HER2 Testing and Clinical Decision Making in GEA

SPEAKER_00
0:06

Welcome to the latest edition of the College of American Pathologists CAP Cast. I'm Dr. Kelsey McHugh, an expert panel member on the Updated Evidence-Based Guideline, HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma. I'm here with another member of the committee and an expert on the updated guideline, Dr. Katherine Strutker. Before we dive into the guideline, Dr. Strutker, can you briefly introduce yourself?

SPEAKER_01
0:33

Hi, I'm Kathy Strutker. I'm a gastrointestinal pathologist at Unity Health Toronto in Canada. I've been involved in HERTE testing going back to 2011 where we started to develop the testing protocols for our province. And I've worked on some publications in the area, which led to my role as an expert member in the previous publication on HERTE testing. And now we're working on developing biomarker testing as a national program.

SPEAKER_00
0:59

And I'm a staff pathologist and associate professor of pathology at Mayo Clinic, Arizona, where I specialize in gastrointestinal hepatobiliary pathology as well as cytopathology. I also serve as the medical director of histology for our group and the GI and liver pathology fellowship program director.

SPEAKER_01
1:19

Alright, we're going to jump right into a series of questions talking about HER2 testing and gastroesophageal adenocarcinoma. And our first question for Dr. McHugh is what are the primary methods used today to test for HER2 in gastroesophageal adenocarcinoma and how do they differ?

SPEAKER_00
1:36

There are three main methodologies used to evaluate HER2 in gastroesophageal adencinomas. These are immunohistochemistry in SIT2 hybridization and genomic methodologies to include polymerase chain reaction and/or next generation sequencing-based assays. While immunhistochemistry and incy2 hybridization assays are applied to tumor tissue and interpreted by a pathologist with the aid of a microscope, genomic methodologies use tumor DNA either from tumor tissue or from a patient's blood, so-called liquid-based testing or circulating tumor DNA testing, to evaluate the HER2 or ERBB2 gene. Each of these methodologies detects slightly different HER2 abnormalities. HER2 immunohistochemistry detects protein overexpression on tumor cells. HER2 in situ hybridization detects HER2 gene amplification or copy number increase within tumor cells, and DNA-based genomic methodologies generally detect HER2 gene mutations and amplifications. Dr. Strutker, how has HER2 status changed the way clinicians approach treatment for patients with gastroesophageal adenocarcinoma?

SPEAKER_01
2:51

Well, I'm old enough to remember that prior to the TOGA trial being published, the treatment options for upper GI tract adenocarcinomas were very limited. Really, basically, surgery and chemotherapy. The prognosis for advanced disease was very poor at less than a year of 50% survival. With the advent of HER2 testing and targeted therapy, patients have had access to Utrestuzumab and related medications, which have improved outcomes significantly. And for some patients, has resulted in complete response. Now, as even more therapies are developed, patients have access to an increasing variety of first, second, and third line therapies. This has very much changed how oncologists approach treatment. It must be very complicated for them because now they have to take into account all the other biomarkers and targeted therapies that are available for upper GI cancers, particularly immunotherapy and quadin 18.2 targeted therapy. They now need to sort through the results of these multiple different biomarkers and balance out what combination of therapies and their associated side effects would be of most benefit to the patient. Dr.

SPEAKER_00
3:58

Strucker, what recent developments or emerging data are you most excited about in HER2 directed therapies?

SPEAKER_01
4:05

I think one of the major changes in the current update of the guidelines regards the increased need for repeat testing on metastatic or recurrent cancer. In the initial guidelines, we stated that it should only be done once, but now we are starting to recognize that the HER2 status can change, particularly post-treatment, but even without treatment, there is always that heterogeneity in upper gastrointestinal tract adenocarcinoma, and so you don't really know what clone is going to metastasize or recur. I'm also excited to see the development of the drug conjugates that allow targeting of HER2-low or HER2 positive cases that become trastuzomab refractory. The being able to use those drugs in the upper gastrointestinal tract cancers comparable to what's happening in breast cancer treatment is going to be very exciting. In our center, HER2 low cases make up a significant fraction of our test cases, and so any method of increasing treatment options for these patients is going to be of very much value to the patients. It's also fascinating to see all the new markers come up, and I mentioned before CPS scoring for PDL1 for immunotherapy treatment and using quadin 18.2 IHC for targeted therapy gives patients more options in combination with HER2 results, which overall is opening up treatment for so many more patients than was available before. Dr. McHugh, how can pathology labs ensure consistency and accuracy when assessing HER2 status?

SPEAKER_00
5:45

Beyond ensuring appropriate analytical validation in line with the CAP's guidelines for validating predictive biomarkers, there are a few additional considerations labs can take into account to ensure their HER2 status results are accurate. While standards for pre-analytical quality of tissue for breast carcinoma have been extensively documented, there are significantly less data for gastroesophageal adenocarcinomas. Nevertheless, the literature does strongly support the concept of ensuring best tissue quality for testing. Optimizing tissue quality and choice of tissue block supports accurate biomarker testing results. In general, pathologists should select the block or blocks with the areas of lowest grade tumor morphology and the least amount of necrosis. When analyzing biopsy material, testing at least three to five biopsy fragments involved by tumor has been shown to lead to good correlation with the HER2 status of subsequent resection material. Some authors do advocate for testing at least six to eight involved biopsy fragments. Do keep in mind that especially if there is tumor heterogeneity in the morphologic patterns present, testing more than one tissue block may be useful. Lastly, when evaluating resection material, selecting the blocks with the highest viable tumor cellularity, the least amount of necrosis, and the least amount of treatment effect is preferred. One final consideration is that in the rapidly evolving landscape of HER2 targeted therapies, determination of HER2 status after disease progression is becoming increasingly important, as Dr. Strucker has mentioned. Even for patients who were initially HER2 positive prior to therapy and disease progression, repeat testing of relapsed or recurrent tumor tissue is now becoming important for targeted therapy selection. For these reasons, this repeat testing should be considered in all patients experiencing disease progression. And just as with the initial HER2 status evaluation, tissue-based evaluation via immunohistochemistry and insight-to-hybridization as needed is preferred over genomic methodologies. Dr. Strucker, if you could convey one key takeaway to clinicians and pathologists, what would it be?

SPEAKER_01
8:06

I think as we both mentioned, one of the major updates and the recommendations is to do the retesting of HER2 and potentially other biomarkers in metastatic and recurrent disease to look for changes compared to the initial testing. We never used to do this in upper gastrointestinal tract cancers. When you look at breast cancer cases, it's fairly routine to retest recurrences and metastases, but those cases are in many cases happening at months at least, but sometimes many years after the initial presentation of the cancer. In gastric cancer, it has all our oncologists have said, well, there's no point in resampling it because we know what this cancer is, there's no point in checking it again. But I think we're starting to see that the biomarkers can change significantly, and it's important for the patient to have this information so that we can do the best treatment that the patient can manage. I know in Canada there has been statements about well, one test is funded and after that not. So I think this is a major change that has to get across to all these different agencies so that they understand the importance to the patient.

SPEAKER_00
9:27

Thank you so much, Dr. Stutker, for this engaging discussion surrounding the updated evidence based guidelines for HER2 testing and clinical decision making in gastroesophageal adenocarcinomas. As we wrap up, I want to thank all of you for listening to this CAPCAST. For more information about the updated guideline, you can visit CAP.org.