Epithelial ovarian cancer (EOC) is the third most common cancer among Indian women.
Despite the advances in their management, EOC patients have the highest mortality
among gynecological cancers.[1] Globally, nearly 70% of EOC is present in stage III/IV and this reflects poor survival
outcomes. This makes cancer prevention and early detection a high research priority.
The presence of pathogenic germline mutation with a predisposition to cancer development
and a personal or family history of cancer are among the most important risk factors
for the development of EOC.
Across different parts of the world, EOC has been reported to have the highest prevalence
of germline genetic mutations (10–40%) among all the cancers occurring in females.[2]
[3]
[4] This variation in prevalence is partly determined by the selection criteria for
genetic testing. Recognizing this high probability of underlying germline mutations,
various professional societies and NCCN, have recommended germline genetic testing
for EOC.[5]
[6] These guidelines suggest using different criteria based on family history, age at
diagnosis, or histology.[5]
[6]
Various societies suggest using different criteria to select patients for genetic
testing for several reasons such as the high cost of testing, prolonged wait times
for genetic counseling, and the adverse impact these results may have on health insurance,
psychosocial and mental state, and family dynamics. Selection based on family history,
age at diagnosis, or histological characteristics help to enrich the cohort for genetic
counseling and testing. However, it is being increasingly recognized that germline
pathogenic or likely pathogenic variants may be identified in EOC patients who do
not fulfill certain genetic testing criteria.[7]
[8] This is due to incomplete penetrance, paternal inheritance, unreliable family history,
or small family size.
Moreover, the frequency and spectrum of BRCA1/2 and other gene mutations vary in different geoethnic groups.[2]
[3]
[9] The frequency and the type of mutations associated with various histologies also
differ.[9]
A study from Ontario evaluating physician practices showed that genetic testing rates
and referrals reduce with the increasing complexity of testing criteria.[10] Research studies employing germline multigene panel testing of large unselected
EOC populations could provide a more reliable estimate of the prevalence of germline
mutations and the most commonly mutated genes in EOC cases in the population. This
information would facilitate genetic counseling and help frame evidence-based guidelines
for genetic testing, which is an expensive test with a turn-around time of 4 to 6
weeks.
This study provides the much-required detailed information of the prevalence in unselected
Indian ovarian cancer patient population (15.5%) while also providing estimates for
various enriched subgroups of patients who are ≤ 50 years (22.2%), serous epithelial
ovarian cancers (25.2%), or those with a family history of cancer (55.6%).[11] The results show that the prevalence of germline mutations is much higher than most
solid tumors. Contrary to expectations, subgroups such as non-serous (13.8%), older
than 50 years (20.8%), or those without a family history (20.2%) also had a clinically
relevant prevalence of germline mutation.[11] This implies that several patients will be unable to qualify for the genetic test
if any selection criteria are used. Identifying the maximum number of index EOC cases
will not only help to personalize their therapy, provide cancer surveillance, and
ensure future cancer prevention but also extend the benefit of identifying family
members who have inherited the mutation and through culturally sensitive and evidence-based
genetic counseling, testing, and risk management approaches.[12]
[13] The recent negative results of the UK Collaborative Trial of Ovarian Cancer Screening
study of lack of benefit of ovarian cancer screening using annual transvaginal ultrasound
or longitudinal CA-125[14] highlights the continued relevance of timely risk-reducing salpingo-oopheorectomy
for women with germline BRCA1/2 mutations.
With patients enrolled from three centers in Delhi, two in Mumbai, and one each in
Bengaluru and Hyderabad, major geoethnic groups within India are likely to be represented.
However, with a relatively small cohort of 239 cases and the non-inclusion of several
large and small Indian states, several geoethnic groups with a different population
prevalence of germline BRCA mutations and founder mutations would be under-represented. Furthermore, it is unclear
if this represents a consecutive patient cohort or some form of selection was present.
As seen previously in many studies that selecting patients based on any criteria can
inflate the prevalence leading to erroneous estimates. In addition to the BRCA1/2 genes, mutations in other genes associated with the development of ovarian cancer
such as PALB2, PRIB1, the core RAD genes, CHEK2 among others were not reported even though a 94 gene NGS panel was used.[2]
[7]
[11] Moreover, copy number variation or large genomic rearrangement were not reported,
which potentially lead to underestimation of the prevalence.
Are we ready to implement genetic counseling and testing in unselected EOC population?
As per the GLOBOCAN 2018 data, more than 36,000 ovarian cancer patients are diagnosed
every year in India, with the vast majority being EOC.[1] Currently, in India, there are a limited number of trained genetic counselors and
pre-test genetic counseling will be the rate-limiting step if unselected population
testing is implemented. Therefore, before the implementation of unselected population
testing, building the required capacity and infrastructure by adopting the mainstreaming
pathway is required. Here, the primary care physician/oncologist provides pre-test
counseling for patients without a significant family history or psychosocial issues
and detailed post-test counseling of mutation carriers in the cancer genetics clinic.
Such a model has been adopted in the UK and Malaysia and has been shown to improve
access to genetic testing by reducing waiting times for counseling.[15]
Thus, this study provides important information on the prevalence of germline mutations
among ovarian cancer patients from India and leads to the realization of many challenges
with its practical implementation across the country. There is a need for such studies
to generate the prevalence of germline mutations in other cancer-predisposing genes
in ovarian cancers of different histologies and other common cancers among Indian
patients. This is among the first few steps toward the expansion of access to genetic
testing among cancer patients and their family members in India.
