Question 1: Breast Cancer 

A 68-year-old woman was treated for stage III, triple-positive breast cancer with doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab (ACTH) in the adjuvant setting. She then developed symptomatic congestive heart failure (CHF) with a left ventricular ejection fraction of 30%. She now presents to your clinic with newly metastatic breast cancer to her liver. A percutaneous liver biopsy confirms metastatic triple-positive disease without a PIK3CA mutation. Her New York Heart Association (NYHA) class is II. The patient is under the care of a cardiologist and is taking a β-blocker and furosemide. Brain MRI is positive for metastatic disease. She would like to have the most aggressive treatment possible. 

1. Docetaxel, carboplatin, and trastuzumab (TCH) 
2. Ado-trastuzumab (T-DM1) 
3. Tucatinib, capecitabine, and trastuzumab 
4. Neratinib and capecitabine 

Question 2: Melanoma 

A 45-year-old man presented with a growing lesion on his right upper arm. Biopsy of the lesion revealed melanoma with a Breslow depth of 4.2 mm and ulceration. PET/CT scan and brain MRI did not show any distant metastases. He underwent a wide local excision and lymphoscintigraphy, with pathology showing complete excision of melanoma. Two sentinel lymph nodes from the right axilla were removed, both with a 1-mm deposit of melanoma. The tumor did not show a BRAF V600 mutation. His Eastern Cooperative Oncology Group (ECOG) performance status is 0. 

1. Adjuvant anti-PD1 immunotherapy 
2. Adjuvant radiation therapy 
3. Active surveillance 
4. Completion lymph node dissection (CLND) 

Question 1 Rationale and References 

Correct answer: D. Neratinib and capecitabine 

Rationale: CHF is a common adverse effect of HER2-targeted antibodies; this is sometimes reversible, but when the left ventricular ejection fracture is below 50%, the risk of exacerbating CHF with additional HER2 antibodies is unacceptable. A patient with symptomatic CHF should receive tyrosine kinase inhibitor–based therapy to best control metastatic HER2-positive breast cancer. The three tyrosine kinase inhibitors currently available for metastatic breast cancer are lapatinib, neratinib, and tucatinib. The NALA trial demonstrated a median progression-free survival of 8.8 months and an overall survival of 24 months for patients with metastatic HER2-positive breast cancer with brain metastases. The HER2climb trial also demonstrated efficacy of a tucatinib-based regimen; however, that regimen contained trastuzumab, for which this patient is not eligible based on her CHF. 

• Saura C, Oliveira M, Feng YH, et al. Neratinib plus capecitabine versus lapatinib plus capecitabine in HER2-positive metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: phase III NALA trial. J Clin Oncol. 2020;38(27):3138-49. DOI: https://doi.org/10.1200/JCO.20.00147     
• Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer [published correction appears in N Engl J Med. 2020 Feb 6;382(6):586]. N Engl J Med. 2020;382(7):597-609. DOI: https://doi.org/10.1056/NEJMoa1914609  

Question 2 Rationale and References 

• Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018;378(19):1789-801. DOI: https://doi.org/10.1056/NEJMoa1802357  
• Ascierto PA, Del Vecchio M, Mandalá M, et al. Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial [published correction appears in Lancet Oncol. 2021 Oct;22(10):e428]. Lancet Oncol. 2020;21(11):1465-1477. DOI: https://doi.org/10.1016/S1470-2045(20)30494-0