Patient With Lung Metastasis and HER2-Low Status: Evolving Treatment Options

Initial Presentation, Workup, and Treatment 

A 53-year-old female had a screening mammogram in early 2020 that noted a 5-cm mass in the right breast, upper outer quadrant. Diagnostic and ultrasound was BI-RADS 5, and biopsy demonstrated a poorly differentiated infiltrating ductal carcinoma (IDC), ER 2%, PR negative, and HER2/neu negative (IHC2+). Staging CT and bone scans were negative for metastatic disease. Stage was determined to be T3, N0, M0. Full-panel genetic testing was negative.  

The patient was referred for neoadjuvant chemotherapy and started doxorubicin (Adriamycin)/cyclophosphamide (AC) with minimal response. She then was treated with nab-paclitaxel and carboplatin.  

After 2 months on this regimen with no clinical signs of improvement, the patient was reevaluated by surgery and restaged. CT scan showed the breast mass to be grossly unchanged, with some decrease in the size of an axillary lymph node. She proceeded to have a large-volume lumpectomy and sentinel lymph node biopsy with oncoplastic closure. She had significant residual disease, with 3 foci of IDC and invasive carcinoma directly invading into the dermis and 4/25 lymph nodes positive for metastasis, i.e., ypT3, yN2. Per the CREATE-X trial,¹ she was initiated on capecitabine, first at a low dose given concurrently with radiation therapy, then escalated to full dose, planned to be given for 6 months. 

Recurrence 

After 4 months, the patient developed a new nodularity at the lumpectomy site. Biopsy showed recurrent IDC, triple negative. Restaging CT scans now showed multiple pulmonary nodules and probable radiation pneumonitis in the right lung.  

FoundationOne CDx testing was reviewed, showing no actionable mutations. PD-L1 was negative. Palliative care was consulted. 

The patient was enrolled on the IRENE clinical trial of retifanlimab-dlwr, an immune checkpoint inhibitor, in combination with pelareorep, an oncolytic virus.²

She progressed after 2 cycles and was then started on sacituzumab govitecan, given with pegfilgrastim. After 2 cycles, her Hgb was <7, and she developed worsening back pain and shortness of breath. She was admitted, transfused, and had therapeutic pleuracentesis. She also received a 5-day course of palliative radiation therapy to the lumbar-sacral spine. Her symptoms remitted briefly. She subsequently had a PleurX catheter placed. Her back pain persisted, so it was managed with fentanyl and oxycodone by the care team. After a family meeting with the multidisciplinary team, the patient opted for home hospice. 

Discussion Points 

If this patient presented today, she would likely receive neoadjuvant pembrolizumab with chemotherapy, even though she was PD-L1 negative, based on the results of the KEYNOTE-522 trial.³ This trial demonstrated that neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab after surgery resulted in significantly longer event-free survival than neoadjuvant chemotherapy alone in patients with early triple-negative breast cancer.⁴

This patient’s HER2/neu status would now be recognized as HER2-low, i.e., IHC 1+ or 2+, and she would be a candidate for antibody-drug conjugate therapy with fam-trastuzumab deruxtecan (TDxD) as second line in the metastatic setting, based on the results of the DESTINY-Breast04 study.⁵ Of note, interstitial lung disease (ILD)/pneumonitis is seen in up to 12% of patients, and patient selection is important. This would be a particular consideration in this case, given the patient’s significant pulmonary disease. 

Early incorporation of palliative care is critical in the management of mTNBC patients. It not only maximizes symptom management, but also equips patients and caregivers in shared decision-making regarding goals of care. 

References 

1. Masuda N, et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med. 2017;376:2147-59. doi:10.1056/NEJMoa1612645
2. George M, et al. IRENE study: Phase 2 study of INCMGA00012 and the oncolytic virus pelareorep in metastatic triple negative breast cancer. San Antonio Breast Cancer Symposium, December 9, 2021. 
3. Schmid P, et al. Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med. 2022;386:556-567. doi:10.1056/NEJMoa2112651
4. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Version 4.2023. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf
5. Modi S, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022:387:9-20. doi:1056/NEJMoa2203690