Keywords
1. Platinum retreatment in ovarian cancer
2. Homologous recombination deficiency
3. CCNE1 copy number alterations
4. RB1 gene loss
5. Genomic profiling in ovarian cancer
Ovarian cancer remains one of the most formidable gynecologic malignancies worldwide, accounting for significant morbidity and mortality in affected women. Advances in genomic medicine have shed light on the heterogeneity of ovarian cancer and its therapeutic responses. A recent study published in BMC Cancer by da Costa et al. has highlighted pivotal findings that could redefine the approach to treating platinum-resistant ovarian cancer—a subtype known for its poor prognosis and limited treatment options.
The study, entitled “Genomic profiling in ovarian cancer retreated with platinum-based chemotherapy presented homologous recombination deficiency and copy number imbalances of CCNE1 and RB1 genes,” provides compelling evidence that genomic alterations can influence the responsiveness to platinum-based chemotherapy in ovarian cancer patients. Patients presenting with homologous recombination deficiency (HRD) appeared more sensitive to such treatment. The full reference for this groundbreaking study is listed below:
da Costa, A.A.B.A., et al. Genomic profiling in ovarian cancer retreated with platinum-based chemotherapy presented homologous recombination deficiency and copy number imbalances of CCNE1 and RB1 genes. BMC Cancer. 2019 May 06;19(1):422. DOI: 10.1186/s12885-019-5622-4.
The Retreatment Dilemma with Platinum-Based Chemotherapy
Ovarian carcinomas frequently develop resistance to initial platinum-based chemotherapy, resulting in limited options for subsequent treatment lines. However, in some cases, patients with disease resistant to platinum drugs are rechallenged with a platinum compound, with varying degrees of success. It’s imperative to discern which patients might benefit from such a retreatment; thus, the study by da Costa et al. is a pivotal step in understanding the underlying genomic landscape that may determine the response to platinum rechallenge.
Homologous Recombination Deficiency (HRD) and Its Association with Treatment Response
The study retrospectively analyzed data from 31 patients with platinum-resistant ovarian cancer who were retreated with platinum-based therapies. The main thrust was to correlate genome-wide copy number alterations and homologous recombination repair mutations with the response to treatment. The revelation was striking: the median values of the four HRD scores were discernibly higher in patients who responded to platinum retreatment (responders) compared to those who didn’t (non-responders).
CCNE1 and RB1 Alterations as Predictors of Response
The escalation in genomic profiling has allowed clinicians to identify specific genetic alterations that could serve as biomarkers for predicting treatment response or survival outcomes. The BMC Cancer study identifies two genes—CCNE1 and RB1—whose copy number imbalances are associated with response to platinum retreatment. CCNE1 gains were linked to a dismal response rate and survival outcomes, whereas RB1 loss appeared to predict a better response to platinum therapy.
The Potential of Targeted-Next Generation Sequencing
Da Costa et al. employed targeted-next generation sequencing (NGS) to explore the mutational profile of 24 genes in ovarian cancer patients. Although BRCA mutations were not associated with response rates, the research posits that employing such cutting-edge technology could eventually lead to individualized therapeutic strategies where treatment decisions are driven by specific genomic aberrations.
Implications and Ethics of the Study
This study has significant implications for the clinical management of ovarian cancer, offering hope that genomic profiling could enhance the precision of treatment for platinum-resistant disease. The research adhered to the guidelines stipulated by the Declaration of Helsinki and received approval from the AC Camargo Cancer Center Ethics Committee (CEP# 1933/14). The need for informed consent was waived due to the retrospective nature of the study.
Future Directions and Conclusion
The insights drawn from this study could pave the way for the use of genomic profiling as a standard approach to identify ovarian cancer patients likely to respond to platinum retreatment. However, larger-scale prospective studies are needed to validate these findings and translate them into routine clinical practice.
The potential to use HRD scores and genetic alterations of CCNE1 and RB1 as prognostic markers opens the door to a future of personalized medicine in ovarian cancer. The fight against this relentless disease may become more effective with the incorporation of such precise biomarkers in clinical decision-making.
References
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30. doi: 10.3322/caac.21442.
2. Jayson GC, Kohn EC, Kitchener HC, Ledermann JA. Ovarian cancer. Lancet. 2014;384:1376–1388. doi: 10.1016/S0140-6736(13)62146-7.
3. Coleman RL, Oza AM, Lorusso D, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy. Lancet. 2017;390:1949–1961. doi: 10.1016/S0140-6736(17)32440-6.
4. Konstantinopoulos PA, Ceccaldi R, Shapiro GI, D’Andrea AD. Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian Cancer. Cancer Discov. 2015;5:1137–1154. doi: 10.1158/2159-8290.CD-15-0714.
5. Garsed DW, Alsop K, Fereday S, et al. Homologous recombination DNA repair pathway disruption and retinoblastoma protein loss are associated with exceptional survival in high-grade serous ovarian Cancer. Clin Cancer Res. 2018;24:569–580. doi: 10.1158/1078-0432.CCR-17-1621.
The findings of this research are crucial as they provide a tangible step towards tailoring treatments for ovarian cancer patients who have limited therapeutic options. By harnessing the potential of genomic profiling, there is renewed hope that the relentless progression of platinum-resistant ovarian cancer can be mitigated, offering patients both improved outcomes and quality of life.