Can pre-emptive germline testing and genomics help resolve challenges in cervical cancer?
By Dr. Aarti Darra, Bioinformatician, Karkinos Healthcare
Cervical cancer is the fourth most common cancer in females worldwide with around 85% cases coming from developing countries. However, it is the second most common cancer in females in India. It is estimated that one woman dies every two minutes due to cervical cancer.
Despite a large number of people affected, the knowledge and awareness about cervical cancer is limited. More than 90% of positive cases are caused due to Human PapillomaVirus (HPV). HPV is a common virus, infecting humans. The virus has a circular DNA genome of 8 kb and encodes for 8 major proteins. There are multiple subtypes of HPV, each determined by specific genetic mutations in the viral genome. The benign subtypes of HPV cause conditions like skin warts, but a small number of subtypes are associated with cancers.
HPV has a long pre-clinical phase and its persistence over decades inside the body can lead to precancerous changes. There are presently 120 subtypes of HPV currently known, out of which 14 subtypes have been associated with an elevated risk of developing cancer and are therefore called high-risk genotypes. Around 55% of cervical cancers are caused by HPV16 and remaining by other high risk subtypes include HPV 18, 31, 45.
How can HPV infections and therefore cancer be prevented?
A safe and effective HPV vaccine is now available, with variable protection against specific genotypes of the virus. Early administration of the vaccine can prevent the infection of the specific HPV subtype and therefore this is also known as primary prevention of cervical cancer. Present vaccines are approved for and are recommended to be administered to individuals between the age of 9 to 14.
HPV infection over a long and persistent period would be required to cause cancer. Therefore early screening of high-risk genotypes as well as cellular changes in the cervix can provide an opportunity for early diagnosis and treatment. The screening of HPV can be performed using a simple RT-PCR test for the high risk subtypes of the virus, from a swab obtained from the female genital tract. The samples can be obtained on your own (self-sampling), or can be assisted by a healthcare provider.
The RT-PCR test is based on the fact that specific high-risk genotypes of HPV can be detected based on specific mutations in their genome very specifically.
If you are positive for a high-risk HPV genotype, it does not mean that you have cancer. It only means that you are at an elevated risk of developing cancer. The infection is self-limiting in many cases, and therefore your healthcare professional would advise you routine monitoring of the HPV infection as well as follow up with additional investigations if necessary.
Why is early diagnosis important?
Current estimates reveal the burden of cervical cancer is staggering. Every year, 1,23,907 women are diagnosed with cervical cancer and 77,348 die from the disease.
These incidences of cervical cancers can be prevented by early diagnosis. It is recommended that the women after 30 must get screened using a cytology based, PAP (Papanicolaou) smear test or Nucleic acid based HPV DNA testing.
PAP smear involves collecting cells from the cervix and examining the cells by preparing a smear and grading it. Detecting cervical cancer using PAP smear gives a greater chance at its cure.
Another is HPV DNA testing where cervical cancers are scanned for the presence of HPV DNA, if the test results come positive, HPV subtyping is performed to identify the genotype causing the infection. The combination of these methods could significantly increase the window of screening time for women tested negative by both the methods.
Can pre-emptive germline testing be useful in cervical cancer?
Evidence from across the world suggests around 10% of patients with cancer have a germline or hereditary genetic variant, which make them predisposed to developing cancer. Understanding the gene and variant could have implications in screening additional members in the family through a cascade approach and in some cases, to determine treatment and follow-up of the patient.
A recent study on germline testing in cervical cancer suggested approximately 6.4% of cervical cancer patients in a cohort from China have germline variants. While guidelines do not yet suggest universal pre-emptive testing in cervical cancer, patients with a family history, previous history/recurrent of cancer and very early onset cervical cancer may possibly avail the benefit of genetic counseling and pre-emptive germline testing.
So, what is the current state of treatment of cervical cancer and how might genomics support cervical cancer treatment?
Treatment for locally advanced cervical cancer involves chemotherapy using a number of anticancer drugs. The current guidelines suggest chemotherapy with either Fluorouracil or Cisplatin alone as the first line of treatment. Gemcitabine, Paclitaxel, and Capecitabine are other medications that are also used. For recurrent and metastatic cervical cancer, concurrent Cisplatin/radiotherapy or monoclonal antibodies like Pembrolizumab combined with chemotherapy, with or without Bevacizumab is suggested in the treatment regimen.
How is pharmacogenomics testing important for Cervical Cancer?
Fluoropyrimidines (fluorouracil, capecitabine, and other analogs) are widely used in cervical cancer. Individuals with mutations in the Dihydropyrimidine dehydrogenase (DPYD) gene, a key gene involved in the metabolism of these drugs are prone to increased toxicity against these drugs. These genetic variants associated with a different rate of metabolism of the drugs are not very rare in the population. This can be mitigated by changing the dose of the drug, using alternatives or avoidance of the drug depending on the specific genetic variants that you have. A number of international bodies have therefore issued guidelines suggesting preemptive pharmacogenomic testing in individuals planned for these drugs.
For metastatic cancer, chemotherapy as the second line/ subsequent treatment is advised and following options are recommended: Bevacizumab, Paclitaxel, Albumin-Bound Paclitaxel, Docetaxel, Fluorouracil, Gemcitabine, Pemetrexed, Topotecan, Vinorelbine, And Irinotecan. As mentioned above, DPYD testing is recommended before administering fluoropyrimidines.
For individuals with metastatic cancer, there are a number of other ways genomic testing can impact the treatment. This include individuals having a high mutation rate in their genome, assessed by a genomic test called tumour mutation burden or TMB for short, as well as individuals who have instability of their genome in specific locations, assessed by another genomic test called Microsatellite Instability or MSI for short , immunotherapy is suggested using pembrolizumab. Another drug, Tisotumab vedotin tftv is a preferred therapy on or after chemotherapy regardless of biomarker status. Lastly, Cemiplimab was added as a preferred, second line/subsequent therapy option.
In certain circumstances, the decision on the choice of therapeutic is based on genomic testing for specific biomarkers, especially for the second line / subsequent therapy. This includes Selpercatinib for RET Gene Fusion–Positive Tumours in patients with locally advanced or metastatic cervical cancer or Larotrectinib and entrectinib (TRK Inhibitors) for NTRK Positive Tumours, and Trastuzumab Deruxtecan for HER2-Positive Tumours.
How can genomics help resolve challenges in cervical cancer?
The role of genomics is key in the screening, diagnosis and management of cervical cancer and the molecular understanding could provide high dividends by making treatment precise and biomarker directed.
There is indeed active interest in understanding the genomic landscape and utilising genomic biomarkers for developing therapeutics and using biomarkers for classification and prognostication of cervical cancer. While most cervical cancers are HPV driven, the HPV-independent subtype has a less favorable prognosis compared with HPV-associated.
Understanding HPV independent cases of cervical cancer could enable the discovery of better diagnostic biomarkers. Moreover, the treatment strategy of squamous cell carcinoma and adenocarcinoma/ adenosquamous carcinoma are subjected to the same treatment even though the clinical features and prognosis differs considerably.
Thus, while pre-emptive genomic testing can provide insights into germline predisposition and can offer pharmacogenomic guidance towards precise treatment, a comprehensive genomic profiling of tumours could enable targeted therapies and in future could fill this gap by identifying potential candidates for targeted therapy in patients with varied histology of cervical cancer.
I am a Bioinformatician working at Karkinos Healthcare, and my dedication extends beyond routine clinical responsibilities, with a particular emphasis on contributing to the betterment of patient outcomes.