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Assistant Professor of Medicine
Harvard Medical School
Attending Physician, Medical Oncology (Breast Program)
Massachusetts General Hospital
Laura M. Spring, MD: consultant/advisor/speaker: Novartis, Puma; researcher: Genentech, Merck, Phillips.
In this commentary, I describe the case of a patient with metastatic triple-negative breast cancer (TNBC) and my approach and rationale for her care.
Patient’s Case Presentation and Initial Diagnostic Workup
A 44-year-old woman presents to her physician with a palpable right breast mass. On examination, she is found to have a 4 cm mass in the lower outer quadrant of the right breast as well as enlarged right axillary lymph nodes. Diagnostic imaging confirmed the examination findings and immunohistochemistry (IHC) tests showed that the tumor is estrogen receptor (ER)–negative, progesterone receptor–negative, and HER2-negative (IHC 0). Biopsies of the right breast mass and right axilla revealed grade 3 TNBC, and germline panel genetic testing including BRCA was negative.
Treatments Received and Treatment Outcomes
After a discussion with the patient and her husband, the patient received the KEYNOTE-522 regimen of neoadjuvant therapy with 4 cycles of pembrolizumab plus paclitaxel and carboplatin followed by 4 cycles of pembrolizumab plus doxorubicin and cyclophosphamide, and she achieved a clinical partial response. She then underwent right breast partial mastectomy and axillary lymph node dissection. Unfortunately, the pathology revealed a residual 1.4 cm tumor in the breast, and 2 out of 18 lymph nodes were positive for metastatic disease. Of note, this patient is at high risk of disease recurrence given the finding of significant residual disease after neoadjuvant therapy for TNBC. Also of importance is the well-established fact that on an individual patient level, achieving a pathologic complete response following neoadjuvant therapy for TNBC is associated with significantly improved long-term outcomes compared with the presence of residual disease. This patient received 9 cycles of pembrolizumab in the adjuvant setting, as well as comprehensive radiotherapy followed by 6 months of capecitabine. In the adjuvant setting, this patient received concurrent pembrolizumab (during radiation and then afterward), with capecitabine initiated after radiation therapy.
Based on the results of the CREATE-X trial, it is known that adjuvant capecitabine for patients with TNBC and residual disease following neoadjuvant chemotherapy prolongs disease-free survival and overall survival among patients with a high risk of recurrence. However, this patient experienced disease recurrence only 2 months after completing adjuvant capecitabine, when she developed right upper quadrant pain. At this time point, laboratory tests demonstrated a transaminitis, and imaging revealed multiple hepatic metastases. A liver biopsy confirmed recurrent TNBC, which was PD-L1 negative. PD-L1 testing of the initial core biopsy was also negative (CPS 0).
Thereafter, the patient received first-line treatment with carboplatin and gemcitabine for metastatic disease, and subsequent imaging demonstrated a partial response. After 9 months of receiving treatment, she developed a cough and imaging showed new lung metastases. At this time, her treatment was switched to sacituzumab govitecan, which is an appropriate second-line treatment choice in the metastatic setting because the recurrence occurred within 12 months of neoadjuvant/adjuvant systemic therapy. The patient received sacituzumab govitecan at the recommended dose of 10 mg/kg once weekly on Days 1 and 8 of 21-day treatment cycles, with plans to continue until disease progression or unacceptable toxicity. While receiving treatment, she developed grade 3 neutropenia, first noted on Day 8 of cycle 4, which was managed with the administration of granulocyte-colony stimulating factor (G-CSF). She also experienced mild fatigue, nausea, and diarrhea. As needed, antiemetics and antidiarrheal medication were used with success. Subsequent restaging scans revealed a partial response, and the patient has continued on treatment with sacituzumab govitecan. She has been receiving treatment for 10 months, and the latest imaging demonstrated a continued partial response.
Role of Sacituzumab Govitecan in TNBC and Conclusions
Sacituzumab govitecan is a first-in-class, Trop-2–directed antibody and topoisomerase inhibitor conjugate. Trop-2 is a cell surface antigen that is overexpressed in approximately 90% of breast cancers. Based on the results of the multicenter, open-label, randomized phase III ASCENT trial, sacituzumab govitecan was granted regular approval for the treatment of patients with unresectable locally advanced or metastatic TNBC after receiving ≥2 systemic therapies, with ≥1 used for metastatic disease (NCT02574455).
On the ASCENT trial, 468 patients with relapsed or refractory advanced TNBC, but without brain metastasis, were randomly assigned to receive either sacituzumab govitecan or single-agent chemotherapy, with a physician’s choice of eribulin, vinorelbine, capecitabine, or gemcitabine. The primary endpoint of progression-free survival was significantly prolonged with sacituzumab govitecan at 5.6 months vs 1.7 months among those who received single-agent chemotherapy (HR: 0.41; 95% CI: 0.32-0.52; P <.001). The median overall survival was 12.1 months with sacituzumab govitecan vs 6.7 months with single-agent chemotherapy (HR: 0.48; 95% CI: 0.38-0.59; P <.001). The most common adverse events associated with sacituzumab govitecan include nausea, diarrhea, fatigue, neutropenia, alopecia, anemia, vomiting, constipation, decreased appetite, rash, and abdominal pain. Early recognition, evaluation, and treatment of diarrhea are important. G-CSF may be used to reduce the incidence of febrile neutropenia.
The growing antibody–drug conjugate field has revolutionized the treatment of breast cancer, and overall, the approval of sacituzumab govitecan represents a major advancement in the management of patients with unresectable, metastatic TNBC. Of importance, ongoing and future studies are exploring the role of sacituzumab govitecan in multiple breast cancer settings, including ER-positive disease (TROPiCS-02) and localized TNBC (NeoSTAR).
Upcoming Live Conversational Webinar on the Management of TNBC
To hear more information on optimizing the treatment of patients with TNBC, sign up here to attend a live conversational webinar with my colleagues Mark D. Pegram, MD, and Sara M. Tolaney, MD, MPH, on Tuesday, November 22, 2022, at 3 PM Eastern time.
What challenges do you experience in your practice when it comes to managing patients with metastatic TNBC? Have you incorporated sacituzumab govitecan into your practice? Answer the polling question and join the conversation in the discussion box below.