Developing diagnostics to identify the molecular drivers of breast cancer and model the mechanisms of disease progression will be a key priority of the investigative efforts aimed at improving patient outcomes in the field over the next decade.
Fabrice Andre, MD, PhD
Fabrice Andre, MD, PhD
Developing diagnostics to identify the molecular drivers of breast cancer and model the mechanisms of disease progression will be a key priority of the investigative efforts aimed at improving patient outcomes in the field over the next decade, according to Fabrice Andre, MD, PhD.
"We need to develop methods to model the biological mechanisms of tumor evolution at the individual level and we need new biotechnology to create new therapies. If we can model the mechanisms of progression, then we can [develop new therapies] to target these mechanisms," Andre said during a keynote lecture of the 2020 ESMO Breast Cancer Virtual Meeting.1
Advancing this biological approach hinges on identifying the molecular mechanisms that drive cancer progression. Several genomic alterations have already been identified as drivers of disease progression in metastatic breast cancer, such as NF1, KRAS, AKT1, and PIK3R1, which activate intracellular signaling. Drivers in the estrogen receptor pathway include ESR1, which is mutated in approximately 15% of patients, and NCOR1, explained Andre, director of Research at the Institut Gustave Roussy in Villejuif, France.
Epigenetic alterations like KMT2C, which presents in mutant form in about 15% of patients with metastatic disease and promotes resistance to endocrine therapy,1 represent an "emerging field in breast cancer for which [clinicians] are going to generate new drugs," said Andre, who added that understanding whether epigenetic modulation is involved in cancer progression for each patient will be critical to personalizing targeted approaches.
Modeling mechanisms of clonal evolution will be equally important as selecting drivers of disease progression: "We know that metastatic breast cancer can be stable for a long time, and [then], suddenly, the cancer can escape, so we need to understand the mutational processes that [allow] escape," Andre explained.
APOBEC, a cytidine deaminase, and homologous recombination deficiency are 2 genomic scars that could aid not only the genomic evasion of targeted therapy, but also the evolution and aggressiveness of disease. Biological models of metastatic disease will need to determine whether or not these mutational processes are active in patients.
The next step in producing biological models involves tracking subclones that can create resistance to therapeutic intervention, and assessing circulating tumor DNA samples at baseline or during patient follow-up may offer an avenue to trace these subclones, Andre said, adding that a biologically based modeling methodology will also need to address the molecular mechanisms that promote resistance to immunotherapy.
Laying a Foundation for New Biotechnologies
Once clinicians are able to identify drivers of disease progression, model mechanisms of clonal evolution and immune escape, and track subclones in each patient with metastatic breast cancer, this knowledge can be used to develop a diagnostic device for target identification that would guide individual treatment decisions. "One of the main priorities in the field of metastatic breast cancer is being able to model the biology [of disease] in each patient in order to propose personalized therapy that specifically targets mechanisms of cancer progression," Andre said.
Improving patient outcomes entails a more comprehensive understanding of the biological mechanisms of tumor evolution and the use of new biotechnologies to develop targeted therapies, particularly as the field gravitates away from a single-gene approach and moves instead towards a complex mode of management, wherein the biology of disease must be assessed in each patient and treated accordingly.
Biotechnologies could be useful in the development of complex drugs that hit multiple molecular targets, and are already present in breast cancer, where they are used to engineer complex drugs like antibody-drug conjugates and construct the conjugates' specific or bispecific antibodies. The application of biotechnology in breast cancer drug development has also yielded new linkers that are tailored to the therapeutic need, and cytotoxic agents. As the field advances, Andre hypothesized that biotechnologies could even be used to develop therapies for individual patients: "My intuition is that, in the future, we could construct a complex drug for each patient based on [their] biology."
Predicting patient outcomes as early as possible in the disease course will also be a priority in the field over the next decade and goes hand in hand with new drug development, Andre explained. For example, identifying patients with very poor outcomes who are in urgent need of experimental therapies would allow the field to more expeditiously fast track investigational agents. Establishing methods to predict patient outcomes could also guide the evaluation and initiation of new therapies in patients at a high risk of relapse.
To move the needle in metastatic breast cancer, the field must prioritize reducing toxicities to subsequently improve quality of life (QOL).1 "For a very long time, [we have known] that we are using drugs that impact [patients'] quality of life," Andre said. "[However], until recently, we did not have evidence based on epidemiology data that the [effects] of systemic treatment are important and relevant for patients."
Andre cited results from a recent epidemiological study of systemic therapy in pre- and postmenopausal women with early-stage breast cancer. The prospective evaluation of patient reported outcomes collected from 4262 eligible patients who participated in the CANTO study (NCT01993498) of cancer treatment toxicities in individuals with nonmetastatic breast cancer2 "clearly showed that the drugs we are using have a deleterious impact on quality of life," Andre said.
Premenopausal women comprised 37.2% of the patient population; 62.8% of women were postmenopausal. Among premenopausal participants, chemotherapy was found to reduce cognitive functioning.1,2 "This is a major need that we need to address," Andre said.
In postmenopausal women, endocrine therapy negatively affected overall health status and quality of life (QOL) score.1,2 Interpreting data from the prospective study as a microcosm of the need to reduce the occurrence of adverse events that debilitate QOL, Andre concluded that "decreasing toxicity to improve [patient] quality of life after cancer is one of the top 4 priorities" in the next decade of breast cancer research.