Patient Profile: A 47-Year-Old Woman With HER2+ CRC and Early Disease Progression


Expert oncologists present the case of a 47-year-old woman with colorectal cancer and early disease progression, and discuss treatment options with the ongoing MOUNTAINEER-03 study.


Cathy Eng, MD, FACP, FASCO: We’re going to move on to the next case. Dr Michael Foote, would you please present clinical case No. 2 regarding a patient with HER2+ [human epidermal growth factor receptor 2–positive] with early progression following adjuvant therapy?

Michael Foote, MD: Absolutely. We have a 47-year-old female with no significant past medical history and no family history of colorectal cancer who presented to her doctor with painless bright red blood per rectum. A colonoscopy was performed, and it showed a rectal sigmoid large lesion at 10 cm that extended to 15 cm from the anal verge, and there was no evidence of bowel obstruction. In fact, she was having a bowel movement every day or 2. An MRI scan was performed, and the tumor was visualized at about 3.4 by 2.4 by 3.3 cm. It extended above the peritoneal reflection and there were no enlarged lymph nodes. A CT scan of the chest was performed and was negative as well. Because of this, she underwent a robotic-assisted low anterior resection, which confirmed a PT3N0M0 stage 2A microsatellite-stable, moderately differentiated sigmoid colon adenocarcinoma, and she opted not to receive adjuvant chemotherapy with advice from her physician.

Unfortunately, about a year later, a CT scan was performed of her chest, abdomen, and pelvis, which showed new sub-centimeter pulmonary nodules that were concerning for metastatic disease, as well as a 3-cm liver metastasis. Here’s a picture of her scans, both from the same time period, just different sections. You can see the lung metastases. They’re not super huge, but they’re present. So she underwent next-generation sequencing of her tumor with MSK-IMPACT. And here are the results. She was RAS wild type, so we didn’t detect a RAS mutation or PIK3CA mutation. HER2 amplification was seen, but it was only 1.7 times. It was below the threshold we would typically witness for a HER2-amplified tumor. However, because of this, we did work up the IHC [immunohistochemistry] and found that she had 3+ staining, which qualified her for a HER2-amplified tumor. But it’s interesting, given the comments earlier about the difference between next-generation sequencing and IHC. Sometimes you might catch people with IHC because in her case it may be that the DNA quality or the tumor purity wasn’t high enough to pick up a true amplification. There’s some subclonality to all this as well.

She started on the MOUNTAINEER-03 trial as a result of this. The MOUNTAINEER-03 trial [NCT05253651] is a phase 3 trial. It’s a randomized global open-label study. It’s for patients in the first line. HER2-directed therapy is combined with chemotherapy, standard FOLFOX [folinic acid, fluorouracil, and oxaliplatin] chemotherapy. It’s randomized vs the standard of care, which would be FOLFOX plus or minus bevacizumab or cetuximab for RAS wild-type left-sided patients.

All the patients who were in this trial were HER2 amplified, and they were all RAS wild type with good performance status. Importantly, they also included patients who had brain metastases, which is an interesting, novel aspect of the study. The primary end point was progression-free survival with several secondary end points, including overall survival and overall response rate.

Cathy Eng, MD, FACP, FASCO: Thank you so much. I’m going to leave this open for discussion by Suneel Kamath, MD; Arvind Dasari, MD, MS; and Arpana Parikh, MD. This was a young woman, 47 years old. Would your treatment approach be different in an older patient population? Maybe somebody with a borderline performance test? I think we talked about this a little earlier, but maybe reiterate your thoughts regarding that.

Aparna Parikh, MD: Yes, I think it’s exactly as we were talking about earlier. For this patient, I think that the MOUNTAINEER-03 trial is a perfect option. But in an older, frailer patient who is chemotherapy-averse or for a patient you’re nervous about giving chemotherapy to, I would feel very comfortable giving just trastuzumab and tucatinib.

But I also want to comment on one point that Dr Foote mentioned in passing, which I think is important, is the brain penetration of tucatinib, which is the unique property of tucatinib. There are some data that when you look at HER2, even in other GI [gastrointestinal] cancers, there may be a little bit more proclivity for brain metastases as well. I think it is a unique property for the drug, but it is something that we clinically see with these HER2 patients, especially ones with lung-only metastases, who have been alive and battling with their disease for some time.

Cathy Eng, MD, FACP, FASCO: Any other comments?

Suneel Kamath, MD: I completely agree. I think for a younger, fitter patient, certainly, chemotherapy plus HER2-directed therapy is the best approach. These tumors are still chemotherapy-sensitive, unlike some targets where you think you really want to go for targeted therapy. HER2-positive tumors still do respond to chemotherapy. A combination of both is ideal for a younger and fitter patient.

Another thing that I think Dr Foote mentioned that was really important is the absence of PIK3CA mutations, which I think is underdiscussed. Checking for that and being sure that they don’t have that in addition to being RAS wild type is key.

Cathy Eng, MD, FACP, FASCO: Any other comments?

Arvind Dasari, MD, MS: I completely agree. In these patients, the risk-benefit ratio is somewhat skewed. Thinking about the most effective therapy with the least amount of adverse effects is the perfect fit for this patient.

Transcript edited for clarity.

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