In the Molecular Tumor Board session at the 2023 SABCS^®, a multidisciplinary panel leveraged challenging, complex clinical cases to highlight how the range of expertise of a molecular tumor board (MTB) can inform and help optimize patient care and treatment in real-world practice.

The session is available on demand for registered 2023 SABCS^® participants through March 31, 2024, on the meeting platform. 

With the advent of precision medicine, MTBs comprise a multidisciplinary group of specialists and are increasingly essential to the interpretation and integration of genomic/molecular testing results into clinical decision making for patients with breast cancer (BC).

The moderator of the session, Pedram Razavi, MD, PhD, Medical Oncologist at Memorial Sloan Kettering Cancer Center, described the domains of biomarker/targeted therapy discovery and application that are inherent parts of the modern landscape of precision oncology. Precision oncology studies are needed to confirm that the target/biomarker is present in pre-treatment samples; validate engagement of and/or expected changes in the target/biomarker in the discovery phase and upon treatment with the matched targeted therapy; and, characterize molecular/genomic changes associated with treatment resistance on or after treatment. He alluded to large databases, such as OncoKB™, that are attempting to systematically curate the continuous and dense stream of genomic/molecular alteration data.

Dr. Razavi said it is no longer fair to ask oncologists to interpret the results from genomic/molecular analyses, for many reasons. Complex interplay between alterations within and across genomic pathways in cancer make it difficult to interpret the clinical significance of specific/individual alterations. Moreover, genomic/molecular alterations vary by cancer type and tumor subtypes. Extensive spatial and temporal heterogeneity in genomic/molecular alterations in breast tumors also compounds the complexity. And, although clinical practice guidelines provide guidance on genomic/molecular testing, the amount and complexity of information can cause a disconnect between guidelines and the ability of clinicians to interpret results and apply precision oncology approaches optimally.

“There is an expanding knowledge gap with wide use of clinical genomics,” he said.

In this context, MTBs are vital, Dr. Razavi noted. MTBs can facilitate interpretation of copy number variations (CNVs), allele-specific copy number changes, and mutational signatures. MTBs can also assist with clonality inferencing and identification of tumor type and relatedness.

The medical oncology contingent of the panel were Giuseppe Curigliano, MD, PhD, Head of Division and Full Professor at the European Institute of Oncology and University of Milano; Joyce O’Shaughnessy, MD, Chair of the Breast Disease Committee at Baylor University Medical Center/SCRI /Texas Oncology; Nicholas Turner, MD, PhD, Professor at Royal Marsden Hospital, Institute of Cancer Research, London; and Nancy Lin, MD, Associate Professor at Dana-Farber Cancer Institute and Harvard Medical School.

Sarah Eskreis-Winkler, MD, PhD, Assistant Professor of Radiology at Memorial Sloan Kettering Cancer Center; and Gaorav Gupta, MD, PhD, Assistant Professor of Radiation Oncology at University of North Carolina at Chapel Hill, provided insights on radiological imaging studies for each of the cases. Surgical and molecular pathology analyses were reviewed by Maryam Shirazi, MD, Medical Director at Tempus Labs, Inc.

The discussion of the first clinical case—of an elderly woman with multiple comorbidities, diagnosed initially with HR-positive, HER2-negative breast cancer (BC) and subsequently, with TNBC—centered on subtype differences between the primary and subsequent tumors. The subtype change and extensive comorbidities support additional genomic analyses, which can provide critical information on actionable alterations amenable to therapy with less toxic, targeted treatments for this patient. Based on genomic/molecular analyses, the two tumors were deemed genomically unrelated; the second tumor was a new primary tumor. The presence of microsatellite instability-high (MSI-H), high tumor mutational burden (TMB-H; a feature less common in BCs, which tend to have intermediate TMB), and programmed death ligand 1 (PD-L1) expression indicated “perfect molecular candidacy” for immunotherapy with pembrolizumab, Dr. Curigliano noted.

The next discussion focused on a patient with HR-positive HER2-negative metastatic BC, who had rapid progression despite treatment with CDK4/6 inhibitors. The panel reviewed how identification of deep deletions in BRCA2 could explain the lack of response/resistance. Dr. Turner explained that, as BRCA2 and Rb loci are closely located, Rb1 loss is more likely with deep deletions in BRCA2. The patient also had BRAF V600E, an “incredibly rare” mutation in primary breast tumors, Dr. Turner said, “although they can be selected for and are more common in secondary than primary tumors.”

In the third case, immunoprofiling and genomic analyses enabled accurate tumor typing in a patient with a history of early-stage BC recently diagnosed with metastatic high-grade neuroendocrine carcinoma (NEC) of pancreatic origin. A mixed response was seen with chemotherapy, with response in the liver, pancreatic, and abdominal lymph nodes, but increased axillary adenopathy. Subsequent pathologic review and genomic analyses of the axillary mass showed this mass to be consistent with adenocarcinoma of breast origin, not NEC. Dr. Shirazi noted that primary NEC of breast is uncommon, and this case was an example of “histological transformation of one type of tumor into a more aggressive type.”

In the final case, the patient had HR-positive/HER2-negative PIK3CA-mutated metastatic BC with rapid progression (less than 3 months) on PIK3C inhibitor (PIK3Ci)-fulvestrant treatment. Targeted next-generation sequencing of circulating tumor DNA (ctDNA), i.e., liquid biopsy, identified the PIK3CAmutation in the pretreatment sample. Subsequent tissue-based testing identified PTEN loss as a likely mechanism for PIK3Ci. ESR1 p.F404V and an ESR1 fusion were also detected via tissue-based testing. The panel agreed that it is important to test tissue in addition to ctDNA, especially when tumor fraction is low or there is discordance between expected and actual responses with biomarker-guided targeted treatments. Moreover, certain alterations, including TMB status and gene fusions, may not be captured reliably using liquid biopsy alone.

Ultimately, the panel emphasized that genomic/molecular analyses are vital tools for optimizing tumor typing, uncovering resistance mechanisms, and selecting and refining treatments. MTBs are critical for delivering on the promise of precision oncology in breast cancer clinical practice.