Realizing the power of cancer genetics

The story of this thesis starts with a little girl of 3 years old. Her mother was diagnosed with breast cancer and a lot of questions arose.
At that time, the science in terms of cancer treatment and the understanding of the underlying etiology was not yet that advanced. Therefore, a lot of questions remained unanswered. As a teenager she faced breast cancer in her mother for a second time and became aware of the severity and the impact of this disease on patient and family. Due to this experience, she was convinced to dedicate her professional career to cancer. As a medical student she approached Prof. Dr. Jacques De Grève, head of the oncology department at that time, with regard to a subject for her master thesis. At that point in time, her professional journey in oncology started. Her personal history and the fact that breast cancer is the most prevalent cancer in women led to a first small research project.
First project: Breast cancer
The objective of the first project was to explore characteristics unique to families exhibiting a high incidence of breast cancer and where genetic testing in the clinic yields negative results (1).
Breast cancer is a disease that occurs in about 12% of women in Western industrialized countries. In a quarter of them, a familial aggregation is present. The two well-known, high-risk breast cancer predisposing genes are BRCA1 and BRCA2, but they only account for 20% of the breast cancer families. In most families the underlying genetic factor is unknown. This underlines the importance of the ongoing search for other genetic factors that predispose to breast cancer.
In the first part of the PhD thesis, she combed through the available patient files at the familial cancer clinic of UZ Brussel. She hoped to identify phenotypic characteristics of breast cancers in which a genetic origin was suspected but not detected at the time. She and her colleagues concluded that there were no specific histological features present in the non-BRCA1/2 familial breast cancer cases. On the other hand, anticipation (= symptoms of a dominant inherited disorder appear at an earlier age with each generation), was seen in several of the non-BRCA1/2 families.
In a separate research effort of her group , truncating mutations in possible cancer predisposing genes were more often found in families with anticipation than in families without anticipation (2).
Project 2: Pancreatic cancer
After several years of experience as a medical oncologist in the clinic, her attention was drawn to pancreatic cancer. Despite a lot of research, hardly anything has changed in terms of the treatment of pancreatic cancer. This makes prevention and early identification of individuals at increased risk of developing pancreatic cancer all the more important.
Pancreatic cancer is a condition whose incidence is rising. Symptoms of pancreatic cancer often present late, despite today’s various diagnostic methods, usually resulting in a diagnosis of cancer in an advanced stage, i.e. locally advanced or metastatic disease. The current 5-year survival rate is a small 7%. Because of these disappointing figures, prevention or early detection would be very welcome. Therefore, identifying individuals at risk for pancreatic cancer is highly warranted because the implementation of adapted surveillance programs will increase the probability of early detection.
Ten percent of pancreatic cancers occur in a familial context. Pathogenic variants in cancer predisposition genes can be identified in three percent of the patients with a familial history of cancer. However, genetic testing is hampered by the poor outcome of patients with pancreatic cancers. Because only 10% of the patients remain disease-free after primary treatment, this results in the early death of the proband and other affected family members.
In order to circumvent the unavailability of index patients for genetic testing, she made use of the knowledge that some genetic risk for pancreatic cancer is shared with breast cancer susceptibility genes, most notably BRCA2, PALB2, ATM and BRCA1. She hypothesized that additional shared genetic etiologies could be uncovered by studying families with both breast and pancreatic cancer.
Next-generation sequencing was performed using a multigene panel of 276 DNA Damage Repair (DDR) genes in a cohort of 41 families with at least three breast cancer cases and at least one pancreatic cancer. In 39 families, she and her colleagues tested close relatives (first or second-degree) affected with breast cancer as the index-patient with pancreatic cancer was deceased.
She identified a likely pathogenic splice site variant (c.1605+2T>A) in the RAD17 gene and 25 variants of unknown significance in other DDR genes. RAD17 is a checkpoint protein that recruits the MRN (MRE11-RAD50-NBS1) complex to initiate DNA signaling leading to DNA double-strand break repair, and therefore a possibly cancer predisposition gene. However, due to the small sample size of the present study and the absence of functional testing of the variant, definitive conclusions cannot be drawn.
Project 3: Precision oncology
Systemic therapy is indicated in patients with metastatic cancer. The latter may include chemotherapy, immunotherapy and targeted therapy. Unfortunately, the response rate of the first two is not always satisfactory in various cancer types. The desire to increase the response rate to systemic therapy brought researchers to the field of precision medicine. Over the years, the meaning of the term precision oncology has changed. Precision oncology predominantly described targeted therapies such as vascular endothelial growth factor (VEGF) inhibitors in its early years. Later, it was used to describe the selection of therapies based on biomarker analyses. Currently, precision oncology refers to using data from next-generation sequencing to guide therapies. The search for specific genetic alterations in cancer cells that could be a potential target for targeted therapy is addressed in the third part of this PhD thesis.
A multi-centric basket clinical trial was initiated in the context of the Precision initiative (3). The Belgian Precision initiative aims to maximize the implementation of tumor-agnostic NGS in patients with advanced cancer and enhance access to molecularly-guided treatment options (MGTOs). Her trial aimed to investigate olaparib efficacy in advanced cancers with a pathogenic or likely pathogenic variant (germline or somatic) in genes that play a role in homologous recombination (HR). An analysis was executed for the ATM, BRCA1, BRCA2 and CHEK2 cohorts. The overall objective response rate across different tumor types was 11% in the BRCA1 (N=27) and 21% in the BRCA2 (N=27) mutated cohorts. Partial responses were seen in pancreatic cancer, gallbladder cancer, endocrine carcinoma of the pancreas and parathyroid cancer. One patient with a BRCA2 mutated colon cancer has an ongoing complete response with more than 19 months on treatment. The median progression free survival in responding patients is 14 months (5-34 months). The clinical benefit rate was 63% in the BRCA1 and 46% in the BRCA2 mutated cohorts. No clinical activity was observed in the ATM (N=13) and CHEK2 (N=14) cohorts. Safety data were consistent with the known toxicity profile of olaparib. It was therefore concluded that patients with any cancer type harboring pathogenic BRCA1/2 variants should have access to olaparib.
Conclusion
In conclusion, and back to the little girl, she must be pleased to have evolved into a professional who has contributed to cancer research with her team members. Who could have imagined that she would identify a possible cancer predisposing gene, RAD17 and that she would give patients access to targeted therapy.