Titles and Affiliations
Professor of Breast Oncology
Head of Division of Breast Cancer Research
Director of Breast Cancer Now Research Centre
Professor of Clinical Oncology and Director of Breast Cancer Now Research Unit,
School of Cancer Studies and Pharmaceutical Sciences, King’s College London
Consultant Clinical Oncologist at Guy’s Hospital and Royal Marsden Breast Units
Member, BCRF Scientific Advisory Board
Research area
Seeking to understand the factors associated with PARP inhibitor and platinum chemotherapy sensitivity and resistance in patients with breast cancer in order to improve outcomes.
Impact
In normal cells, DNA damage is recognized and repaired to ensure the genomic integrity of the cell. However, in breast cancer cells with inherited mutations in genes such as BRCA1 or BRCA2, the ability to repair damaged DNA is impaired. This vulnerability in cancer cells has been exploited with treatments, such as PARP inhibitors which block alternative DNA repair processes that these tumor cells depend on. Although these drugs are effective, tumor cells can further mutate to restore BRCA function and overcome the lethal effect of the therapy. Dr. Tutt and his team are studying this phenomenon and hope to define steps that can block it, reduce PARP inhibitor and platinum resistance, and design new ways to treat these drug-resistant breast cancers. They hope to find wider groups of patients who might benefit from these therapy approaches.
Progress Thus Far
In laboratory studies, the team has found that the restored BRCA gene produces an abnormal protein that is detectable by the immune system, notably the immune system can recognize the protein in blood samples. Dr. Tutt and his team observed an immune response against tumors with specific gene faults in BRCA1 or BRCA2 genes. However, the response was not enough for tumor cell killing or tumor control. Studies are ongoing to understand how to harness this to help the immune system fight the resistant tumor. Lastly, Dr. Tutt and others have found that in addition to inherited mutations in BRCA genes, loss of function can also occur through a process called methylation, particularly in triple-negative breast cancers. They have shown that BRCA1 methylation is detectable after neoadjuvant chemotherapy and surgery, suggesting that the methylation remaining after treatment is enough to silence BRCA1 and cause the corresponding DNA repair defect.
What’s Next
Dr. Tutt and his colleagues are continuing to search for evidence of an anti-tumor response in patient blood and tumor samples, specifically to identify the immune cells that could potentially kill the mutated tumor cells. Using blood samples from patients whose tumors are PARP inhibitor resistant the team will also continue to develop methods for studying circulating tumor cells (CTCs), determining if the mutations causing drug resistance can be detected in CTCs. Ongoing studies will include designing a trial to test PARP inhibitors in tumors that have silenced BRCA1 through methylation and developing a methylation test that can be done using a blood sample. This would allow patients with BRCA1 methylated tumors to be more closely monitored after chemotherapy and surgery so that patients who may benefit from PARP inhibitor therapy can be identified.
Biography
Andrew Tutt, MB, ChB, PhD, FMedSci is a Consultant Clinical Oncologist, Clinical Trialist, Laboratory Team Leader and Director of the breast cancer research teams at The Institute of Cancer Research in London, United Kingdom. He leads a team focused on understanding the fundamental biology and etiology of breast cancer molecular subtypes to inform the discovery and development of new therapeutics and biomarkers.
Dr. Tutt has made seminal contributions to the development of new therapies targeting aberrant DNA damage responses in breast and ovarian cancers. His clinical experience and expertise in basic cancer biology has driven the rapid translation of fundamental discoveries that have resulted in the development and licensing of new drugs and changed guidelines on genetic testing in oncology clinics. He has published a myriad of papers in prestigious journals such as Nature, The New England Journal of Medicine, The Lancet, Nature Medicine, Journal of Clinical Oncology, Annals of Oncology, Cancer Research, Science Translational Medicine and Cancer Discovery. In recognition of his many achievements, Dr. Tutt has been awarded the Fellowship of the Academy of Medical Sciences, the Fellowship of the European Academy of Cancer Sciences, the 2021 ESMO Breast Cancer Award, and the 2022 AACR Team Science Award and most recently the Robert Sutherland Award for Excellence in Translational Research.
“If not for BCRF, I would not be as effective in connecting my research work in familial and triple-negative breast cancer to the wider network of clinical trialists, therapy and biomarker developers.”
