Personalization of Therapy in High-Grade Serous Tubo-Ovarian Cancer-The Possibility or the Necessity?

Abstract

High-grade serous tubo-ovarian cancer (HGSTOC) is the most lethal tumor of the female genital tract. The foregoing therapy consists of cytoreduction followed by standard platinum/taxane chemotherapy; alternatively, for primary unresectable tumors, neo-adjuvant platinum/taxane chemotherapy followed by delayed interval cytoreduction. In patients with suboptimal surgery or advanced disease, different forms of targeted therapy have been accepted or tested in clinical trials. Studies on HGSTOC discovered its genetic and proteomic heterogeneity, epigenetic regulation, and the role of the tumor microenvironment. These findings turned attention to the fact that there are several distinct primary tumor subtypes of HGSTOC and the unique biology of primary, metastatic, and recurrent tumors may result in a differential drug response. This results in both chemo-refractoriness of some primary tumors and, what is significantly more frequent and destructive, secondary chemo-resistance of metastatic and recurrent HGSTOC tumors. Treatment possibilities for platinum-resistant disease include several chemotherapeutics with moderate activity and different targeted drugs with difficult tolerable effects. Therefore, the question appears as to why different subtypes of ovarian cancer are predominantly treated based on the same therapeutic schemes and not in an individualized way, adjusted to the biology of a specific tumor subtype and temporal moment of the disease. The paper reviews the genomic, mutational, and epigenetic signatures of HGSTOC subtypes and the tumor microenvironment. The clinical trials on personalized therapy and the overall results of a new, comprehensive approach to personalized therapy for ovarian cancer have been presented and discussed.

Keywords: biomarkers; cancer subtypes; chemo-resistance; epigenetic signature; genomic signature; ovarian cancer; prediction.

Figure 1

“DEPHENCE” system in ovarian cancer treatment. During primary cytoreductive surgery, the samples of the primary tumor and peritoneal metastases are collected for identification of genomic and/or epigenomic signatures. A tumor could be also sampled during exploratory laparoscopy before neoadjuvant chemotherapy. The prognosis of chemo-sensitivity or chemo-refractoriness is a base for planning the therapy. In the case of anticipated chemo-refractoriness, the non-standard therapy is started, whereas in the case of expected chemo-sensitivity, the standard chemotherapy is started. However, independently of the basic therapy, multimodal supplementary treatment is always introduced, including anti-OCSCs and TME therapy combined with immunotherapy or immune-potentization of the patient’s immune system. After the first line of treatment observation of the patient with a classical approach supplemented with repetitive liquid biopsies to monitor for response to therapy and eventually the recurrence are performed. In the case of recurrence, the tumor is again biopsied, or liquid biopsy is performed (it is a better option since ctDNA is freed from all tumor localizations, while harvest of the tissue during ordinary biopsy gives material from only one localization). Again, the genomic/epigenomic signature of the tumor is tested together with markers of chemo-resistance and appropriate personalized therapy is implemented. Similarly, to the first-line treatment, the second-line of therapy is also supplemented with anti-OCSCs and anti-TME drugs and/or immunotherapy. Due to the ovarian cancer genomic heterogeneity and temporal heterogeneity, the therapy should be tailored to the tumor genotype/phenotype and may be completely different in consecutive lines of treatment. After the second-line therapy patient is again subjected to observation and liquid biopsy, until another recurrence. OCSCs—ovarian cancer stem cells; TME—tumor microenvironment; The arrow represents Time.