HJNO Sep/Oct 2022

HEALTHCARE JOURNAL OF NEW ORLEANS I  SEP / OCT 2022 53 Sukesh Manthri, MD Medical Oncologist Terrebonne General | Mary Bird Perkins Cancer Center new target for antibody-drug conjugates (ADCs). Low HER2 expression occurs in both hormone receptor (HR) positive and HR-negative disease. Low HER2 expres- sion appears more frequently in hormone receptor-positive/HER2-negative tumors than in triple-negative tumors. Approximately 60% of HER2-negative metastatic breast cancers express low levels of HER2, yet these have always been de- fined and treated as HER2-negative breast cancers. Currently, chemotherapy remains the only treatment option for metastatic breast cancer patients with HR-positive tu- mors following progression on endocrine (hormone) therapy. Few targeted options are available for metastatic breast cancer patients for those who are HR-negative. Targeting the lower range of expression in the HER2 spectrum may offer another ap- proach to delay disease progression and extend survival in patients with metastatic breast cancer. In the NSABP-B47 trial, we found that adding trastuzumab to standard adjuvant chemotherapy did not improve invasive disease-free survival (IDFS) in patients with early-stage breast cancer and lowHER2 lev- els. Trastuzumab does not benefit women without IHC 3+ or ISH-amplified breast cancer and, therefore, should not be added to treatment regimens for women with low HER2 expression. The novel agents being tested for the treatment of HER2-low BC patients are categorized as ADCs, deploying anti-HER2 epitopes in their monoclonal antibody com- ponent, though with different cytotoxic war- heads than trastuzumab emtansine, and a combination of trastuzumab plus deruxte- can as an ADC is a breakthrough for this new subset of patients. In April 2022, the FDA granted Breakthrough Therapy Des- ignation for T-DXd in HER2-lowmetastatic breast cancer. T-DXd is also being studied in multiple other HER2-targetable cancers, in- cluding gastric, lung, and colorectal cancers. Three decades after the characterization of the oncogenic human epidermal growth factor receptor 2 protein, anti-HER2 thera- pies have just started to advance in the field of HER2-low BC treatment. These clinical trial results for novel agents are building the foundation for the exciting new field of HER2-low BC treatment. n REFERENCES 1 Tarantino, P.; Hamilton, E.; Tolaney, S.M.; et al. “HER2-Low Breast Cancer: Pathological and Clini- cal Landscape.” Journal of Clinical Oncology 38, no. 17 (June 10, 2020): 1951-1962. doi: 10.1200/ JCO.19.02488 2 Eiger, D.; Agostinetto, E.; Saúde-Conde, R.; de Azambuja, E. “The Exciting New Field of HER2- Low Breast Cancer Treatment.” Cancers (Basel) 13, no. 5 (March 1, 2021): 1015. doi: 10.3390/can- cers13051015 3 Modi, S.; Jacot, W.; Yamashita, T.; Sohn J, et al. “Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer.” New Eng- land Journal of Medicne 387, no. 1 (July 7, 2022): 9-20. doi: 10.1056/NEJMoa2203690 Sukesh Manthri, MD, is a medical oncologist at Ter- rebonne General | Mary Bird Perkins Cancer Center, in Houma. He received a medical degree from the Prathima Institute of Medical Sciences in India. He completed a clinical research fellowship in Cleveland Clinic Florida followed by an internal medicine resi- dency at Southern Illinois University in Springfield. Subsequently, he completed a hospice and pallia- tive medicine fellowship at Saint Louis University in Missouri and was a medical oncology fellow at East Tennessee State University in Johnson City. In 2020, he received the Dr. Thomas G. Ronald Award for Ex- cellence in the Care of the Cancer Patient.He is board certified in oncology, internal medicine,hospice,and palliative medicine. bi-specific antibody targeting HER2 and HER3. DESTINY-Breast04 is a global, random- ized, open-label, registrational Phase III trial evaluating the efficacy and safety of Enhertu (trastuzumab deruxtecan or T-DXd) (5.4mg/ kg) versus physician’s choice of chemother- apy (capecitabine, eribulin, gemcitabine, pa- clitaxel, or nab-paclitaxel) in patients with HR-positive (n=480) or HR-negative (n=60) HER2-low unresectable and/or metastatic breast cancer previously treated with one or two prior lines of chemotherapy. Patients were randomized 2:1 to receive either En- hertu or chemotherapy. In the hormone receptor–positive cohort, the median pro- gression-free survival was 10.1 months in the trastuzumab deruxtecan group and 5.4 months in the physician’s choice group (haz- ard ratio for disease progression or death, 0.51; P<0.001). Overall survival was 23.9 months and 17.5 months, respectively (haz- ard ratio for death, 0.64; P=0.003). Among all patients, the median progression-free survival was 9.9 months in the trastuzum- ab deruxtecan group and 5.1 months in the physician’s choice group (hazard ratio for disease progression or death, 0.50; P<0.001), and overall survival was 23.4 months and 16.8 months, respectively (hazard ratio for death, 0.64; P=0.001). DESTINY-Breast04, in which trastuzumab deruxtecan showed a clinically meaningful survival benefit in patients with HER2-low metastatic breast cancer, is the first trial to demonstrate that selecting patients for treat- ment based on low expression of HER2 has the potential to change the diagnostic and treatment paradigms for these patients. The