Targeting BRAF V600E in Malignant Phyllodes Tumor: Evidence for Precision Oncology in a Rare Breast SarcomaJonathan Chi, Kamalesh K. Sankhala, Amin Mirhadi, Mark AgulnikKey Words: oncology, genetics and genomics, pathology and laboratory medicine, radiology and imaging, surgeryKey Clinical Message: Comprehensive genomic profiling identified a BRAF V600E mutation in malignant phyllodes tumor, enabling effective use of BRAF/MEK–targeted therapy. This case supports precision oncology as a viable strategy to reduce tumor burden and extend disease control in rare breast sarcomas.AbstractTargeted therapies are an accepted standard transformative approach in oncology, offering precision-based treatment strategies that are both less toxic and highly effective in reducing or eradicating tumor burden. We present the case of a patient with a malignant phyllodes tumor who, following mastectomy, underwent comprehensive genomic profiling through Foundation One sequencing, which identified a BRAF V600E mutation. On this basis, she was enrolled in the Targeted Agent and Profiling Utilization Registry (TAPUR) trial and initiated therapy with the BRAF inhibitor vemurafenib in combination with the MEK inhibitor cobimetinib—an FDA established regimen for melanoma but rarely applied in the context of breast malignancies or sarcomas. This report represents one of the first documented cases evaluating the efficacy of vemurafenib-cobimetinib in a breast sarcoma subtype. In conjunction with definitive surgery, adjuvant radiation, and microwave ablation, this targeted regimen was associated with a favorable toxicity profile and a measurable reduction in tumor burden. Taken together, this case underscores the critical role of next-generation sequencing in uncovering actionable genomic alterations and highlights the expanding potential of precision oncology in a rare breast sarcoma subtype.IntroductionPhyllodes tumors (PT) of the breast are rare fibroepithelial neoplasms, often difficult to clinically distinguish from fibroadenomas due to overlapping histologic features. The World Health Organization (WHO) classifies PT into three categories based on histological analysis: benign, borderline, and malignant.1 The distinguishing factors separating these categorizations are subjective, defined by stromal cellularity, stromal atypia, mitosis, stromal overgrowth, and tumor margin.2 This histologic ambiguity frequently contributes to diagnostic uncertainty and adds to existing challenges in establishing reliable primary breast sarcoma diagnosis.3The mainstay of treatment for malignant PT is surgical resection, while the role of adjuvant radiotherapy remains controversial with respect to improving disease-free survival.4 Local recurrence is a central concern with surgery alone, with results varying based on resection margins. Although a negative margin of ≥1 cm is generally considered adequate for borderline and malignant PT, this is not always surgically achievable.5 Despite optimal surgery and adjuvant radiation, malignant phyllodes tumors have a risk of metastatic disease, particularly to the lungs, though the risk is lower for borderline and benign types. A significant portion of these malignant tumors (up to 27%) can metastasize.6 And given this, there is a need for effective therapies in the metastatic setting. Current chemotherapeutic approaches are suboptimal.7,8These limitations highlight the need for novel, patient-specific therapeutic strategies to optimize outcomes.The expanding characterization of the PT genomic landscape has created opportunities for targeted therapies that may be less morbid than surgery and more tolerable than conventional sarcoma directed chemotherapy.We present a case of a patient with a malignant PT harboring a BRAF V600E mutation. This mutation results in constitutive activation of the BRAF kinase within the RTK/RAF/RAS signaling cascade. Unlike wild-type RAF isoforms, BRAF V600E signals as a monomer, bypassing the requirement for dimerization, and thereby drives persistent MAPK pathway activation, enhanced tumor proliferation, and oncogenic progression.9 Defining the clinical relevance of BRAF V600E in PT may yield actionable therapeutic insights, expand treatment options beyond chemotherapy, and further inform the development of histology-agnostic precision oncology strategies.10Case History/ExaminationWe present the case of a female who presented at age 49 with a left breast mass. Of note, the patient had a past medical history relevant for poliomyelitis, diagnosed at age 1. The patient was in her usual state of health until 2016, when she experienced bleeding from her left nipple and observed an increasing nodule in her left breast.Differential Diagnosis, Investigations, and TreatmentAn initial biopsy of the left breast mass was consistent with a benign phyllodes tumor. However, due to increased tumor growth and concern for malignancy, she underwent lumpectomy in November 2017 to excise a 7 cm malignant phyllodes tumor of the left breast and a 2.2 cm malignant phyllodes tumor of the superior left breast (Figure 3). Margins from the larger tumor were involved with disease. Patient was advised to undergo a left breast mastectomy on January 23, 2018 because of a positive margin at her initial surgery (Figure 3).In March 2018, the patient noticed 2 new nodules in her left chest wall near her prior surgical site. These enlarged rapidly. Biopsy was done and pathology confirmed recurrent sarcoma of the left breast with underlying infiltrate or sarcomatous malignancy invading into the skin dermis. This diagnosis was consistent with malignant PT with extensive sarcomatoid overgrowth.In 2018, Foundation One genetic profiling revealed a BRAF mutation in the tumor (Figure 1). The patient then enrolled in TAPUR: Testing the Use of FDA Approved Drugs That Target a Specific Abnormality in a Tumor Gene in People With Advanced Stage Cancer (TAPUR) NCT02693535. In May 2018, she initiated targeted therapy with vemurafenib (960 mg orally twice daily) in combination with cobimetinib (60 mg orally once daily, administered on days 1–21 of each 28-day cycle) (Figure 3).Figure 1Foundation 1 genetic profiling for the initial Phyllodes tumorPatient received treatment with dose reduction (vemurafenib 25% dose reduction and cobimetinib 33% dose reduction) due to recurrent skin rash. She briefly discontinued treatment in September 2018 and underwent surgery for the chest wall recurrence (Figure 3). Pathology showed no evidence of residual malignancy. The patient received adjuvant radiation therapy following surgery, to the chest wall, in October 2018 (Figure 3). Following radiation in February 2019, the patient resumed her targeted therapy with vemurafenib in combination with cobimetinib, at a modified dose until June 2019 (Figure 3). After a disease free interval of 6 months, a CT scan of the chest, abdomen, and pelvis, revealed new lung metastases, confirmed on core needle biopsy to be a spindle cell tumor, consistent with metastasis from malignant Phyllodes tumor of breast (Figure 2A). She resumed vemurafenib 25% dose reduction and cobimetinib 33% dose reduction in December 2019, and underwent microwave ablation of the enlarging left upper lobe lung lesion in January 2021, showing improvement in tumor size (Figure 2B, 3)Figure 2