Concluding our 4-part 2022 interview series on cancer, Dr. Achim Regenauer answers questions for Life underwriters on cancer and genetics, questions relating both to cause and to advances in clinical medicine.
There are over 200 known inherited cancer susceptibility syndromes. The majority of these are inherited in an autosomal dominant manner, i.e., from a single mutated gene passed down from either parent. Although many of these are rare syndromes, they account for at least 5 – 10% of all cancer incidences. Just to clarify definitions, these syndromes are not the same as ‘familial cancer’.
Yes there are, and the more of these criteria that are met, the higher the likelihood is that the individual will develop such a syndrome. The criteria are as follows: having two or more relatives with an identical type of cancer on the same side of the family; several generations being affected; earlier ages of cancer diagnosis than is typically for a specific cancer type; and having multiple, primary cancers.
Familial cancer refers to increased cases in families compared to the average, i.e., to what would be expected based only on chance. The increase is often in the range of another (in addition to inherited increases) 10 -15%. In comparison to inherited cancer susceptibility syndromes, familial cancers aren’t linked to a single inherited cancer gene, but to the interaction of low-penetrance genes and the gene environment, and/or to environmental/lifestyle factors.
For underwriting, added together, inherited and familial cancer represents a significant proportion of all cancer incidences. There is also a notable risk of adverse selection. The importance of family history in underwriting questionnaires becomes clear.
Most cancer – 75% to 80% – is in fact sporadic. Basically, each cancer is a genetic disease—that is, cancer is caused by a buildup of mutations in specific genes. Aging, exposure to hormones, environmental toxins and certain viruses can increase the chance of genetic mutations. Normally, the specific genes I just referred to help cells to grow and divide in a controlled manner. The mutation/s for cancer damage this process and, as a result, cells can grow and divide out of control and become cancer.
Sequencing the whole genome (WGS) differs from traditional genetic testing in the sheer volume and complexity of data that it generates. Usually, cancer cell genomes have countless mutations differing them from the host cell genome, though only a few will be clinically material. It is extremely challenging to find out which mutations have which significance for the development of cancer, and which are harmless variations. Thanks to a significant reduction in genomic sequencing costs, digital technology and bioinformatic tools that can analyze complex and large-scale data, understanding of the underlying biology of many types of cancers is set to fundamentally advance over coming years. In the meantime, a new sequencing technology, dubbed next-generation sequencing (NGS), is already available.
NGS enables a higher, faster, more precise and lower cost throughput of genomic sequencing. NGS has led to improved cancer classification and the more precise and earlier diagnosis of cancers, potentially improving the patient’s prognosis.
NGS is invaluable because many cancer therapies are based on actionable genomic alterations/target molecules which pave the way towards personalized medicine (precision oncology). The scope of NGS application is high and expanding fast. In 2019, for example, the number of anticancer therapies targeted against a molecular alteration was already 641.
To give some examples: BRAF V600E for certain melanoma, colorectal cancer and non-small-cell lung carcinoma (NSCLC), HER2 for some breast and gastric cancers, and KIT/PDGFR for gastrointestinal stromal tumors (GISTs)2; all these are approved by the US’s FDA and Europe’s EMA.
Another area of NGS application is for tumor-agnostic therapies. These therapies target specific genomic anomalies or molecular features regardless of a tumor’s site of origin. One example is the administration of pembrolizumab for tumors with a high mutational burden, independent of whether the cancer is neuroendocrine, cervical, anal, vulvar, salivary, endometrial or small-cell lung cancer (SCLC).
Last but not least, looking at cancer evolution, genomic sequencing technologies can also predict, via longitudinal monitoring, treatment resistance and the potential for relapse.
In the US, a National Survey of Precision Medicine in Cancer Treatment3 was conducted in 2017 with impressive results: 75.6% of the surveyed oncologists reported using NGS testing to guide their treatment decisions.
Yes. NGS is currently preferred for patients who have an advanced cancer where actionable mutations are known and adjusted targeted therapies exist. These criteria apply particularly to NSCLC lung cancers, for which it is difficult to obtain traditional tissue samples for testing (biopsy), and to colorectal carcinoma, but also to other rare cancers in advanced stages.
NGS is not generally utilized for cancers in early stages with recognized and effective forms of standard cancer treatment.
However, it’s important to be aware of the fact that this is a snapshot view – the molecular landscape is changing fast, and with each detection of new actionable mutations, the application of NGS will increase.
Yes, and in fact oncology is really in the driving seat for all disciplines in medicine, so this is an exciting field to follow. I should also mention that the term ‘precision oncology’ is commonly used but is not internationally defined. ’Personalized oncology’ and ‘personalized medicine’, for example, are also often referred to.
Beyond targeted, individualized treatments, such as I have described above, genomic sequencing is increasingly applied to decisions around which drug and what dosage of drug, and to detect resistant mutations and residual disease.
For underwriters, precision oncology equates to improved patient outcomes (reduced mortality). It also means a lot more underwriting data. Looking to the medium term, we can expect more molecular cancer subtypes, an assessment of the metastatic potentials and notable changes in survival rates.
As to diagnosis, with NGS we can better distinguish between germline and somatic cancers and better understand molecular pathways – this will topple the traditional classification system of cancers.
And last but not least, in terms of screening, multiple liquid biopsy early cancer detection tests4 are on the horizon.
All-in-all, the insurance industry is challenged to track the swift, ongoing advances taking place in this field and to transfer all new knowledge to underwriting and products.
Advances in medicine over the next decade will largely be determined by oncology. Compared to the previous decade, there is much to indicate that the mortality improvement for many cancers will be significantly higher. Thoroughly monitoring these advances and accordingly updating our underwriting manuals is essential for the future of the industry.
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Achim Regenauer, Chief Medical Officer, Europe and Asia Pacific
3 https://ascopubs.org/doi/full/10.1200/po.18.00169 – A survey of 1,282 practising US oncologists.