Genetic Testing Should be Made Available to All Women

By Patricia Thangaraj

Genetic testing should be made available to all women with breast cancer. Recent data reviewed supports the need for genetic testing to be offered to each newly diagnosed patient with breast cancer or those that have a strong family history.

This is coming from Adjunct Scientist at the Women’s College Research Institute (WCRI), Dr. Kelly Metcalfe, who referred to a research study conducted in the U.S.A. entitled, “Consensus Guidelines on Genetic Testing for Hereditary Breast Cancer from the American Society of Breast Surgeons”

Adjunct Scientist at the Women’s College Research Institute (WCRI), Dr. Kelly Metcalfe

She said that the study suggested that all women and not just those with a family history or those diagnosed at an early age should undergo genetic testing. ”This is not to say that all women would be interested in getting tested, but those who are should be given access to this test.

Dr. Metcalfe said that it is important to take note of the percentages of women who would have a mutation. Referring to another study conducted in the U.S.A., entitled, “Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients with Breast Cancer,” where they looked at consecutive patients that came in with a new diagnosis of breast cancer and not just those who met a certain criteria, she said that the researchers found that of those 488 women who underwent the panel testing, 10% of women had no risk factors for having a genetic mutation, yet they ended up having a mutation in one of these genes that is related to breast cancer.

She said that this is a cause for concern and therefore, medical facilities should consider ensuring that all women get tested for breast cancer. “So that’s a pretty high rate and maybe that is a cause for us to test all women with breast cancer.” Fortunately, some facilities are now doing a panel test generally, which includes not only BRCA1 and BRCA2, but other genes as well.”

The WCRI Adjunct Scientist said that the next consideration must therefore be centered around when these women should be tested with respect to a breast cancer diagnosis. She stated that the three options for women are:

  • Before a Breast Cancer Diagnosis: Screening and Prevention
  • At the time of a Breast Cancer Diagnosis: Personalized Treatment
  • After a Breast Cancer Diagnosis: Prevention of New Cancers

She said that the focus and rationale of why they would do each of the above steps at a different timepoint varies. If they do the testing at the time of a breast cancer diagnosis, the focus is on providing personalized treatment to ensure that these women would survive breast cancer and if it is after a breast cancer diagnosis, they would concentrate on how they can prevent those new cancers from occurring including new breast cancers and ovarian cancer. 

Genetic Testing After a Breast Cancer Diagnosis

This is for those women who have completed both their diagnosis and their treatment based on the best available treatment option that was available to them stemming from a woman’s actual tumour. It also includes those women who find out years later that she has either a BRCA1 or BRCA2 mutation.

Highlighting a study that the WCRI conducted with some of their colleagues in Europe and North America entitled, “Predictors of Contralateral Prophylactic Mastectomy in Women with a BRCA1 or BRCA2 Mutation: The Hereditary Breast Cancer Clinical Study Group,” she said that they looked at women who had a breast cancer diagnosis and then had genetic testing afterwards, only to find out that they had a BRCA1 or BRCA2 mutation.

The idea was to find out how these women would then have used this information with respect to making the decision to have a contralateral prophylactic mastectomy, which is essentially removing the breast that did not have the breast cancer. They found out that the difference in the uptake of the women who decided to have this surgery done depended on where they lived. So if a woman who was diagnosed with breast cancer lived in Europe, only 6% of these women decided to go ahead and have their opposite breast removed in order to prevent the recurrence of breast cancer. Meanwhile, in North America, it was 29%.

The Professor at the Lawrence S. Bloomberg Faculty of Nursing at the University of Toronto, explained that they divulged further into this area, looking at women who got a contralateral breast cancer after their initial diagnosis of breast cancer. It was revealed that women in Europe were more likely to develop a contralateral breast cancer, which is to be expected since the uptake in the number of women opting to do a contralateral prophylactic mastectomy was lower among women living in Europe compared to those women living in North America.

“You can see that women in Europe were significantly more likely to be diagnosed with a contralateral breast cancer and this is not surprising because we know their uptake of the preventive surgery is much lower than what we observed in North America, where there is a lower risk of developing a contralateral breast cancer. And we know from our previous research, that this would probably lead to a difference in survival in these two groups of women.”

Therefore, there is a very small percentage of women who would opt to have a contralateral prophylactic mastectomy after a cancer diagnosis. “So this really shows us then that if we do genetic testing after a woman has done her cancer treatment, a minority of women would elect to go on and have a contralateral prophylactic mastectomy, she added.

Genetic Testing At The Time Of A Breast Cancer Diagnosis

Then there is genetic testing at the time of a breast cancer diagnosis. The WCRI conducted a Rapid Genetic Testing Study on women at the time of a breast cancer diagnosis. The aim was to find out if they could provide this fast genetic testing, where a woman got her results back before she had her surgery. It was also to find out if it had an impact on her decision in relation to the type of treatment that she opted for.

It included:

  • Surgical Decisions
  • Medical Decisions
  • Psychosocial Functioning
  • Satisfaction

She said that if it didn’t, then perhaps, it is not worth putting these women through the turmoil since they already have a lot going on that they have to deal with.

“Because if it doesn’t, maybe it is not worth doing this testing at the time of a diagnosis. There is so many other things going on at this time. She is seeing a surgeon, she is seeing a medical oncologist, a radiation oncologist and dealing with all of these other decisions that are so important for her.”

Dr. Metcalfe continued, “And we are also very interested in the psychosocial functioning. So is adding genetic testing at the time of a breast cancer diagnosis was harmful in terms of the distress that a woman was already receiving or already experiencing; were we causing her more distress by also adding genetic testing on top of everything else? And we were also interested in satisfaction.”

So in this study:

  • Eligible women were identified by participating surgeons and referred into the study at the time of a breast cancer diagnosis.
  • Subject contacted within 24 hours for an appointment with a genetic counsellor.
  • They received a complete in-person genetic counselling session.
  • Results were made available 10 business days later.
  • There was a completion of questionnaires at the baseline one week and one year after the genetic testing was conducted.

Dr. Metcalfe went on to state that the eligibility criteria for their study was “slightly different” from the Ontario provincial guidelines for genetic testing in that they were a bit more lenient.

  • Women were eligible to participate if all of the following criteria were met:
  • First primary invasive breast cancer
  • No previous prophylactic breast surgery
  • Age 18 or older
  • Able to read and understand English so that she could complete the questionnaires
  • No previous testing for BRCA1 or BRCA2

In addition, she also had to have met one of the following criteria:

  • Jewish ethnicity
  • Triple Negative Breast Cancer
  • Diagnosed with breast cancer at 50 years or younger
  • Family history of breast cancer (i.e. first and/or second degree relative with a breast cancer diagnosis at age 50 or younger or ovarian cancer, or male breast cancer at any age.
  • Synchronous bilateral breast cancer

This study, which was completed, had 1000 female participants at the time of a breast cancer diagnosis from four hospitals in Toronto. 16 mutations were identified in these women, so roughly a 6% incidence rate of BRCA1 or BRCA2 mutation. These women were in their 40’s at the time of a breast cancer diagnosis, said Dr. Metcalfe.

The table also shows that approximately 45% of them did not meet the Ontario eligibility criteria for genetic testing, which means that this 45% of women would never have been offered genetic testing, she stated.

For BRCA1, 9% of the women who they identified a mutation in did not meet the criteria. So they would have missed the mutation if they had relied on the Ministry of Health criteria for genetic testing and 22% of women of the BRCA2 carriers would have been missed, she added.

“So that’s a lot of women who wouldn’t have been offered genetic testing, wouldn’t have known that they had a BRCA1 or BRCA2 mutation at the time of a breast cancer diagnosis.”

The WCRI Adjunct Scientist said that they also looked at the decisions women made on the treatment options available to them. In the table, she pointed out that when it came to having a bilateral mastectomy, 72% of those women with a BRCA1 or BRCA2 mutation elected to have a bilateral mastectomy compared to about 19% of women with a negative test result.

“So this 72%, remember we talked earlier about the uptake of contralateral prophylactic mastectomy after learning that you had a BRCA1 or BRCA2 mutation, which is after a breast cancer diagnosis, and remember that only 29% of women in North America elected to have that additional surgery. So quite different when we are thinking about uptake rates depending on when a woman is offered genetic testing in relation to her breast cancer diagnosis.”

Additionally, within that first year after a breast cancer diagnosis, 40% of the BRCA1 and BRCA2 mutation carriers had a prophylactic oophorectomy.  She said that this really speaks to the women’s motivation to use the information they have to make important decisions regarding their health because they have a lot going on within that first year after a breast cancer diagnosis in terms of the treatment and the times that these treatments take.

Therefore, the fact that 40% of them were able to make the decision and actually follow through on getting their ovaries removed within that first year is “quite remarkable.” She added that she believes that as they look at the longer term data of uptake rates, they would see an increase of women opting for an oophorectomy.

Dr. Metcalfe stated that an important question they asked themselves was: Does providing genetic testing at the time of a breast cancer diagnosis impact on their psychosocial functioning? The aim was to find out if they ended up causing more stress for these women if they conducted these tests.

Therefore, they looked at women at the time of genetic testing, which she illustrates in these graphs. This included women before they saw the genetic counsellor, one week after received their genetic test results and then one year after they received the results. They evaluated cancer-related distress, anxiety and depression. The focus here was to find out whether there were differences between women who identified with a BRCA1 or BRCA2 mutation and those who had a negative genetic test result. The graph also illustrates women with a variant of unknown significance, explained Dr. Metcalfe.

“So you can see that there are no differences. And when we statistically looked at these differences, there were never any significant differences in cancer-related distress or anxiety at any time point. The only significant difference that we saw was that one year when we were comparing our BRCA positive to our negative, and what we saw was that women with a BRCA1 or BRCA2 mutation had significantly lower levels of depression that women who had a negative genetic test result that one year.”

She said that they discovered that women finding out that they have a BRCA1 or BRCA2 mutation at the time of a breast cancer diagnosis did not have an impact on their psychosocial well-being.

“So this data really suggests to us that finding out that you have a BRCA1 or BRCA2 mutation at the time of breast cancer diagnosis doesn’t really have an impact on your psychosocial functioning. It isn’t causing more psychosocial distress, depression or anxiety at any timepoint in a woman’s trajectory.”

Dr. Metcalfe said that it was that one week which they were really concerned about because that is the time when women generally tend to experience the highest level of distress during a breast cancer diagnosis. It is therefore the normal trajectory that one would expect to see with women with breast cancer. In the beginning of a diagnosis, distress, depression and anxiety are at their highest and this tends to decrease overtime, regardless of whether a woman has a BRCA1 or BRCA2 mutation or not. All of the women in the study experienced that decrease as they got better.

How will health systems support genetic testing for all women with breast cancer?

The WCRI Adjunct Scientist said that they also looked at how health systems would support genetic testing if these institutions were to offer it to all women. This table shows the volumes of genetic testing in Ontario. She said if you look at the volumes of referrals between 2007 and 2016, there were significant increases. However, they have not seen an increase in the numbers of genetic counsellors to be able to counsel all of these women.

Therefore, the process of genetic counselling and testing needs to be revaluated so that the shortages of genetic counsellors can be addressed, she said.

“Since 2016, the criteria for genetic testing has actually expanded slightly. So that’s why we are going to see these numbers go up even higher. So we need to be able to think of how we are going to deliver genetic testing and counselling differently to be able to meet these patient volumes that we are expecting.”

Another issue relates to the wait times across Ontario, which also varies in that some women are waiting a long time to access genetic counseling and testing services, explained Dr. Metcalfe.

Referring to a study conducted by Jeanna McCuaig of the Princess Margaret Cancer Centre as part of her PhD, Dr. Metcalfe said that in that study, they looked at the different models that are available with respect to delivering more genetic testing and counseling.

“One of these models is called Direct Genetic Testing and this has very little pretest genetic counselling. So typically, many of you would have come in, you would have met with a genetic counselor you discussed everything and then you decided to have genetic testing. With this it is a little bit different, Women don’t come in to visit with the genetic counsellor, they received some written information, (some) videos potentially.”

She stated that an ongoing study that they are doing at the WCRI is centered around providing genetic testing without having to do genetic counselling first.

“There has been some evidence that this may be an effective model. Where we don’t know is if it is effective though is at the time of a breast cancer diagnosis. So can we offer this type of model – to offer rapid genetic testing at the time of a breast cancer diagnosis, where we don’t offer any pre-test counseling.”

The Women’s College Hospital is offering rapid genetic testing to women across Canada. The tests can be conducted at home. Dr. Metcalfe explained that rationale behind this was because at the time of a breast cancer diagnosis these women are already seeing a lot of different specialists and therefore, to eliminate the need for them to see one more specialist for an in-person visit to do genetic counselling, it would be more beneficial for these women to do these tests at home.

However, they have to evaluate this method to make sure that this is an effective model at this point in time of a woman’s breast cancer treatment.

Here there are doing a panel genetic testing as opposed to only BRCA1 and BRCA2 as they did in their first study. They send a saliva kit to women, who provide a saliva sample and then couriers it to lab and these results are available within 10 days. The genetic counselling is focussed on those women who have a mutation and who need that extra support in terms of understanding what this means for them and how they can use this information to make informed decisions about their treatment, explained Dr. Metcalfe.

They were looking to enroll 1000 Canadian women at the time of a breast cancer diagnosis in this study to look at the outcomes just like they did in the first rapid generic testing study because in that first study, they offered a traditional model of genetic counseling.

To date, they have tested over 200 women and 25% of these women have self-referred into the study. So for this study, women interested in participating in the study do not need a doctor to refer them. Instead, they can self-refer, which would help to ensure that the WCH is increasing access to genetic testing for women across Canada.

To date, just over 10%, so close to 11% of these women have received positive genetic test results. You can see the different genes there. It is not just BRCA1 or BRCA2, but they also have ATM, CHEK2, PALB2 and 1PTEN. And 11% have received a variant of unknown significance. When they looked at the data from those 206 women, 94% of them were satisfied or very satisfied a week after receiving their genetic test results

“So some encouraging evidence as we are embarking on this study, that this may be an effective model for these women at the time of a breast cancer diagnosis.”

Dr. Metcalfe said that in order to evaluate what all of this research means; the next step would be to go back and look at what the ultimate goal of genetic testing is for women with breast cancer.  They want to reduce the risk of these women dying from that first breast cancer, reduce the risk of a second breast cancer, prevent other cancers such as ovarian cancer from occurring and they also need to think of these women’s relatives because they now have information on breast cancer which they can share with their relatives, many of whom would not have been diagnosed with breast cancer.

The doctors and patients can then work together to reduce the risk for those relatives either not getting cancer or if they do get cancer, that it is diagnosed very early, when it is at a treatable stage. She stated that they are making “really good progress” in terms of meeting these ultimate goals of genetic testing.

For them to realize these goals, they need to think of personalized treatment for women with BRCA-associated breast cancer. “Women need to know if they have a BRCA1 or BRCA2 mutation to make these decisions so that they can ultimately increase their chances of survival. We want to see as many women as possible survive these breast cancers as possible.”

They also have to look at new models to ensure women have access to genetic testing. The model that they are evaluating at the WCH is rapid genetic testing, which serves is the first start in this process. There are also other models that are being assessed such as the surgeon offering the genetic testing. “So I think together across the country, across the world, we are thinking about new ways to be able to deliver genetic counseling and testing because we just can’t keep doing things the way we have been doing just because of the numbers of people that need to be tested.”

Dr. Metcalfe said that they also need to think of other cancer predisposition genes such as PALB2, ATM and CHEK2 because they do not have as much information on these newer genes. Therefore, they are now looking to conduct research into these genes with respect to the effectiveness of treatment.

In this regard, the WCH currently has a study going on with women with breast cancer who have mutations in PALB2, ATM and CHEK2, where they are collecting all of the necessary clinical and treatment information from them to try to determine what the best treatment is for women with mutations in some of these genes. So we still have a lot of work to do,” concluded Dr. Metcalfe.



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