CME
Physicians: Maximum of 0.75 AMA PRA Category 1 Credit™
Released: May 09, 2024
Expiration: November 08, 2025
Tumor-Agnostic Prevalence of HER2 Alterations (Mutations and Amplifications)
Recent molecular analysis data for several solid tumors—and highlighted here for gynecologic cancers—show that HER2 gene alterations (eg, mutations, amplification, or multiple alterations) are most prevalent in cervical and endometrial cancer, followed by ovarian and vaginal cancer.
Implications of HER2/neu Testing in Serous/Carcinosarcoma Endometrial Cancer
Tumor IHC scoring using the traditional breast cancer positivity scoring of HER2 IHC 3+ or 2+ with in situ hybridization (ISH) positivity is seen in approximately 25% to 30% of cases of serous/carcinosarcoma endometrial cancer.1,2 I would venture to say that expression of any HER2 (eg, IHC 3+, 2+, and 1+), not including amplification, may be as high as 50% in serous tumors.
So, the prevalence of HER2 positivity depends on how you are defining HER2 status by IHC in gynecologic cancers. We do see that the true positives, as I like to call them—the IHC 2+ ISH+, IHC 3+ in uterine serous carcinomas—are associated with response to targeted therapies against HER2.2 Here we are talking about the monoclonal antibodies trastuzumab and/or pertuzumab. Although carboplatin plus paclitaxel and trastuzumab is not officially approved by the FDA for this indication, it is listed in the National Comprehensive Cancer Network (NCCN) guidelines for the frontline treatment of HER2-positive (IHC 3+ or 2+ and ISH+) metastatic uterine serous/carcinosarcoma endometrial cancer. Note that this was by breast scoring historically, and now it has its own uterine classification based on gastric scoring—but more on that later.
What we have recognized from these early results and emerging clinical data is that there are significant differences between HER2 expression in uterine cancer compared with breast cancer—and this should come as no surprise because it was recognized even earlier in gastric cancer.
But what are the differences?
For example, we can see significant intratumoral heterogeneity in gynecologic cancers. However, I do not know how similar the tumor heterogenicity is compared with that of gastric cancers—either more than or less than, because both of these tumors have significant intratumor heterogeneity, but you can see up to 2 degrees of difference in staining intensity across tumors at >50% of cells, so it really is quite significant.
When we look at the gastric cancer criteria for scoring a uterine carcinoma, the use of trastuzumab or pertuzumab, the positives are known as IHC 3+, and this is 30% strong complete or basolateral/lateral staining and/or HER2 2+ with fluorescence in situ hybridization (FISH) amplification, and that amplification has a HER2/CEP17 ratio ≥2.0.
Clinical Implications of Key Biomarkers in Endometrial Cancer
For endometrial cancer, it is quite encouraging that almost every 6 months we have a new predictive biomarker that we either confirm or are studying in a clinical trial. Some of these are listed in the table, which is up to date as of the first quarter of 2024. Overall, we can see HER2 highlighted in the middle as a prognostic biomarker predictive of response with trastuzumab and, more recently, T-DXd. It is important to remember that we have demonstrated utility for this biomarker in uterine serous carcinoma. In both early- and later-stage disease, those with disease that expresses HER2 or with amplification with higher IHC scoring do have a worse prognosis.
Molecular Testing in Ovarian and/or Cervical Cancers
With the recent FDA approval of T-DXd, the NCCN incorporated testing and use of HER2-targeted ADCs into the recurrent ovarian cancer space. As you can see on the slide, HER2-positive status by IHC has been added as an actionable biomarker for ovarian cancer, along with BRCA, microsatellite instability/mismatch repair, BRAF status, and folate receptor α status by IHC. HER2 use as a biomarker in ovarian cancer is supported by the results of the phase II DESTINY-PanTumor02 trial, but we will talk more about that later in this module.
In cervical cancer, the NCCN guidelines now also recommend HER2 testing by IHC, just as in ovarian cancer, with reflex testing via FISH for equivocal IHC. This is mainly an adenocarcinoma opportunity in cervical cancer. I would say that if you have a patient with newly diagnosed stage IVB cervical cancer or with positive peripheral lymph nodes that is also adenocarcinoma or adenosquamous histology, I would be making sure I knew the HER2 status of that tumor right off the bat—and this is because you are going to need a therapy in the recurrent setting, as unfortunately these tumors are not curable and do recur. Moreover, for a patient who has already recurred following frontline chemotherapy, you also want to make sure you knew their HER2 status.
I have found 1 or 2 HER2-positive tumors in patients with squamous cervical cancer. We can do that by either sending for the IHC locally or sending it as part of a larger panel with next-generation sequencing (NGS) plus IHC with a commercial assay. From now on, I would test all my patients with recurrent cervical cancer for HER2 status, but if there are any limitations to testing (eg, insurance coverage or other constraints), this really is a must know for patients with adenocarcinomas, where we can see approximately 77% of cases having some expression of HER2.3
ASCO/CAP Guidelines for HER2 Classification: IHC
The American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines for HER2 classification based on the breast cancer HER2 IHC testing criteria defined HER2 positive as circumferential membrane staining that is complete, intense, and in >10% of tumor cells. These patients are recommended to receive HER2‑targeted therapy.4,5 Based on these guidelines, HER2 2+ is considered equivocal or weak to moderate complete membrane staining observed in >10% of cells, and this is the group for whom we do recommend reflex testing for ISH or using a new specimen for IHC if available.
Then we have the group of HER2-negative tumors, which are those that are HER2 IHC 1+, or incomplete membrane staining that is faint and in >10% of cells; these often are grouped with HER2 IHC 0, where we see no staining at all. Previous recommendations were for no HER2‑targeted therapy in these settings, and that remains true outside of a clinical trial. However, I would advise that as we get these results (ie, HER2 IHC 1+ and 0), we need to be very specific about the HER2 results in the patient’s records, because there are ongoing clinical trials that are including HER2 IHC 1+, especially for uterine cancers. These studies are investigating very active drugs where some activity has been observed even in patients with HER2 IHC 1+ tumors.6
ASCO/CAP Guidelines for HER2 Classification: ISH
On this slide, we have the additional details on the ASCO/CAP guidelines for HER2 classification using ISH. Group 1, or positive HER2 IHC 2+, includes those for whom the initial HER2/CEP17 ISH ratio is ≥2.0 and the copy number is ≥4.0; these require no further testing. Then, groups 2, 3, and 4 are the equivocal groups, and you can see them all further subdivided here, with group 5 being the clear negatives.
In the equivocal groups, you can add on ISH to further characterize how positive the disease is for HER2. At the bottom of the table, if a tumor was HER2 equivocal and had a HER2/CEP17 initial ratio of <2.0 and a copy number >6.0, that becomes a positive. By contrast, groups 2 and 4 are called negative, but they include a comment. Those are all of the things we want to keep track of moving forward, because these patients may benefit from novel agents as we get more details around the appropriate biomarkers and cutoff points, particularly for gynecologic cancers.
Guideline and Expert Recommendations for Type and Frequency of HER2 Testing in Gynecologic Cancers
The table lists a summary of current guideline and expert recommendations for type and frequency of HER2 testing in patients with gynecologic cancers.
For serous endometrial cancer and, more recently, carcinosarcoma, we want to obtain IHC first and then FISH for equivocal cases, which are 2+. Currently, the recommendations are for all serous/carcinosarcomas. We must remember to test carcinosarcomas and any patient with TP53-abnormal endometrial cancer, because we can see some high‑grade endometrioid tumors with TP53 alteration where we may find HER2 expression. I do think this will change with time, however, and will be more universal—testing for HER2 across all endometrial cancers, at least those that are at an advanced stage—but for now this is the recommendation.
For ovarian cancer, HER2 testing is for any patient with platinum-resistant disease, and as soon as the patient experiences disease recurrence, I would test for HER2 status via IHC, with reflex ISH testing as necessary.
Same idea for cervical cancer—I would recommend testing for HER2 status, if you have the ability to, for any patient with advanced or recurrent disease from first recurrence. We need to be able to plan for future therapies, because advanced cervical cancer ultimately relapses. To reiterate, if there are limitations for HER2 testing for your patients with cervical cancer, this is a must know, at least for adenocarcinomas.
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