Titles and Affiliations
Molecular Geneticist
Director of the Gynecology DMT Research Laboratory
Pathology and Laboratory Medicine
Research area
Understanding the genetic drivers of rare forms of breast cancer to improve the accuracy of diagnosis and to develop novel treatment approaches.
Impact
The molecular make-up and clinical behavior of rare subtypes of breast cancer are often distinct from those of more common subtypes. Little is known about rare “special types” of breast cancer which account for up to 25 percent of all invasive breast cancers. Dr. Weigelt’s research focuses on defining the genetic drivers that promote the growth of these rare cancers. In the current study, her team is investigating the basis for the aggressiveness and poor response to chemotherapy of a rare type of breast cancer called metaplastic breast cancer. She and her colleagues use cutting-edge technologies to characterize the cellular composition of the immune tumor microenvironment to understand how it may mediate treatment response in metaplastic breast cancers. The results of these studies have the potential to identify new molecular targets to tailor the treatment for these patients.
Progress Thus Far
Dr. Weigelt and her team have previously shown that metaplastic breast cancers (MpBCs), a rare type of triple-negative breast cancer, have unique defects in the way the cancer cells repair their DNA which may be associated with its aggressiveness and resistance to PARP inhibitor therapies. Using a novel whole-genome sequencing technology, they found that the majority of MpBCs harbor large chromosomal alterations, often affecting genes involved in DNA repair and cancer development. In other studies, Dr. Weigelt’s team investigated the molecular mechanisms driving invasive lobular carcinoma (ILC), a special histologic type often characterized by mutations in the CDH1 gene which controls cell adhesion and tissue architecture. They identified novel CDH1 inactivating mechanisms in breast cancer and found nearly half of tumors with these novel CDH1 changes had mutations in genes involved in DNA repair.
What’s next
In the next year, Dr. Weigelt’s team plans to define the genetic and immune features associated with response to immune checkpoint blockade (ICB) in patients with MpBCs. Genetic data, metaplastic histologic subtype, and immunophenotypic data will be integrated to identify predictors or ICB response. Building on their recent findings on CDH1 in ILCs, they will also focus on the comprehensive genomic characterization of a morphologic variant of ILC. This variant has been associated with worse outcomes and exhibits higher levels of chromosomal instability than classic ILCs. Using several cutting-edge technologies, they hope to define their structural arrangement, identify potential oncogene amplifications, and examine the intratumor heterogeneity of this form of ILC. Together, these analyses may uncover novel drivers of MpBCs and ILC and help to optimize the treatment for these patients.
Biography
Britta Weigelt, PhD, is a Molecular Geneticist and the Director of the Gynecology DMT Research Laboratory at Memorial Sloan Kettering Cancer Center in New York, USA. She received her PhD from the Netherlands Cancer Institute/ University of Amsterdam, The Netherlands, and undertook her postdoctoral training at Lawrence Berkeley National Laboratory, Berkeley, USA, and Cancer Research UK London Research Institute, London, UK.
Dr. Weigelt has a long-standing research interest in the refinement of the classification of breast cancers and the identification of novel drivers and potential therapeutic targets by bringing together traditional pathology tissue-based techniques with genomics, bioinformatics, functional genomics, and signal transduction studies. She was part of a team that identified and functionally validated pathognomonic somatic genetic alterations in special histologic types of breast cancers and other rare cancer types, which can be employed for their detection and classification, including PRKD1 E710D somatic mutations underpinning polymorphous adenocarcinoma, IDH2 hotspot mutations or TET2 inactivating mutations in conjunction with PI3K pathway gene alterations in tall cell carcinomas with reversed polarity of the breast, and the co-occurrence of HRAS Q61 hotspot mutations with PIK3CA or PIK3R1 somatic mutations in adenomyoepitheliomas of the breast.
Dr. Weigelt has published her findings in over 280 peer-reviewed articles and is an author of chapters of the World Health Organization Classification book series, including the one on Breast Tumors. She is also on the Editorial Board of the Journal of the National Cancer Institute, The Journal of Pathology, Modern Pathology, and the European Journal of Cancer.
