Molecular Insights in Patient Care © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 13 Number 9 | September 2015 1066 Prolonged Response to Trastuzumab in a Patient With HER2-Nonamplified Breast Cancer With Elevated HER2 Dimerization Harboring an ERBB2 S310F Mutation Saranya Chumsri, MD a ; Jodi Weidler, PharmD b,* ; Siraj Ali, MD, PhD c ; Sohail Balasubramanian, MS c ; Gerald Wallweber, PhD b ; Lisa DeFazio-Eli, PhD b,† ; Ahmed Chenna, PhD b ; Weidong Huang, MD b ; Angela DeRidder, MD d ; Lindsay Goicocheal, MD d ; and Edith A. Perez, MD a Abstract In the current genomic era, increasing evidence demonstrates that approximately 2% of HER2-negative breast cancers, by current standard testings, harbor activating mutations of ERBB2. However, whether patients with HER2-negative breast cancer with activating mutations of ERBB2 also experience response to anti-HER2 therapies remains unclear. This case report describes a patient with HER2-nonamplified heavily pretreated breast cancer who experienced prolonged response to trastuzumab in combination with pertuzumab and fulvestrant. Further molecular analysis demonstrated that her tumors had an elevated HER2 dimerization that corresponded to ERBB2 S310F mutation. Located in the extracellular domain of the HER2 protein, this mutation was reported to promote noncovalent dimerization that results in the activation of the downstream signaling pathways. This case highlights the fact that HER2-targeted therapy may be valuable in patients harboring an ERBB2 S310F mutation. (J Natl Compr Canc Netw 2015;13:1066–1070) Case Report A 51-year-old Caucasian female initially presented to an outside hospital with stage IIIA (pT3pN2aM0) in- vasive ductal carcinoma of the breast approximately 7 years before her presentation to our institute. The pri- mary tumor was initially positive for estrogen (ER) and progesterone receptor (PR), but HER2-negative (1+) by immunohistochemistry (IHC). At that time, she From a Mayo Clinic, Jacksonville, Florida; b Monogram Biosciences/ LabCorp, South San Francisco, California; c Foundation Medicine, Cambridge, Massachusetts; and d University of Maryland Greenebaum Cancer Center, Baltimore, Maryland. * Current affiliation: Cepheid, Oncology Research and Development, Sunnyvale, California. † Current affiliation: N-of-One, Inc., Lexington, Massachusetts. Submitted December 18, 2014; accepted for publication May 11, 2015. Drs. Chumsri, DeFazio-Eli, DeRidder, Goicocheal, and Perez have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors. Drs. Ali and Balasubramanian are employed by Foundation Medicine. Dr. Weidler is a stockholder of LabCorp and Cepheid, and is an employee of Cepheid. Dr. Wallweber is an employee of Monogram Biosciences. Dr. Chenna is an employee of LabCorp. Dr. Huang is an employee of Monogram Biosciences/LabCorp. Correspondence: Saranya Chumsri, MD, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL 32224. E-mail: chumsri.saranya@mayo.edu underwent left lumpectomy with sentinel lymph node biopsy, which revealed a 5-cm moderately differentiated grade 2 infiltrating ductal carcino- ma, and both of the sentinel lymph nodes (2 of 2) were positive for metastatic ductal carcinoma. She subsequently underwent axillary lymph dis- section, which showed 2 additional involved axil- lary lymph nodes out of 22 lymph nodes. Thus, a total of 4 of 24 axillary lymph nodes were in- volved by metastatic ductal carcinoma. She received adjuvant chemotherapy with dose-dense AC (doxorubicin and cyclophos- phamide) followed by 1 cycle of paclitaxel, but developed an allergic reaction. The patient subsequently received 3 additional cycles of docetaxel. After adjuvant chemotherapy, she also completed adjuvant radiation and was on adjuvant tamoxifen for 3 years until she was found to have extensive liver metastases. At that time, she underwent an ultrasound-guided liver biopsy, which showed metastatic carcinoma consistent with breast primary. However, im- munohistochemical staining of the liver biopsy showed no expression of ER (0%) or PR (0%) and no overexpression of HER2.