By Patricia Thangaraj

The Bhalwani Familial Cancer Clinic at the Princess Margaret Cancer Centre will make germline genetic testing available to all breast cancer patients in the near future.

This is according to Medical Oncologist and Clinician Scientist at the Princess Margaret Cancer Centre, Dr. David Cescon who delivered a presentation on “Universal Genetic Testing to Advance Precision Breast Cancer Therapy” as part of a webinar entitled “Breaking Ground: Moving Towards Universal Genetic Testing in Cancer.”

He said that germline genetic testing has been shown to have numerous benefits in the delivery of precision therapy or individualized therapy for people who have been diagnosed with breast cancer – those for whom cancer is not prevented, which results in a breast cancer diagnosis.

“Many people have probably heard the term personalized medicine or precision cancer therapy and the cornerstone of this approach in which we attempt to match optimal therapy to a given individual is in the modern day really hinged upon the genomics of that cancer.”

He stated that cancer cells acquire genetic changes as they develop from normal cells and in some cases, those genetic changes are linked with BRCA1 or BRCA2 gene mutations and when additional changes occur, cancer is likely to develop.

“You’ve heard from Raymond how cancer cells acquire genetic changes as they develop from normal cells and in some cases, those genetic changes pre-exist in their inherited form like those BRCA1 or 2 mutations, which are common and predisposed to breast cancer. Those changes however, they don’t form a full cancer state, but additional changes are required to permit the cancer to develop all of its properties of uncontrolled growth and the ability to spread.”

Identifying Targeted Therapies

Based on their understanding of those variations in the cancer genome in contrast to healthy cells, they can then proceed to identify targeted therapies for breast cancer patients and this is referred to as precision cancer therapy.

“With a knowledge of those variations in the cancer genome as compared to healthy cells, we have a number of approaches that permit us to identify specific therapies including therapies for breast cancer that may benefit one individual based on their cancer features, but not another and this is really the process of precision cancer therapy.”

However, in order to capitalize on this knowledge, they must also understand not just the changes that occur, but how those changes are likely to impact the cancer cell’s behaviour and the role that this plays in a patient’s response to a given therapy.

Dr. Cescon said that they have conducted clinical trials at the Princess Margaret Cancer Centre that can help identify potential matches, which they can then test in breast cancer patients and this could lead to the discovery of new therapies.

“Of course, developing precision cancer therapy requires us to understand not only the changes that occur, but the consequences of those changes to the cancer cell’s behaviour and how it may influence the response or lack of response to a given therapy and as an integrated cancer centre at Princess Margaret where we have research that spans the basic laboratory through clinical trials, we really contribute substantially to the development of that engine that fuels precision cancer therapy, identifying those potential matches and testing them in patients in clinical trials to eventually arrive at new therapies that we can use in our clinics everyday.”

The Importance of Precision Cancer Therapy

The Medical Oncologist explained that there is no ‘one size fits all’ when it comes to cancer therapy and this is where treatment individualization or precision cancer therapy is significant because it allows oncologists to treat breast cancer patients more effectively.

“This goal of treatment individualization is to advance from a group of patients treated with cancer therapy who if all given the same treatment, would experience differential benefits from those therapies. So you can see at the bottom here, some of those patients would not benefit, but would experience toxicity from those therapies. Others might have some benefits that does not exceed the toxicity, and in an ideal situation, patients would have substantial benefits with no or limited toxicity. And so our goal of treatment individualization or precision cancer therapy is to move as many people from that bottom of that list up to the top, where we can most precisely use treatments to deliver maximal benefit to each individual.”

He explained that they attain treatment individualization or precision cancer therapy using tools such as biomarkers and other advanced radiographic techniques.

“And this is achieved with two main tools – biomarkers, which allow us to characterize the cancers and identify those matches that will work and that can include germline genetics, as well as genomics, additional characterization of the tumour, standard histology or pathological evaluation of the tumour and in some cases, other advanced radiographic techniques and of course, an increasing arsenal of available therapies which are relevant to those tumours as defined by those given biomarkers.

Two Major Classes of Breast Cancer

Dr. Cescon stated that when it comes to cancer therapy, there are two major classes of breast cancer patients and the treatment that they administer would depend on the type of breast cancer the patient has. For those diagnosed with early breast caner, they focus on curative therapy.

“When we think of the application of therapy for people diagnosed with breast cancer, there is two major classes of breast cancer, those who have early breast cancer for whom the goal is curative therapy. So to remove the tumour and to deliver drug-based treatment to prevent a recurrence while at the same time, avoiding over treatment for those who do not require that.”

Meanwhile for those patients with metastatic breast cancer, their goal is to extend survival and enhance the quality of life for these patients with this hard to treat cancer.

“For patients with metastatic breast cancer, which is unfortunately for the most part incurable, our goals are to extend survival and to maximize quality of life and to treat symptoms of that disease.”

Patient Related Factors in Individualizing Breast Cancer Treatment

The Medical Oncologist explained that there are various patient related factors that play a role in personalized medicine or precision cancer therapy and some of these components include the stage of the cancer, the size of the tumour and the subtype of cancer among other aspects.

“So how can the patient related factors that I have just described, contribute to individualizing breast cancer treatment in 2022? Certainly, patient clinical factors are very important as well as the tumour features including the stage of the disease, how large the tumour, whether or not there are lymph nodes involved, the subtype of cancer, we think of the hormone receptors and the HER2 receptor as standard features of the cancer that informs drug-based treatment, all factors that contribute to how high is that patient’s risk of recurrence.”

This is where germline genetic testing comes into play because it allows oncologists to develop more effective targeted therapies for early high-risk breast cancer patients who have a BRCA1 or BRCA2 mutation and a new therapy known as the PARP inhibitor, which was approved recently would only serve to advance clinical trials in this area as this therapy has been proven to have significant benefits in improving the outcomes for these patients.

“In a timely fashion, germline genetics is also now contributing to our drug-based treatment of patients with breast cancer in that a new therapy has been approved, just last week in fact on Friday, for the treatment of patients with high-risk early breast cancer who have a germline BRCA1 or 2 mutation. And that’s the use of a targeted therapy called the PARP inhibitor, which has been specifically shown to improve the outcomes in that group of patients.”

The Role of a Liquid Biopsy Test

A liquid biopsy test also presents oncologists with an opportunity to develop precision therapy or individualized therapy for breast cancer patients in the future. This would reduce the chances of a recurrence, explained the Clinician Scientist at the Princess Margaret Cancer Centre.

“What about new and emerging factors beyond those features of the tumour or the features of the patient and here again, circulating tumour DNA or a non-invasive liquid biopsy blood test, may have a role in our future individualization of therapy to prevent an intercept recurrence.”

He said that the circulating tumour DNA, which can be identified in the blood before a cancer is even diagnosed can have a huge impact on diagnosing the cancer in its earlier stages or preventing the cancer from occurring in the first place.

“So as you’ve heard, circulating tumour DNA, which can be detected in the blood, represents fragments of the cancer cell’s genetic material. Prior to the diagnosis of the cancer, this material may be detectable in the blood, and that could form the basis for the type of early diagnosis or prevention strategies.”

The situation would vary from patient to patient, but in the majority of cases, after a cancer has been diagnosed, patients would have a noticeable amount of a circulating tumour DNA and this is where standard therapy could be used to reduce the circulating factors in a breast cancer patient’s blood.

“Following a diagnosis of a cancer where most patients would have a detectable level of a circulating tumour DNA. Standard therapy we understand, results in the marked reduction of these circulating factors in the blood. You can see that noted in the graph here, where for patients whose cancer is eliminated by standard treatment, we would not expect to detect any circulating tumour DNA because there’d be no cancer cells to shed that circulating tumour DNA.”

Unfortunately, standard therapy does not work for all patients and in cases like these, oncologists can use the existence of the circulating tumour DNA in a patient’s blood after he/she has undergone treatment, which could serve as a mechanism to pinpoint those patients who would need more treatment so that they can be cured.

“However, we know that not all patients are cured by that standard therapy and in those patients who are not cured, the surveillance for the emergence of the circulating tumour DNA or the persistence of the circulating tumour DNA, after what we believe has been curative treatment, could provide a way to identify those patients who are not cured, and thus who might benefit from additional therapy to achieve a cure.”

Referring to a diagram, he went on to say that the detection of that residual disease in these patients after the initial treatment of their breast cancer could then show oncologists which patients would benefit from additional therapy or participation in clinical trials while the absence of this circulating tumour DNA, could identify those patients who would not need more therapy because they have been cured.

“So as shown in this schema here, the detection of that residual disease which may be present immediately following or at some later time point after the initial treatment of their early breast cancer, could identify them as candidates for additional treatment or participation in therapeutic clinical trials or in contrast to the absence of such residual disease detection by circulating tumour DNA, could permit the avoidance of unnecessary treatment for patients who are cured and who might be demonstrated to be cured by such a test.”

Utilizing Germline Genetics in Curing Breast Cancer Patients

Dr. Cescon disclosed that their team at the Princess Margaret Cancer Centre are currently engaging in these therapeutic clinical trials where they are utilizing their knowledge of germline genetics, BRCA1 and BRCA2 gene mutations and liquid biopsy tests to pinpoint high-risk breast cancer patients and if the blood test comes back positive for a circulating tumour DNA or residual disease, then those patients can receive additional therapy beyond the standard treatment that they have already received.

“So while this is certainly being viewed as a promising way of the future, the investigation of these strategies is happening now. So shown here is a clinical trial which is taking place at Princess Margaret, in which we’re participating in a global study, which takes advantage of both germline genetics, knowledge of BRCA status and circulating tumour DNA in the form of a liquid biopsy test to identify patients with high-risk cancer, who can undergo surveillance with such a blood test, and if that blood test shows evidence of circulating tumour DNA, or residual disease, those patients are eligible for the evaluation of an additional treatment added beyond the standard treatment that they’ve already completed.”

This presents oncologists with a breakthrough in surveillance and targeted treatment based on the characteristics of the tumour and the patient’s personalized blood marker, which would help them identify and treat those patients whose breast cancer is likely to come back.

“So this offers an opportunity for surveillance and targeted therapy, based not only on the tumour features, but on the persistence of an individualized blood marker such that a large number of patients could be screened with the goal of only treating those very few individuals who are destined to recur.”

Ongoing Research at the Princess Margaret Cancer Centre

The Clinician Scientist said that this research, which is currently being conducted at the Princess Margaret Cancer Centre, offers hope to breast cancer patients with triple-negative breast cancer and BRCA1 and BRCA2 mutations. However, their team is also working on developing liquid biopsy tests for breast cancer patients with other subtypes such as HER2-positive breast cancer.

In fact, this study has recently been authorized by Health Canada and has a target launch date of September. Meanwhile, they are continuing to develop similar clinical trials for estrogen receptor (ER) positive or hormone receptor positive breast cancer.

“That study, which I showed, which is underway, is focussed on triple negative and BRCA related breast cancer. As leaders in this field at the Princess Margaret in liquid biopsy and cancer interception, we’re also leading efforts for other breast cancer subtypes including a similar interception trial for HER2 positive breast cancer, which has recently been approved by Health Canada and will be launching hopefully in September, and work is ongoing for similar studies in ER positive or hormone receptor positive breast cancer, which is the most common form of the disease.”

He said that the benefits of universal germline genetics adds another dimension to their understanding of breast cancer patients tumours, which would hopefully lead to further individualized therapy, where they can cure for as many patients as possible.

Dr. Cescon thanked the Princess Margaret Cancer Foundation whose allocation of funds makes their research possible and stated that they are eager to continue advancing treatment options for breast cancer patients with the Foundation’s ongoing financial support.

References: Breaking Ground: Moving Towards Universal Genetic Testing in Cancer