- decodeMR Team
Breast Cancer- New Avenues into the therapeutic options - Q & A session with an expert
According to the World Health Organization, more than 2.3 million cases of breast cancer occur each year, making it the most common cancer among adults. In 95% of countries, breast cancer is the first or second leading cause of female cancer deaths. Despite the progress made in breast cancer research and treatment, the disease continues to impact individuals and communities worldwide. This ongoing battle against breast cancer makes it imperative to increase awareness and ensure access to quality care.
To shed light on the ongoing efforts to combat breast cancer, we spoke with Dr. Ahmad Sufian Ab Rahman, a renowned Medical Oncologist from Malaysia, who suggested various steps to ensure timely diagnosis of breast cancer and discussed emerging therapeutic options to manage the disease effectively.
Dr. Ahmad Sufian Ab Rahman is a Consultant Medical Oncologist currently serving at UCSI Hospital / Cancer CRI Centre / Columbia Asia Bukit Rimau, Malaysia.
In terms of the national breast cancer screening program, Malaysia have not got the mandated funded screening program where all patients within a specified age range would be eligible for a free screening in our country. However, we've got our national breast cancer screening guidelines, which outline that patients in the age range of 50 to 70 years old will need to undergo screening mammography once every two years.
Doctor, we understand that breast cancer screening is essential for early diagnosis and starting treatment at the earlier stages of the disease. What approaches can be taken to ensure the timely diagnosis of breast cancer?
Dr. Ahmad - In the context of Malaysia and Southeast Asia, although the incidence of breast cancer is lower than in the Western population, our mortality-to-incidence ratio is comparatively higher. On top of that, the proportion with diagnosis of stage III and IV breast cancer is much higher than our Western counterparts as well as some other advanced Asian countries. Nationally, it's around 50 to 60 percent, and in some pockets of the country, it could be as high as 60 to 70 percent. The critical leverage would therefore be pushing for initiatives that would effectively increase the early pick-up rates and move the diagnosis from stage III and IV to early-stage breast cancer at diagnosis. To do this, screening availability is important, and at the same time, other initiatives would require consolidation and support from various stakeholders. Among them:
1. Self-awareness among our patients. If the patient realizes that she develops any unusual lumps, then she needs to seek urgent medical attention. Not only females but any male with unusual changes around the nipple area should also seek medical consultation. For our women, there could be some additional challenges during their pregnancy or breastfeeding period due to breast changes associated with the changes in hormone levels. As a general rule, for any new changes in the breast that is unusual at any level of age, seeking a medical opinion is a must.
2. Health information would be important. Knowing the changes in the breast that are suspicious for breast cancer, such as thickening or puckering of the skin, nipple discharge, bleeding, and asymptomatic or symptomatic lump, all become vital for our population to be educated about. Sourcing reliable information from trusted medical professionals and credible websites should be the approach taken to ensure the right decision is taken and disinformation is dispelled.
3. The third thing is to understand the nature of breast cancer in the Asian population. It bears some differences when compared with the Western population. For instance, our Asian population with breast cancer tends to be diagnosed much earlier, with the peak incidence being about 10 to 20 years earlier than the Western population. We are therefore talking about the age range of early 30s and onwards. In addition, in our Asian population with breast cancer, we tend to have a higher incidence of HER2-positive breast cancer. The breast density is also higher, which means that some screening modalities that have been used for the Western population might not be optimal as a single modality for our Asian population. For a timely diagnosis, it would be important for the multimodality of diagnostic investigations to be considered and validated. On top of the routine mammography, ultrasound, and MRI breast might be required. And now, other modalities like digital tomosynthesis might give a higher sensitivity than the use of mammography. Knowing all these things would help us diagnose and treat breast cancer more effectively.
4. Expansion and streamlining of national breast cancer screening program. The breast cancer screening program is not yet universally funded in Malaysia. This makes it hard for some women to access breast cancer screening even when they might fall under the high-risk groups. The ability to have a well-supported national screening program would be critical and, at the same time, allow for the measurement of desired outcomes targeted by national screening program policy.
5. Competency to tackle the challenges associated with the culture, socioeconomic, and local norms. There are cultural challenges that impede the willingness of some women to seek an urgent medical opinion. The fear of relationship issues, the decision made by the partner rather than the woman herself, the inability to afford treatment and continue to earn a livelihood, and the taboo in talking about cancer are among the challenges that will need to be overcome. Therefore, a continuous and strong health campaign by the ministry, health agencies, health professionals and advocacy groups needs to continue and be made more aggressive so that we can really see the effectiveness that would be achieved from the screening.
Is there any particular reason why the Asian population with breast cancer tends to be diagnosed much earlier than the Western population?
Dr. Ahmad - I think this is a matter that will need to be studied and researched further. Certainly, there is an ethno-genomic difference between our population and the Western population. Our lifestyle, environment, and overall longevity could also play a role.
The reason is that triple-negative breast cancer tends to be the most aggressive. It tends to relapse much earlier. Usually, the relapse period would be two to three years after the treatment with adjuvant therapy. The prognosis associated with triple-negative breast cancer is also much worse than ER and PR-positive breast cancer.
Are there mandatory breast cancer screening programs in Malaysia?
Dr. Ahmad - In terms of the national breast cancer screening program, we have not got the mandated funded screening program where all patients within a specified age range would be eligible for a free screening in our country. However, we've got our national breast cancer screening guidelines, which outline that patients in the age range of 50 to 70 years old will need to undergo screening mammography once every two years. A clinically high-risk group would need to go for annual mammography, and this was specified further based on the age range.
Our national breast cancer screening guidelines also have a recommendation for the high-risk group defined by genetic risk factors. This is the population with BRCA1/BRCA2 positive germline mutation or other high-risk, cancer-susceptible genes. You will find a specific recommendation, such as an early annual screening at the age of 30 to 39 using mammography and MRI.
In Malaysia, we have government and non-governmental organizations (NGOs), including the National Cancer Society of Malaysia (NCSM) and MAKNA, that provide more affordable screening or funding for mammography. Patients can also access the screening program at various university hospitals and private hospitals at their own cost.
We understand that Triple-Negative Breast Cancer (TNBC) does not respond to the existing therapies which target ER, PR, and HER2 receptors ,. Are there any emerging therapeutic targets for TNBC?
Dr. Ahmad - With regards to triple-negative breast cancer, we know this is the histological subtype of breast cancer that is most difficult to treat and manage. The reason is that triple-negative breast cancer tends to be the most aggressive. It tends to relapse much earlier. Usually, the relapse period would be two to three years after the treatment with adjuvant therapy. The prognosis associated with triple-negative breast cancer is also much worse than ER and PR-positive breast cancer. We are talking about a median overall survival of between 12 to 15 months. There have been huge scientific endeavors to try to find new therapies and targets that can be used in triple-negative breast cancer. More recently, there have been a few updates, and we can divide these into adjuvant and metastatic settings.
The adjuvant setting is where the cancer is at its early or locally advanced stage, whereas the metastatic setting is where cancer has spread, so a stage four disease.
In the adjuvant setting, there are a few avenues now. One of them is the KEYNOTE-522, which looks at the use of immune checkpoint inhibitor, pembrolizumab, in combination with chemotherapy to be used as a neoadjuvant therapy, meaning before the operation. This goes for four cycles, and then it's continued with adjuvant therapy, so pembrolizumab plus the remaining chemotherapy after the operation, and that is to continue for nine cycles. Now the study showed that event-free survival was significant. We've got here at the three years mark, the event-free survival was 84.5% in the population receiving pembrolizumab versus 76.8% in the population not receiving pembrolizumab. That's about an 8% of absolute increase in benefits at a population level.
The other thing that we've also noticed is that a sub-cohort of patients with triple-negative breast cancer could have germline BRCA1/BRCA2 mutation, and in this sub-cohort, the OLYMPIA trial showed that if you use the Olaparib as an adjuvant therapy for one year, that could improve the overall survival by about four to six percent. So again, there's a role in the cohort that has got germline BRCA1 or BRCA2 mutation that this medication can be used.
In the space of a metastatic setting, we've also got a few other options. The first one is the KEYNOTE-355, the use of pembrolizumab in combination with chemotherapy - a platinum-based agent (Cisplatin/ Carboplatin), plus paclitaxel, nab-paclitaxel, or gemcitabine. In the population with a combined proportional score of 10% or more, the use of triplet therapy has shown significant overall survival and progression-free survival. If I could quote here, the median overall survival was 23 months versus 16 months in the population that did not receive pembrolizumab. Again, this study showed a significant benefit of using Pembrolizumab with chemotherapy.
At the same time, the race in the scientific field for what we call antibody-drug conjugate (ADC) has shown some fruitful results. We now have got a medication called Sacituzumab Govitecan used in heavily pre-treated triple-negative metastatic breast cancer. It has shown the overall survival benefit in the ASCENT trial, leading it to be approved for use as a second line or further line down the track for triple-negative breast cancer. Sacituzumab Govitecan is now approved by the FDA to be used in this setting.
Now interestingly, last year, there was another scientific breakthrough with the findings of a new cohort called HER2 low breast cancer. This is a cohort of patients that used to be diagnosed either to be ER PR positive HER2 negative, or patients who have triple-negative breast cancer. When you look back at the histological staining with IHC, this population would have an IHC score of one plus or two plus but negative with FISH. The use of Trastuzumab Deruxtecan in this population, either for patients who are ER PR positive breast cancer or triple-negative breast cancer in a trial called DESTINY breast 04, has shown that this sub-cohort benefited from the use of Trastuzumab Deruxtecan. That's another treatment that is again a game changer in triple-negative breast cancer.
And last but not least, in the molecular profiling setup, triple-negative breast cancer would need more scientific research and discovery. And this is where the use of molecular profiling would be important so that you can match new mutations, mutational signatures, or transcriptomic signatures with new therapies in this type of cancer.
Do you think approval of pembrolizumab plus chemotherapy eliminates the challenge of understanding the therapeutic target for TNBC?
Dr. Ahmad - I don't think so. When we look at the molecular and mutational signature levels, we know that at the mutational signature or transcriptomic signature, you could see certain subtypes that tend to respond more to immunotherapy and certain subtypes that would not respond well to immunotherapy. So, it is not a single treatment that would be able to address all the sub-cohorts. Using pembrolizumab as an adjuvant treatment improved the pathologic complete response, which is fantastic. If you look at the difference, the difference was about 8%. So yes, immunotherapy is one of the modalities, but it has not solved the problem completely in the space of triple-negative breast cancer, and certainly, we still have a long way to go.
It is physically and emotionally challenging, and it affects the relationship, job, productivity, ability to have family and children, and other aspects of life. Cancer, in many ways, is a life-changing diagnosis. In saying that, many things can be done to ensure that patients are given the opportunities and support to run through their lives as “normal” as possible.
Breast cancer surgery aims to eliminate cancer from the breast with the least degree of deformity ,. Could you comment on the role of oncoplastic surgery in breast conservation of breast cancer patients?
Dr. Ahmad - It is really pertinent, especially in our population, where breast cancer occurs in younger women. I think there is a big challenge in terms of confidence, physical appearance, and relationships. It is multi-dimensional. I think this is where breast conservation surgery becomes important and bridges some of these challenges, especially when a mastectomy needs to be performed. Another avenue to think about is the role of neo-adjuvant therapy in limiting the extent of the operation that is required to be performed. If we give neoadjuvant therapy first in triple-negative breast cancer before performing a breast operation, the extent of the operation can be reduced and consolidated instead of using radiation treatment.
What is the rate of recurrence after oncoplastic surgery?
Dr. Ahmad - As to the rate, I would refer this to our breast surgeon. As to the factors that influence recurrence, there are various factors that could determine which we call prognostic factors. The tumor size, the surgical margin, histology subtype, intrinsic subtype, age, lymph node involvement, and stage of cancer would be among them. In the context of triple-negative breast cancer, whether the patient gets the pathologic complete response or not, would also be a prognostic factor.
Breast cancer management can be a physically and emotionally challenging journey for women. So, what would be your key takeaway message for effectively managing their disease?
Dr. Ahmad - You are absolutely right. It is physically and emotionally challenging, and it affects the relationship, job, productivity, ability to have family and children, and other aspects of life. Cancer, in many ways, is a life-changing diagnosis. In saying that, many things can be done to ensure that patients are given the opportunities and support to run through their lives as “normal” as possible.
Multi-disciplinary care would be important to effectively manage their disease. Clear and shared goals of care need to be outlined and agreed upon between patients and their cancer care providers. Above and beyond this, other things need to be addressed as follows:
First, I think it is important to destigmatize breast cancer in our population. It is the commonest type of cancer in our population, and we need to empower our women with the knowledge and bravery to seek urgent medical attention. The destigmatization and empowerment of women are important.
Number two, I think it is important that a good support system is created, whether at an individual and family level or at the societal level. Individual level means that you have the right family members to talk to and the right friends who can support you, but they do not overwhelm you. Having good support from the partner would be important. Having somebody to talk to about your worries would become critical. And in Malaysia, as in any other country, there are patient advocacy groups that you can join and see whether they are useful or not for your journey with breast cancer.
When women go through the initial treatment process, it could be overwhelming and draining for them. Getting back to some of the usual structure and routine in their lives would be important. So good exercise, a healthy diet, having friends, if they used to work then being involved and keeping themselves a bit busy with some of the work or meaningful activities can help them. Again different people are different, and you need to evaluate what would provide you with the strength to carry on.
And I tell my patients that psychological support is non-replaceable. One of the ways would be to use the compartmentalization approach. So, for instance, I've got a diagnosis of cancer, but the diagnosis of cancer should not define me. I'm still a human being with the sorts of activities that I do. And cancer is one side of the life story. Every now and again, I think about cancer. But after that, I put the diagnosis back in the box, and I will carry on. To do this, psychological support would play an immense role, and of course, spiritual support as well.
Thank you for the insightful discussion, it was truly valuable.