Future Directions in Treating HER2+ Breast Cancer

Joyce O'Shaughnessy, MD: There's been tremendous progress in treating HER2 [human epidermal growth factor receptor 2]-positive breast cancer. It used to be the poorest prognosis early stage breast cancer that we had because it was driving, we had no way to inhibit it, basically. The initial approval in 2005 of adjuvant trastuzumab made a sea change in the outcome of these patients. But still with disease-free survival, about 25% of patients were having recurrent disease, about 16% having distant metastasis. Again, pertuzumab has made a definite difference in the invasive disease-free survival, no question about it—the standard of care now for node-positive or T2 or greater breast cancers.

The addition of the T-DM1 [trastuzumab emtansine] is another major improvement in outcome for these patients, now getting those with residual disease, which are our highest risk patients after preoperative trastuzumab, pertuzumab, and chemotherapy, getting them up now into the high 80% chance of remaining disease free. But still we have recurrences. We still have recurrences in ER [estrogen receptor]-positive disease. They can be late recurrences. We still have brain metastasis, which is an increasing problem for patients with any type of disease burden at presentation. They have likely seeded the brain, ER-negative more than ER-positive. But there’s a spectrum of ER-positive biology, some of it is very close to ER-negative disease. These are our remaining concerns.

The neratinib data, I believe, based on the ExteNET trial in the non-cross-resistance that we see in the metastatic setting of neratinib, will further reduce that risk. Based on trials such as the NEfERT-T trial, which was metastatic disease, it reduced the risk of progression in the brain with the neratinib. It’s likely that we will see a reduction in brain metastasis with the utilization of neratinib. Neratinib in combination with T-DM1 [trastuzumab emtansine] in the metastatic setting is a safe and effective combination. An obvious question is regarding utilization of neratinib in the adjuvant setting in patients who still have residual disease who are getting T-DM1 [trastuzumab emtansine] and whether to add the neratinib there to try to decrease brain metastasis.

Another agent coming along, very similar thinking, is the tucatinib. We are awaiting FDA approval in the metastatic setting for tucatinib. It is clearly effective in the metastatic setting at preventing progression of brain metastasis, even untreated brain metastasis. This is a very exciting agent for the brain, being combined now in the metastatic setting with T-DM1 [trastuzumab emtansine], also entering the adjuvant setting in combination, T-DM1 plus or minus neratinib. Again, it’s a very exciting new avenue.

We also have newer antibody drug conjugates such as trastuzumab deruxtecan, recently approved by the FDA for the metastatic setting, going head-to-head in the metastatic setting against T-DM1 [trastuzumab emtansine]. If it is more effective than T-DM1 [trastuzumab emtansine], it too will go into an adjuvant setting in a KATHERINE-like model. So there are lots of agents. The progress is not yet over for HER2-positive breast cancer. We’re getting there, but the job is not quite done yet.

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