Ovarian Cancer
Ovarian cancer is among the clearest examples of germline and somatic testing directly shaping the clinical conversation. Homologous recombination status has become a central axis of how advanced high-grade serous disease is discussed.
Disease categories
Major disease categories
- High-grade serous carcinoma
- Low-grade serous carcinoma
- Endometrioid carcinoma
- Clear cell carcinoma
- Mucinous carcinoma
- Germ cell and sex cord-stromal tumours
Molecular
Molecular considerations
BRCA1 and BRCA2 alterations, both germline and somatic, and broader homologous recombination deficiency are central in high-grade serous disease. TP53 alteration is near-universal in high-grade serous carcinoma. Low-grade serous disease carries a different profile including KRAS and BRAF alterations.
Markers commonly discussed in ovarian cancer
- BRCA1/2 (germline and somatic)
- HRD status
- TP53
- CA-125
- MMR / MSI
- KRAS / BRAF (low-grade serous)
- FRα
Not exhaustive, and not every marker is assessed in every patient. Which of these is relevant depends on the individual case and should be discussed with the treating team.
Testing
Genomic testing considerations
Both germline and somatic testing are widely discussed in high-grade serous ovarian cancer, since somatic BRCA alterations occur in tumours without a germline finding.
Germline
Germline considerations
Germline testing is broadly discussed in epithelial ovarian cancer irrespective of family history, with implications for relatives and for cascade testing.
Molecular monitoring
ctDNA and liquid biopsy considerations
ctDNA is under study; CA-125 remains the more established circulating marker in routine discussion.
Single-cell & computation
Single-cell and algorithmic approaches
Single-cell analysis in gynaecological cancer is applied to clonal structure at relapse, where the question is whether resistant disease was present from the outset or emerged under treatment. Single-cell DNA sequencing can identify reversion events in a subpopulation before they are detectable in bulk. Algorithmic work includes homologous recombination deficiency scoring from sequencing data, mutational signature analysis, and molecular classification pipelines.
In practice
What a review of this disease typically surfaces
The pattern most often seen is germline testing performed without somatic testing, or the reverse. Somatic BRCA alterations occur in tumours where the germline is normal, so one test does not substitute for the other. Homologous recombination deficiency status is frequently absent from the record. Where resistance has developed, reversion alterations are rarely looked for despite being a recognised mechanism.
Patterns observed across precision oncology case reviews. Every case differs; these are the questions worth checking, not conclusions about any individual patient.
Decisions
Treatment decision questions
Questions worth raising with a treating team when a decision is being made:
- Has both germline and somatic BRCA testing been considered?
- Has homologous recombination deficiency status been assessed?
- Is the histological subtype secure, given how differently the subtypes behave?
Resistance
Resistance and recurrence questions
- Has a reversion alteration been considered where resistance has developed?
- Has the molecular profile been reassessed?
Trials
Clinical trial considerations
Homologous recombination status and prior therapy are frequently determinative for eligibility.
When a precision oncology review may help
A review is most useful where the standard pathway has been exhausted or where the picture is more complicated than a protocol accounts for — rare presentations, treatment resistance, complex or apparently contradictory molecular findings, or a decision between several defensible options.
The output is a structured analysis and a set of questions for the treating team. It is not treatment, and it does not replace the treating oncologist.