Abstract
The emergence of precision medicine and our latest understanding of the biological characteristics of ovarian cancer (OC) have led to the discovery of drug targets, novel anticancer agents, and their predictive biomarkers. The genetics of OC is an evolving biomarker for predicting outcomes. Several completed and ongoing clinical trials used this concept for better patients’ selection and stratification. The exploitation of specific molecular vulnerabilities in OC for drug development such as BRCA and BRCAness is a milestone in the current management of this women’s cancer. Without a doubt, OC is one of the solid cancers that have benefited from genetic biomarkers for the implementation of targeted agents such as PARP inhibitors in clinical practice. This progress is discussed in this chapter based on recent studies and clinical trials.
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4.1 Introduction
Few therapeutic advances were achieved in improving survival outcomes in the first-line therapy of ovarian cancer (OC). However, predictive and prognostic biomarkers have considerably changed outcomes in some settings in women with this aggressive cancer (Le Page et al. 2020a; b; El Bairi et al. 2017a, b; Madariaga et al. 2020). An illustrative example is the important number of clinical trials, prospective studies, and retrospective real-world cohorts that have demonstrated the favorable impact of BRCA mutations on therapy response and prognosis in OC (Madariaga et al. 2019; Lorusso et al. 2020). Moreover, BRCA mutations and other variants in homologous recombination repair (HRR) genes are now used for OC patients’ selection for poly-ADP-ribose polymerase inhibitors (PARPi). BRCA, BRCAness, and HRR are associated with genomic instability and synthetic lethality in OC and are potential predictors of pharmacological sensitivity to platinum agents and PARPi (Konstantinopoulos and Matulonis 2018). Remarkably, as a result of the relevant success of cancer genetics in the field of translational oncology, there is an increasing number of clinical trials in OC that use genetic alterations as biomarkers for patient’s selection, stratification, and prediction of drug response; particularly using umbrella and basket trial designs (Tsimberidou et al. 2020). As described in the other chapters of this book, some of their results provided considerable information for clinical use and it is not surprising to see other starting and ongoing trials in this highly active research area of OC. The current chapter focuses on the impact of genetic variants on outcomes in OC.
4.2 Ovarian Cancer Genetics as a Biomarker of Response to Chemotherapy and Survival Outcomes
Platinum-based chemotherapy is currently considered the backbone of OC therapy. Carboplatin and cisplatin bind to DNA and induce structural adducts which in turn cause considerable damages to cancer cells, and therefore driving cell cycle arrest and mitochondrial apoptosis (Galluzzi et al. 2012). Enhanced response to these anticancer drugs is observed in patients with mutated BReast Cancer 1 and 2 genes (BRCA1/2) which confer impairment of DNA repair mechanisms (Quinn et al. 2009; Madariaga et al. 2019). Several preclinical reports have shown that cells harboring BRCA variants have superior sensitivity to platinum-based chemotherapy (Madariaga et al. 2019). This loss of function is considered the key driver of responsiveness to these agents and is a well-established predictive biomarker in OC. Clinically, women with both germline and somatic mutated BRCA were found to have increased response to platinum-based chemotherapy (Alsop et al. 2012; Gorodnova et al. 2015; Vencken et al. 2011; Pennington et al. 2014; Leunen et al. 2009) (for detailed review, see: Le Page et al. 2020a, b). During a relapse, these improved outcomes were also observed in platinum-resistant OC with BRCA mutations (Alsop et al. 2012). Thus, platinum re-challenge is an approach for recurrent OC patients with germline mutated BRCA carriers (Madariaga et al. 2019). In addition to high immune infiltrates, increased mutational burden, and loss of heterozygosity, BRCA mutations are considered as key determinants of exceptional long-term OC survival (Yang et al. 2018; Hoppenot et al. 2018). This was further confirmed by several meta-analyses of survival outcomes in OC (summarized in Table 4.1). Remarkably, a large study that enrolled 316 high-grade serous OC patients found that BRCA2, but not BRCA1, was associated with superior chemotherapy response and also improved survival outcomes (Yang et al. 2011). Mechanistically, both BRCA1 and BRCA2 are important complementary members of the genes involved in DNA damage repair. However, accumulating evidence suggests that the principal function of BRCA2 is the regulation of RAD51 that has a pivotal role in double-strand break repair (Davies et al. 2001) rather than tumor suppression ensured particularly by BRCA1. Functions of BRCA1 encompass cell cycle arrest checkpoint control (Yarden et al. 2002; Sharma et al. 2018), mitotic spindle assembly (Joukov et al. 2006; Xiong et al. 2008), and centrosome duplication (Mullee and Morrison 2016; Kais et al. 2012; Sankaran et al. 2007; Hsu and White 1998) and their failure can predispose to cancer initiation rather than conferring sensitivity to platinum DNA-crosslink agents. Therefore, these fundamental data may explain this difference in survival and drug response in this previous study. Importantly, the “mutator phenotype” hypothesis in OC patients with mutations beyond BRCA1 is a potential driver of chemotherapy response in this setting as well. Despite these important observations, the acquisition of reversion mutations in BRCA genes can restore BRCA proteins expression and induce resistance to platinum-based therapy and also PARPi (Milanesio et al. 2020). Therapeutically, a recent meta-analysis documented that pharmacological blockade of DNA end-joining repair signaling may improve the stability of drug response by preventing the acquisition of reversion BRCA mutations (Tobalina et al. 2021). Promisingly, detection of these reversion mutations can be performed using real-time liquid biopsy approaches. Based on massively parallel targeted sequencing, Weigelt et al. showed recently that prospective evaluation of circulating-free DNA has the potential to non-invasively identify putative BRCA1 or BRCA2 reversion mutations with restored functions in women with OC and breast cancer (Weigelt et al. 2017). Similarly, two other recent reports confirmed these findings and showed that detected BRCA mutations using liquid biopsy in OC patients are associated with acquired resistance to treatments (Christie et al. 2017; Lin et al. 2019). Methylation phenomena in BRCA1 promoter were also suggested as a biomarker of chemosensitivity in OC (Ignatov et al. 2014). However, a meta-analysis of individual data (n = 2636) demonstrated that patients with BRCA1-methylated OC had similar survival outcomes as compared to those with non-BRCA1-methylated tumors (Kalachand et al. 2020). Other mutated genes outside the BRCA family (Table 4.2) such as members of the HRR pathway particularly RAD51, which are found in approximately 50% of high-grade serous OC, were also found to predict chemosensitivity (Fuh et al. 2020; da Costa et al. 2019). Moreover, this HRR deficiency has also a value for prognostic stratification of OC patients (Takaya et al. 2020; Morse et al. 2019). Patients with this fundamental vulnerability had high infiltration of immune cells particularly tumor-infiltrating lymphocytes (TILs) which correlate with better survival and may make these women highly responsive to immune-checkpoint blockade (Ledermann 2019; Morse et al. 2019; Konstantinopoulos et al. 2015) (see Chap. 3 for details). Currently, this biomarker is used for predicting response to PARPi rather than platinum-based chemotherapeutics. The European Society for Medical Oncology (ESMO) stated that assays for clinical evaluation of HRR deficiency are useful in predicting the likely magnitude of benefit from PARP inhibition but additional biomarkers with improved accuracy are needed to better stratify patients (Miller et al. 2020).
Research in this area of biomarkers discovery has also provided other perspectives for non-platinum chemotherapy such as the natural compound trabectedin and pegylated liposomal doxorubicin (PLD) (Madariaga et al. 2019; El Bairi et al. 2019). Trabectedin (known as Yondelis®) is a marine compound isolated from the colonial tunicate Ecteinascidia turbinate that acts as a cytotoxic alkylating agent and also as a vascular disruptor (El Bairi et al. 2019). It was approved in several countries of the European Union for the treatment of OC as a late-line therapy in combination with PLD for recurrent platinum-sensitive disease. The efficacy of trabectedin was found associated with deficient HRR systems in various clinical trials (El Bairi et al. 2018; Ventriglia et al. 2018). Previously, an exploratory analysis of the randomized phase 3 OVA-301 study that compared the efficacy of trabectedin and PLD versus PLD alone in women with recurrent OC showed that germline BRCA1 mutant tumors had improved median PFS (13.5 vs. 5.5 months, p = 0.0002), OS (23.8 versus 12.5 months, p = 0.0086), and higher response rates (49 vs. 28%) (Monk et al. 2015). Moreover, women with BRCA wild-type OC had no improvements in median OS (19.1 versus 19.3 months; p = 0.9377) (Monk et al. 2015). BRCA status and BRCAness were also used for patients’ selection in the MITO-15 phase II study that investigated trabectedin in women with recurrent OC (Lorusso et al. 2016). BRCA status was not associated with response to trabectedin nor with survival (Lorusso et al. 2016). However, the recent findings of another randomized phase III trial that compared the efficacy of trabectedin combined with PLD in the same previous setting showed significant overall survival (OS) benefits for patients harboring BRCA mutations (34.2 vs. 20.9 months; HR: 0.54, 95% CI: 0.33–0.90; p = 0.016) (Monk et al. 2020). Similarly, improved outcomes for median PFS were also noticed for patients with BRCA mutant tumors (HR: 0.72, 95% CI: 0.48–1.08; p = 0.039) (Monk et al. 2020). The DNA damaging agent PLD used in the recurrent setting was also found to be more effective in tumors with BRCA mutations. Two previous retrospective studies demonstrated that BRCA-associated OC women had improved sensitivity to PLD, greater PFS (Adams et al. 2011), and also OS (Safra et al. 2014). Regarding taxane chemotherapy which is used in combination with carboplatin in the first-line setting as a standard of care and as a single agent for recurrent platinum-resistant disease; data on BRCA as a predictor of response are sparse. In prostate cancer, the correlation between mutated BRCA and poor response to docetaxel was noticed (Nientiedt et al. 2017). In addition, mutated BRCA1-associated breast cancer was found less sensitive to taxane chemotherapy (Kriege et al. 2012). In OC, the inhibition of endogenous BRCA1 expression was reported to be associated with decreased sensitivity to antimicrotubule agents (Quinn et al. 2007). Moreover, median OS in patients with higher BRCA1-expression was found improved after treatment with taxanes (23 vs. 18.2 months; HR: 0.53; p = 0.12) (Quinn et al. 2007). Other emerging genes that might impact drug response and prognosis in OC can be found in Tables 4.2 and 4.3.
4.3 Ovarian Cancer Genetics and Response to PARP Inhibitors
DNA damage response pathway is one of the invested targets in drug discovery for OC. PARP 1 and PARP2 are the principal enzymes of this pathway and are recruited during DNA lesions to orchestrate repair effectors activity (Lord and Ashworth 2017). PARP bound to damaged DNA and transfer poly-ADP-ribose units to various target proteins (PARylation process) required for DNA breaks repair such as topoisomerase and DNA ligase (for review, see: Franzese et al. 2019). Inhibition of PARP mediated DNA repair appeared to be a potential strategy that is widely known as synthetic lethality (Lord et al. 2015; Lord and Ashworth 2017) and has moved successfully into clinical trials several PARPi including rucaparib (Rubraca®), olaparib (Lynparza®), veliparib (ABT-888), niraparib (Zejula®) as well as the next-generation of this category such as talazoparib (Talzenna®). In 2005, two preclinical reports were published in Nature by Farmer et al. and Bryant et al. showed that mutant cancer cells with BRCA dysfunction are highly sensitive to PARP inhibition (Farmer et al. 2005; Bryant et al. 2005). Based on these substantial findings, this new concept was used as a rationale for developing trial designs of several PARPi for various cancers harboring this signature. In OC, many clinical studies that investigated oral PARPi have achieved their primary objectives and showed positive results from phase II-III trials in the front-line, for recurrent disease, or maintenance settings following platinum-based chemotherapy (Table 4.4).
4.3.1 Olaparib
Olaparib was the first-in-class developed PARPi and approved by the FDA and EMA in 2014 for treating OC (Franzese et al. 2019). Early trials (NCT00516373 and NCT00494442) showed favorable safety and tolerability profile which were represented mainly by reversible fatigue, anemia, and mild gastrointestinal symptoms (Fong et al. 2009, 2010; Audeh et al. 2010). Interestingly, these dose-finding trials demonstrated significant antitumor response in OC patients with BRCA mutations (Fong et al. 2010; Audeh et al. 2010). In a second interim analysis of OS and a preplanned analysis of data by BRCA mutation status of a randomized and double-blind phase II study (NCT00753545) that used olaparib as maintenance treatment for recurrent platinum-sensitive OC, Ledermann et al. found that patients with mutated BRCA had significantly longer PFS as compared with wild-type subjects (11.2 vs. 7.4 months) (Ledermann et al. 2014). However, in terms of OS, no significant difference was seen between the two groups (HR: 0.73; 95% CI: 0.45–1.17; p = 0.19 for BRCA mutated status and (HR: 0.99; 95% CI: 0.63–1.55; p = 0.96) for wild-type BRCA) (Ledermann et al. 2014). Moving from this immature evidence, the greatest clinical benefit was observed in BRCA-mutated recurrent and platinum-sensitive OC patients in another randomized phase II trial (NCT01081951) combining olaparib with standard chemotherapy (Oza et al. 2015). PFS in patients with mutated BRCA was significantly improved (HR: 0.21; 95% CI: 0.08–0.55; p = 0.0015) (Oza et al. 2015). These data were supported by an updated analysis of OS of NCT00753545 trial and showed that BRCA-mutated platinum-sensitive recurrent OC patients appear to have longer OS despite it did not achieve the planned level for statistical significance (p < 0.0095) (Ledermann et al. 2016). Confirmatory results from two randomized phase III trials (SOLO-1 and SOLO-2/ENGOT-Ov21) using olaparib as maintenance therapy for OC were reported recently. Pujade-Lauraine et al. conducted a phase III randomized, double-blind and placebo-controlled and multicenter trial to evaluate the efficacy of olaparib as maintenance treatment for platinum-sensitive, relapsed and BRCA mutated OC (Pujade-Lauraine et al. 2017). This study (NCT01874353; SOLO-2/ENGOT-Ov21) enrolled 295 patients including 196 in the olaparib arm and showed significantly higher PFS as compared with the placebo arm (19.1 months vs. 5.5 months p < 0.0001 respectively) (Pujade-Lauraine et al. 2017). More recently, results from SOLO-1 (NCT01844986) phase III trial that assessed olaparib (n = 260) versus placebo (n = 131) as maintenance therapy this time for newly diagnosed OC with BRCA mutations and after first-line standard chemotherapy demonstrated a gain of 3 years in PFS (despite not reached) in the group who received olaparib after 41 months of follow-up (HR: 0.30; 95% CI: 0.23–0.41; p < 0.001) (Moore et al. 2018). Remarkably, a recent meta-analysis that enrolled 8 randomized trials (1957 patients) including SOLO-2 found that patients with BRCA carriers exhibited significant survival benefits from olaparib and thus showing decisive additional evidence for this genetic biomarker but with an increased risk of severe anemia which requires regular hematologic surveillance (Guo et al. 2018). Promisingly, further evidence will be released by the ongoing SOLO3 phase III trial that randomizes relapsed OC patients who have received at least 2 prior lines of platinum-based chemotherapy and with BRCA carriers to receive olaparib versus standard of care (NCT02282020). Moving beyond BRCA biomarkers, it seems that a subset of OC patients with mutations in HRR genes other than traditional BRCA may also benefit from olaparib which can expand the use of this drug in the future (Hodgson et al. 2018). Similarly, findings from a comparative molecular analysis of the NCT00753545 trial showed that long-term responders to olaparib maintenance may be multifactorial and related to HRR profile (Lheureux et al. 2017). In the confirmatory SOLO-3 phase III trial, patients with BRCA mutated status were randomly assigned to receive olaparib or a non-platinum drug for the platinum-sensitive setting for which objective response rate was the primary endpoint as mandated by the FDA (Penson et al. 2020). The superiority of olaparib was noticed and reached 72.2 as compared to 51.4% in patients treated with standard of care (Penson et al. 2020). The addition of olaparib to bevacizumab for the first-line maintenance therapy was investigated in the PAOLA-1 phase III trial (Ray-Coquard et al. 2019). This study randomized 806 OC patients with mutated BRCA to receive olaparib and bevacizumab or bevacizumab + placebo in a 2:1 fashion. A significant hazard ratio of 0.59 resulted in the comparison for PFS. In patients with HRR deficiency, the hazard ratio for progression or death reached a value of 0.33 suggesting the clinical benefits of adding olaparib to anti-angiogenesis in this setting (Ray-Coquard et al. 2019).
4.3.2 Rucaparib
Women with OC who have BRCA mutant tumors that were enrolled in the ARIEL-3 randomized and controlled phase III (n = 564) for the recurrent platinum-sensitive disease had superior median PFS (HR: 0.23, 95% CI: 0.16–0.34, p < 0.0001) (Coleman et al. 2017). Similarly, patients with HRR deficiency had also improved PFS (HR: 0.32, 0.24–0.42, p < 0.0001). In the ARIEL-2 phase II trial for the recurrent platinum-sensitive setting that stratified patients into multi-cohorts including those with BRCA status, median PFS was also improved in the group treated with rucaparib and having BRCA mutations (HR: 0.27, 95% CI: 0.16–0.44, p < 0.0001) (Swisher et al. 2017). Notably, RAD51C and RAD51D genetic variants were found associated with acquired resistance to this PARP inhibitor in OC (Kondrashova et al. 2017). Furthermore, reversion mutations in BRCA were also identified in circulating tumor DNA of OC patients with reduced rucaparib PFS as compared to women with no reversion mutations at baseline (median 1.8 vs. 9 months; HR: 0.12; p < 0.0001). Thus, combinatorial approaches may be promising to overcome drug resistance to rucaparib (Lin et al. 2019).
4.3.3 Niraparib
To the best of our knowledge, niraparib has been investigated in two randomized phase III trials for OC, NOVA (n = 553) and PRIMA (n = 733) (see Chap. 3). In the NOVA study that explored the efficacy of niraparib in the recurrent platinum-sensitive setting, 203 women had germline mutated BRCA and had superior PFS as compared to those treated with placebo (HR: 0.27; 95% CI: 0.17–0.41) (Mirza et al. 2016). Remarkably, women with HRR deficiency had also improved PFS (HR: 0.38; 95% CI: 0.24–0.59) (Mirza et al. 2016). When niraparib was investigated as a monotherapy in the maintenance setting after response to front line therapy in NOVA study, enrolled women with HRR deficient tumors had clinically and statistically improved PFS (HR: 0.43; 95% CI: 0.31–0.59; p < 0.001) (González-Martín et al. 2019). In late lines of recurrent OC therapy, the QUADRA phase II trial explored the efficacy of niraparib in heavily pre-treated patients and showed a clinical activity of this PARPi in women with HRR deficiency including those with or without BRCA mutations (Moore et al. 2019).
4.3.4 Veliparib
Veliparib is a new synthetically lethal therapeutic approach for treating OC (Boussios et al. 2020). Previously and based on early signs of efficacy in a phase II trial (Coleman et al. 2015), veliparib as a single agent was studied for platinum-resistant or partially sensitive recurrent OC in a combined phase I/II trial (Steffensen et al. 2017). Veliparib was given to women that have exclusively germline mutated BRCA showed clinical activity in this heavily pretreated population including 65% of overall response rate, PFS of 5.6 months, and OS of 13.7 months (Steffensen et al. 2017). VELIA (n = 1140) was a landmark three arms phase III trial that explored the efficacy of veliparib in the first-line therapy of OC (Coleman et al. 2019). Women with BRCA mutant and HRR deficient tumors treated with veliparib in combination with carboplatin/paclitaxel doublets had favorable outcomes including superior PFS (HR: 0.44 and HR: 0.68 respectively, p < 0.001 for both) (Coleman et al. 2019). In a recent biomarker analysis of a phase II study, homeobox A9 (HOXA9) promoter methylation in circulating tumor DNA was demonstrated to confer resistance to veliparib (Rusan et al. 2020). Longitudinal monitoring of OC patients based on this liquid biopsy approach showed that methylated HOXA9 at baseline was significantly correlated with worse outcomes included reduced PFS and OS (p < 0.0001 and p = 0.002, respectively) (Rusan et al. 2020). Therefore, this may provide perspectives for real-time monitoring using this potential predictive biomarker.
4.4 Ovarian Cancer Genetics and Surgical Outcomes
Usually, cytoreductive debulking surgery is performed for OC patients after primary diagnosis and staging, followed by adjuvant platinum-based chemotherapy or after receiving neoadjuvant chemotherapy (NACT) for women with poor performance status, large tumors, and important volumes of ascites (Vitale et al. 2013). Furthermore, secondary debulking surgery can be performed during recurrences but its role in improving outcomes is still controversial (Lorusso et al. 2012). Resectability and optimal cytoreduction are influenced by several factors such as disease location, the expertise of surgeons as well as probably genetic status such as BRCA mutations (Narod 2016; Ponzone 2021). Interestingly, to see whether OC patients with BRCA mutations have superior surgical outcomes as compared with those with wild status, some recent reports looked into this matter based on different observational study designs. Earlier in 2012, a retrospective report of 367 stage IIIC-IV high-grade serous OC from the Memorial Sloan Kettering Cancer Center investigated germline BRCA mutation status as a predictor of optimal cytoreduction compared to wild-type tumors (Hyman et al. 2012). OC patients with mutated BRCA and who underwent surgery had relatively superior rates of optimal debulking as compared with wild-type patients (84.1% vs. 70.1% respectively, p = 0.02) (Hyman et al. 2012). However, based on multivariate analysis, this study demonstrated that mutated BRCA status is not associated with residual tumor volume (OR: 0.63; 95% CI: 0.31–1.29; p = 0.21) suggesting that optimal cytoreduction may be due to surgery alone instead of OC genetics (Hyman et al. 2012). In another retrospective study that enrolled 27 cases with recurrent OC treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) and 84 matched controls treated with systemic chemotherapy alone, women with positive BRCA carriers were found to have longer PFS in the HIPEC group as compared with the controls (20.9 vs. 12.6 months, p = 0.048) (Safra et al. 2014). Consequently, this confirms the recently published data supporting the impact of the emerging HIPEC in treating OC (van Driel et al. 2018; Spiliotis et al. 2015; Cascales-Campos et al. 2015) especially in patients with BRCA mutational status. However, an opposing conclusion from a recent study found that patients with BRCA1 mutated OC are less likely to achieve no residual disease after debulking surgery than wild-type patients (19% vs. 39%; p < 0.0001) (Kotsopoulos et al. 2016). Importantly, the same study found that improved survival outcomes observed in OC patients with mutated BRCA status may be due to higher initial sensitivity to platinum-based therapy and, notably, no residual disease at debulking is the strongest predictive factor of long-term survival (Kotsopoulos et al. 2016). Recently, Petrillo et al. evaluated the impact of BRCA mutational status on outcomes including optimal debulking in a large multicenter report of women with newly diagnosed high-grade serous OC with stage IIIc and IV disease (Petrillo et al. 2017). Patients with mutated BRCA had significantly higher peritoneal tumor load but without having different median PFS when treated with NACT or debulking surgery (p = 0.268). Remarkably, patients with wild-type BRCA status and who benefited from primary debulking surgery had superior median PFS as compared to those treated with NACT (26 vs. 18 months; p = 0.003) (Petrillo et al. 2017). Similarly, Marchetti et al. showed in their recent retrospective cohort that women with BRCA wild-type ovarian tumors who underwent complete secondary cytoreductive surgery had superior 5-year post-recurrence survival as compared to those with no surgical intervention (54% vs. 42%; p = 0.048) (Marchetti et al. 2018). However, Naumann et al. showed that optimally resected high-grade OC had frequent BRCA mutations and dramatically improved median OS (110.4 vs. 67.1 months; HR: 0.28, 95% CI: 0.11–0.73, p = 0.009) when treated with HIPEC compared with patients wild type tumors (Naumann et al. 2018). More recently, Gordonova et al. analyzed the medical record of 283 consecutive women who underwent complete or optimal debulking and compared their outcomes based on BRCA status (Gorodnova et al. 2019). Again, this study showed that BRCA status did not predict outcomes in patients subjected to primary surgery (p = 0.56) (Gorodnova et al. 2019). To the best of our knowledge, only one report has prospectively assessed the impact of BRCA status on optimal debulking. This was a cohort report that enrolled 107 OC patients including 51.4% of BRCA mutated cases (Rudaitis et al. 2014). No significant difference between OC patients harboring BRCA mutations and those with wild-type status was seen in terms of optimal debulking surgery (58.2% vs. 53.9%, p = 0.6994). However, BRCA mutated OC patients had improved median PFS (19 months, 95%; CI: 13–25) compared with wild-type subjects (13 months, 95%; CI: 10–16) (p = 0.039) (Rudaitis et al. 2014). In conclusion, it seems that BRCA carriers have no impact on optimal debulking for OC patients. However, most of these studies are retrospective in their design and thus, should be commented with caution because of the high risk of biases. Until to date, no definitive answers were provided and most current studies especially clinical trials are investigating BRCA as biomarkers for chemotherapy and targeted therapies.
4.5 Conclusion
The genetics of OC is becoming actionable with the arrival of precision medicine in gynecologic oncology. This progress is also supported by the recent development of sequencing technology. To date, several therapies require genetic information of OC patients before their use. Remarkably, this approach has deeply improved outcomes in some settings of this aggressive women’s cancer. More research on biomarkers is needed to ensure that patients can achieve maximal clinical benefits from the emerging targeted agents in OC. In this perspective, the currently active clinical trials using BRCA status for patients’ selection and stratification can improve personalized medicine in the near future (Tables 4.5 and 4.6). For additional reading, see Box 4.1.
Box 4.1 Recommended reading of particular interest
DOI | |
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Kuroki L, Guntupalli SR. Treatment of epithelial ovarian cancer. BMJ. 2020;371:m3773. | |
Mirza MR, et al. The forefront of ovarian cancer therapy: update on PARP inhibitors. Ann Oncol. 2020;31(9):1148–1159. | |
Chan JK, et al. Selecting new upfront regimens for advanced ovarian cancer with biomarker guidance. Gynecol Oncol. 2020;159(3):604–606. | |
Haunschild CE, Tewari KS. The current landscape of molecular profiling in the treatment of epithelial ovarian cancer. Gynecol Oncol. 2020:S0090-8258(20)33953-6. | |
Byrum AK, et al. Defining and Modulating ‘BRCAness’. Trends Cell Biol. 2019;29(9):740–751. | |
Wakefield MJ, et al. Diverse mechanisms of PARP inhibitor resistance in ovarian cancer. Biochim Biophys Acta Rev Cancer. 2019;1872(2):188307. | |
Lord CJ, Ashworth A. BRCAness revisited. Nat Rev Cancer. 2016;16(2):110–20. | |
Lheureux S, et al. Epithelial ovarian cancer: Evolution of management in the era of precision medicine. CA Cancer J Clin. 2019;69(4):280–304. |
Acknowledgment and Conflicts of Interest
KE is an editor in Springer Nature Journals and a previous editor for a Springer Book (https://springerlink.bibliotecabuap.elogim.com/book/10.1007/978-3-030-53821-7).
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KE wrote the chapter. OA and SA revised and supervised the chapter writing. The final draft was reviewed and approved by all the authors. The contents of the chapter reflect the authors’ perspectives and not of their institutions of affiliation.
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El Bairi, K., Al Jarroudi, O., Afqir, S. (2021). Genetic Alterations in Ovarian Cancer as Prognostic and Predictive Biomarkers of Therapy Response and Surgical Outcomes. In: El Bairi, K. (eds) Ovarian Cancer Biomarkers. Springer, Singapore. https://doi.org/10.1007/978-981-16-1873-4_4
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