCs carry significant side effects, their benefit must outweigh their risks to justify their use in patients.
Serious Side-Effects from Targeted Drugs Require Proactive Management
All treatments come with their own risks. This is true of targeted therapies as well. Many of these side effects are manageable. But some can be life-threatening.
The drug with the most benefit for the HER2-low population, Enhertu carries a risk of lung toxicity. This risk can be greater than 10%. Lung toxicity commonly manifests as interstitial lung disease (ILD) and/or pneumonitis.
ILD is a scarring of the tissues that make up the lungs. It is generally irreversible, worsens over time, and leads to increasing shortness of breath and cough. Pneumonitis is a widespread inflammation of the lungs, which can cause patients to have trouble breathing, cough, tiredness, loss of appetite, and weight loss. Although both ILD and pneumonitis can be managed with medications, they can also be life-threatening. At least 3 deaths were attributed to ILD caused by Enhertu in a recent study.
These side effects are a reminder to the oncology community to proceed with caution. Once their patients have been classified as HER2-low and eligible for targeted therapies, they must discuss the side effects with the patients before starting therapy. Additionally, they must exceptionally be diligent about monitoring and managing the side effects. The patients, on the other hand, must assume the risks of HER2-low therapies.
“[However], with proper patient and care team education, [these side effects] can be safely managed by community oncologists,” emphasizes Dr. Yuan.