Testing for HER2 Expression in Breast Cancer Patients

Joyce O'Shaughnessy, MD: HER2 [human epidermal growth factor receptor 2] testing remains complex and sometimes challenging, but it’s among the most critical tests that we order as oncologists. We don’t actually want to be giving HER2-based therapy to breast cancers that are not really HER2 driven. Because of the law of unintended consequences, it may not be benign at all with regard to development of resistance mechanisms, and so forth. We only want to be giving HER2-targeted therapy to breast cancers that are actually HER2-positive. If a breast cancer is 3+ score on IHC [immunohistochemistry], and the ASCO [American Society of Clinical Oncology]/CAP [College of American Pathologists] guidelines recommend we start with IHC testing, we’ve got a definitive answer, and we can stop.

If it comes back 2+, and one could argue even 1+ or zero because there are false negatives on the IHC, I always get a HER2 FISH [fluorescence in situ hybridization] in the curative setting. If the FISH comes back definitively positive with more than 6HER2gene copies per cell, a ratio above 2, we’re set. But oftentimes, there will be some equivocation between the HER2 FISH and the IHC. It’s very important to send that to an outside reference laboratory. I always utilize Michael Press, MD, PhD, at Keck School of Medicine of USC [University of Southern California]. He has a very large service laboratory. You can find that online, fill out the forms, and I do send him testing requests about once a week. It’s very important to get this right. By and large, it’s only about maybe 5%, 8% of patients where you’re in the equivocal range where you don’t have a definitive based on IHC or FISH. Again, just send it to the experts, and get the right answer.

When a woman presents with HER2-positive breast cancer that’s either T2, so more than 2 cm, or any clinically positive lymph nodes, and that would be either by physical examination, breast imaging, PET [positron emission tomography]/CT [computed tomography] scan. Even if it’s not biopsy-proven but it’s deemed to be a clinically positive node, the standard of care is for her to receive preoperative therapy. That is mainly because we need to know if she develops a pathologic complete response or not. This is because our adjuvant therapies are different based on whether she completely clears the cancer out of her breast and axilla or whether she still has residual disease. We treat very differently, so we must know that. That’s why preoperative therapy is so important.

We essentially have 2 options. One is to start with an anthracycline-based regimen, a doxorubicin and cyclophosphamide—AC—followed by taxane, trastuzumab, and pertuzumab. The other option, what I usually use, is the docetaxel, carboplatin, trastuzumab, and pertuzumab, the TCHP regimen, because I think the pathologic complete response rates are identical with those 2 approaches. The TCHP [docetaxel, carboplatin, trastuzumab, pertuzumab] has less cardiac risk. That’s essential to utilize 1 of those 2, and the key there is that pertuzumab is indicated for patients who have T2 disease or any lymph nodes positive. We definitely want to add that on to the chemotherapy and trastuzumab.

This patient received that and then at definitive surgery, we’re looking for pathologic complete response. That means no invasive cancer in the breast and lymph nodes. If there’s DCIS [ductal carcinoma in situ] still left in the breast, that’s fine, that’s still a pathologic complete response. But if there’s any amount of residual disease, even at the millimetric level in the breast or the lymph nodes, then that woman would have been eligible for the KATHERINE trial, where patients with residual disease were randomized to finish up their trastuzumab. There were 20% of patients who had preoperative pertuzumab, but 80% had not had pertuzumab because it was just transitioning into the standard of care.

Randomized to finish up the trastuzumab or to get the T-DM1 [trastuzumab emtansine], the trastuzumab covalently attached to a very powerful microtubule inhibitor cytotoxic agent called maytansine, T-DM1. In that trial, there was an 11% absolute improvement in the invasive disease-free survival, very large, with switching over to trastuzumab, which is basically the antibody on the control arm hooked up to this very powerful cytotoxic agent. That immediately became the standard of care for patients. So that’s the adjuvant setting.

Now, if she had had a pathologic complete response, the standard of care was to finish up the year of trastuzumab and pertuzumab per the APHINITY trial, all FDA labeled NCCN [National Comprehensive Cancer Network] guidelines. So if she has a pathologic CR [complete response], then finish up trastuzumab and pertuzumab. You can give the radiation therapy to breast and regional lymph nodes, along with either the trastuzumab, pertuzumab or with the T-DM1 [trastuzumab emtansine], very safe, and then start your endocrine therapy for patients whose breast cancers are ER [estrogen receptor]-positive. So this patient was really treated right along the FDA approved NCCN guidelines standard of care.

Transcript edited for clarity.

Case: A 54-Year-Old Woman With Stage 2HER2+ Breast Cancer

Initial presentation

• A 54-year-old, postmenopausal woman presented with a painless palpable mass on the right upper outer quadrant of her right breast
• PMH/SH: unremarkable, no family history of cancer
• PE: ~ 4-cm palpable right breast mass, clinically node negative, no visible sink involvement

Clinical workup

• Labs: WNL
• Ultrasound showed a right breast mass, and two axillary lymph nodes
• Mammogram confirmed a right—sided, poorly defined speculated 4.2-cm mass
• PET/CT showed increased uptake in the right breast diffusely, with 2 FDG—avid axillary lymph node involvement; no evidence of distant metastases
• Ultrasound—guided FNA biopsy of the breast mass confirmed grade 3 infiltrative ductal carcinoma
  • Hormone receptor/HER2 Status:HER2+:3+ by IHC,80%ER+, PR-
• Stage T2N1M0; ECOG PS 0

Treatment and Follow-Up

• The patient was started on preoperative docetaxel + carboplatin + trastuzumab + pertuzumab (TCHP), and pegfilgrastim every 3 weeks for 6 cycles;
  • Achieved clinical complete response
• She underwent right mastectomy; residual disease: 1 positive axillary lymph node, and 1-cm RD in the right breast; 4 sentinel lymph nodes removed, 1 positive for disease; she also received post mastectomy radiation therapy of her chest wall and regional lymphatics
• She was started on trastuzumab emtansine every 3 weeks for 14 cycles + aromatase inhibitor PMRT + letrozole planned for 10 years
• Extended adjuvant neratinib was initiated
  • Week 1: 160 mg (4 tablets) PO qDay; week 2: 200 mg (5 tablets) PO qDay; week 3: 240 mg (6 tablets) PO qDay for 1 year
  • IV zoledronic acid every 6 months was added to her regimen for 3-5 years