When a patient is diagnosed with breast cancer, foremost on her mind is how much time she has left to live.
Advances in diagnosing and treating cancer have led to steadily improving survival rates, so the outlook for women diagnosed today is better than in the past.
With early stage breast cancer, the survival rate at the 10-year mark is 96%.
But the reality is that many individuals have metastatic breast cancer, i.e. cancer that has spread to other organs in the body.
In such cases, only one in five patients will still be alive 10 years after diagnosis.
Says Cancer Research Malaysia (CRM) chief scientific officer Professor Datin Dr Teo Soo Hwang: “In the past, we looked down the microscope to tell us what type of cancer it was, but this didn’t help us to give the right treatment.
“We needed better methods such as genetic ones to understand why some patients go on to survive the disease and others don’t.
“The challenge is, even though Asians make up 50% of the world’s population and cancer population, we make up less than 5% of genomics research.
“Nearly 78% of the studies out there were conducted in European populations.
“It is critical for us to close the gap in Asian genomics research, otherwise we may miss important genetic information that may be rare in Caucasians, but common in Asians.”
She offers a simple explanation of what genomic research is all about: the genome is essentially like a reference book, which scientists can make a copy of to figure out if any of the instructions in it have mutated or been altered.
“For example, in a recipe book, if we copy the recipe wrongly and use four eggs instead of 40 eggs, it will result in a cake that is ‘mutated’ with excess protein.
“In cancer cells, there has been a mutation at the DNA (deoxyribonucleic acid) level, which results in a change of instruction to the cell, which then produces proteins that are mutated, which then tells the normal cells to behave wrongly and grow when they shouldn’t grow,”
To map the genome of Asian breast cancer cells, CRM collaborated with the University of Cambridge in the United Kingdom and Subang Jaya Medical Centre in Selangor, to collect samples from over 1,000 patients for analysis.
To date, the collaboration that began in 2012, has built the largest genetic and genomic database of Asian breast cancers.
Last month (December 2020), they published a study in the journal Nature Communications titled The Molecular Landscape on Asian Breast Cancers Reveals Clinically Relevant Population-Specific Differences.
“Through our study, we discovered that Asians are at higher risk of an aggressive type of breast cancer, are more likely to have a mutated TP53 gene, and have an enriched immune tumour profile,” says Prof Teo, who led the study.
Aggressive subtype
From years of research, we know that there are three different types of breast cancer: hormone receptor positive (80% of cases), human epidermal growth factor receptor-2 (HER2) positive and triple negative.
In the study, the genomic sequences of 560 breast cancer tumour samples were analysed and it was discovered that the aggressive subtype that expresses the HER2 protein is more common in Asian women compared to Caucasians.
Most people with breast cancer have a normal amount of the HER2 protein (that comes from the HER2 gene), which means they are HER2-negative.
In HER2-positive cases, the HER2 protein levels are unusually high.
These proteins play a role in healthy breast cells by controlling how fast they divide, grow and repair themselves.
When the HER2 gene makes too many copies of itself, it leads to a situation called “protein overexpression” and results in breast cells that divide and grow too quickly.
Compared with HER2-negative breast cancers, HER2-positive breast cancers tend to grow quickly, spread more easily and recur more often.
A patient’s HER2 status can change as the cancer grows or returns, i.e. a HER2-positive cancer can become HER2-negative and vice versa.
Prof Teo says, “With hormone receptor positive breast cancer, we know of certain risk factors, e.g. early menarche, whether you’ve had kids, how old you were when you had kids etc, but we know almost nothing about the risk factors associated with HER2-positive cancer, so this is an important area of research.
“We know that patients who are HER2-positive need targeted therapy and we have to ensure that they have access to these treatments.”
Adds consultant breast surgeon Emeritus Prof Datuk Dr Yip Cheng Har, who was part of the study: “The HER2 subtype of breast cancer is one of the most aggressive and fastest growing, and it is becoming clear that the risk factors may be different from other types of breast cancer.
“Our study highlights that Asians have a higher risk of this type of aggressive disease and underscores the need to do more research in Asians so that we can save more lives.”
Mutated ‘guardian’
The study also discovered that Asians are more likely to have a mutated TP53 gene.
The TP53 gene, often called the “guardian of the genome” because it protects normal cells from becoming cancer cells, was found to be altered more frequently in Asian breast cancers compared to that of Caucasians.
“TP53 is frequently mutated in the more aggressive hormone negative breast cancers in Caucasian women.
“In Asian breast cancer patients, we observed an increase in TP53 mutations in hormone receptor positive cases, which is associated with poorer survival,” says University of Cambridge senior research associate Dr Chin Suet-Feung, who co-led the study.
Adds Prof Teo: “We don’t understand too much about it at this point and there is no specific therapy that targets this TP53 mutation.
“Presently, there are many approaches, but again, we don’t know yet which of these therapies will work more efficiently to remove the mutation before it does more harm.”
Active immune cells
Perhaps the most exciting discovery, Prof Teo reckons, is that Asians tend to have an enriched immune tumour profile.
“Across all different types of breast cancer, Asians have immune active cells (“hot cancers”) that are present within the cancerous tumours; but for some reason, the immune cells are not able to recognise these tumour cells as a foreign entity and do not actively destroy them,” she shares.
According to the scientist, if these immune cells could be activated to recognise that the cancer cells around them are foreign entities, they would be able to destroy the cancer cells.
Immune inactive “cold cancers”, by contrast, are cancers that, for various reasons, haven’t been recognised by or provoked a strong response from the immune system.
These immune cells are thus unable to even penetrate the tumour.
In “hot cancers”, immunotherapy might be able to help kick the immune cells within the tumour into action.
Immunotherapy is a type of biological therapy that uses substances made from living organisms such as white blood cells, tissues and organs of the lymph system, to stimulate or boost your immune system so that it works harder to find and attack cancer cells.
Prof Teo says, “What we are now testing is whether people with this immune profile are more likely to respond to checkpoint inhibitor therapy (a type of immunotherapy).”
Interestingly, research shows that almost no one in the African continent has this particular immune profile.
It’s also rare in the European population.
But more than half of the Asian population and nearly 90% of the Polynesian population have this immune profile. (See map above)
CRM, in partnership with oncologists at Universiti Malaya and National University Hospital, Singapore, have already rolled out a clinical trial called Auror, which aims to test the effectiveness of immunotherapy in Asian metastatic breast cancer patients with these “hot cancers”.
“If we can find some way to lift the invisibility cloak that cancers have to evade detection by the immune system, we may be able to improve survival for Asian breast cancer patients,” says the study’s first author Dr Pan Jia Wern.
A second clinical trial called Tenor, is expected to open within the next three months.
This will look at the genomic footprints carcinogens have left in the DNA of cancer cells, as they are known to damage DNA and cause mutations that can lead to cancer.
Prof Teo says: “A fellow scientist friend put it this way: If we go the beach and see footprints in the sand, we can tell which one was generated by a bird, dog, human, etc.
“Similarly, by examining the genome, we can tell which one was left by carcinogens such as nicotine, radiation or different sources.
“Then we can identify genomically unstable cancers.”
She concludes, “Our next step is to figure out why Asians are different from Caucasians because we don’t want Asians to be left out in the fight against cancer.”
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