The Role of Biomarker Testing in Ovarian Cancer

Targeted Therapies in Oncology, October 1, 2022,
Pages: 78

There is no single best treatment algorithm for ovarian cancer. Treatment decisions, which become increasingly complex with disease progression, are informed by several patient-specific clinicopathologic parameters and genomic results.

The indentification of predictive and prognostic biomarkers has become increasingly important in the diagnosis and treatment of ovarian cancers (OCs), especially as newer biomarkers emerge.

OC is the fifth leading cause of cancer mortality in women in the United States.1-3 Despite many significant advances in treatment, more than 70% of patients with stage III to IV OC will have a recurrence within the first 5 years after diagnosis, which is often fatal.4

There is no single best treatment algorithm for ovarian cancer.4 Treatment decisions, which become increasingly complex with disease progression, are informed by several patient-specific clinicopathologic parameters and genomic results.4 For most patients, surgery for staging and cytoreduction followed by platinum-based systemic chemotherapy with or without targeted biological agents with induction therapy, or as maintenance treatment, is the frontline standard of care.3-6

Recurrence results “in a cycle of surgeries and additional rounds of chemotherapy,” Bradley J. Monk, MD, FACS, FACOG, said in an interview with Targeted Therapies in Oncology™, adding that, “Biomarker testing can help predict the potential magnitude of a therapeutic effect in patients with OC.” Monk is a professor of gynecologic oncology at Arizona Oncology (US Oncology Network) and University of Arizona College of Medicine, the medical director of the gynecologic program at US Oncology Research, and a codirector at GOG Partners.

Biomarkers for Treatment Choice

There are several potential therapeutic targets in gynecological cancers, including tumor-intrinsic signaling pathways, homologous recombination deficiency (HRD), angiogenesis, immunologic factors, and hormone receptors.7

Genetic tests available for evaluating BRCA and HRD status are shown in the TABLE8-15. In addition to commercial tests, some medical/research institutions have their own assays for evaluating many of these genes.16-18

“Guidelines recommend biomarker testing in all patients with OC,” Monk said. “OC biomarkers can be analyzed using single-gene tests or as part of a multigene panel, and BRCA1/2 testing was included in multigene panels beginning in 2013.” However, one study showed only 30% of patients diagnosed with OC between 2013 and 2014 received genetic testing.19


VEGF, a vascular permeability factor, is a key regulator of physiological and pathological angiogenesis and a major contributor to tumorigenesis. Patients with OC have elevated VEGF levels, which contribute to the accumulation of ascites. In an analysis of tumor VEGF levels in 110 patients with OC, high VEGF was associated with worse survival outcomes (P < .01).20,21 The fi rst and most studied anti-VEGF agent, bevacizumab (Avastin), led to improvements in overall survival (OS) in patients with higher-stage disease, greater disease burden, and ascites.22-25 Although no molecularly defi ned biomarker that predicts benefi t from bevacizumab has been described, high tumor expression of colocalized MET/VEGFR-2 was associated with significantly reduced OS (HR, 2.00; 95% CI, 1.08-3.72; P = .03) and the VEGFR2 rs2305945 G/G variant was associated with worse progression-free survival (PFS).26


Wild-type breast cancer 1 (BRCA1) and BRCA2 oncogenes are critical for DNA repair by the homologous recombination pathway.27 Therefore, deletions or mutations in these genes causes genomic instability and predisposes affected individuals to familial breast cancer and OC.27,28 Between 14% and 15% of all epithelial OCs have germline BRCA1/2 mutations, but the rate can be as high as 22.6% in high-grade serous OC, plus 6% due to somatic mutations.29-31 OCs with BRCA1/2 mutations are especially susceptible to agents that induce DNA double-strand breaks and DNA interstrand crosslinks, such as platinum compounds (eg, cisplatin and carboplatin) and PARP inhibitors.20 For patients with BCRA1/2-mutated OC who have not received bevacizumab, maintenance with olaparib (Lynparza) or niraparib (Zejula) increases median PFS.32,33 The addition of olaparib to bevacizumab maintenance in patients who received bevacizumab up front also increases median PFS.34 Survival benefi t has been maintained long term, with extended results from the PAOLA-1 trial (NCT02477644) showing 5-year OS rates in patients with advanced OC and a BRCA mutation of 73.2% with the olaparib and bevacizumab combination compared with 53.8% with placebo (HR, 0.60; 95% CI, 0.39-0.93).35

DNA Damage Response Genes

After BRCA1/2 mutations, defi ciencies in the mismatch repair (MMR) system are the most common cause of hereditary OC.36 The MMR system, which is a complex pathway of 7 genes, corrects mutations arising during DNA replication or damage, playing a crucial role in maintaining genome stability.37

Another DNA damage response gene is CHEK2, which encodes a protein kinase activated in response to DNA damage and interacts with BRCA1, promoting cellular survival.38 The missense variant of CHEK2, I157T, is signifi cantly associated with ovarian cystadenomas (odds ratio [OR], 1.7; P = .005), borderline ovarian tumors (OR, 2.6; P = .002), and low-grade invasive cancers (OR, 2.1; P = .04) but not high-grade OC (OR, 1.0).38

Homologous recombination repair genes

Homologous recombination deficient cells cannot repair DNA double-strand breaks, making them reliant on the single-strand repair mechanism. This can be exploited by the use PARP inhibitors. The PARP enzyme is needed to repair single-strand DNA breaks, so PARP inhibition leads to an accumulation of double-strand breaks. The use of PARP inhibitors in patients with homologous recombination deficient tumors leads to tumor cell death by a phenomenon called synthetic lethality.29 Both niraparib and the combination of bevacizumab/olaparib are effective for the treatment of patients with HRD.35,39

Genetic and epigenetic alterations in homologous recombination repair (HRR) genes, leading to defective DNA repair, are present in approximately half of epithelial OCs.29 HRD can also be induced by the overexpression of specific microRNAs.29 Mutations in some HRR genes, including BRCA1 and BRCA2, as well as ATM, ATR, BARD1, BLM, BRIP1, CHEK1, CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD51C, RAD51D, RBBP8, SLX4, and XRCC2, are associated with platinum sensitivity and prolonged survival.29,40,41

Loss of heterozygosity

Loss of heterozygosity (LOH) is a common form of chromosome instability, in which a heterozygous somatic cell becomes homozygous due to the loss of an allele.29 LOH is also correlated with an increased response to platinum-based chemotherapy.42 Response to therapy (platinum and PARP inhibitors) is influenced by genomic instability caused by chromosomal alterations, nucleotide substitutions, insertions, and deletions that accumulate in the absence of DNA repair due to DNA damage response gene mutations (germline and somatic).29,43,44

These biomarkers can be used in counseling patients about the magnitude of benefit that they may receive from using a PARP inhibitor for maintenance therapy because patients who are platinum sensitive with no BRCA mutation but are HRD positive, LOH high, or have a germline or somatic mutation in other HRR genes have an even stronger benefit from maintenance PARP inhibition than those who are HRD negative and LOH low with no HRR gene mutations.29 Patients who are weighing the benefi ts of using other maintenance therapy options such as bevacizumab or discussing whether the adverse effect profiles are worth the added benefit may find this information useful.

Finally, the use of these biomarkers may play a role in the near future in expanding the number of patients who could receive— and be expected to benefit from—PARP inhibition, either in the up-front setting before the patient’s platinum-sensitivity status is known or in platinum-resistant patients.29

Microsatellite instability/stable and PD-L1

A high proportion of OCs with germline MMR mutations (MSH2, MSH6, MLH1, PMS2) demonstrate microsatellite instability (MSI).7 MSI is predictive o f sensitivity to immune checkpoint inhibitors, such as PD-1 or PD-L1.45 Therefore, the use of these agents is becoming increasingly popular in the treatment of various cancers because it is associated with longer survivals compared with chemotherapy and targeted therapy.45,46 Pembrolizumab (Keytruda), for example, has a tumor-agnostic indication for the treatment of patients with unresectable or metastatic cancer with MSI high or MMR deficiency.47 However, a recent quantitative meta-analysis showed that PD-1/PD-L1 inhibitors alone have limited effi cacy for OC (combined objective response rate, 19%; 95% CI, 13%-27%), whereas combination regimens with chemotherapy should be studied further (combined objective response rate, 36%; 95% CI, 24%-51%).45

Prognostic Biomarkers

As is the case with several other cancers, TP53 is frequently mutated i n OC; in fact, almost all (97%) high-grade serous OCs have mutations in TP53.48 Although many studies have investigated TP53 as a biomarker in OC, there are still disputes over its prognostic and predictive values.48 Another candidate prognostic biomarker is CKB, a cytosolic isoform of creatine kinase. Due to its high expression in early-stage OC, CKB is a potential biomarker for the early detection of OC.20

Diagnostic Biomarkers

The survival rates for early-stage (I and II) OC are much higher (70%-90%) than for later-stage (III and IV) OC (30%). Furthermore, in the absence of an effective screening strategy, up to 80% of OCs are diagnosed in the late stage. This gives a strong rationale for OC screening.31

Currently, OC screening is done using a combination of blood-based biomarkers—notably, cancer antigen 125 (CA125, also called mucin 16 [MUC16]) and human epididymis protein 4 (HE4)—and transvaginal ultrasound imaging.49,50 Although CA125 and HE4 are the best available diagnostic biomarkers for OC, they have insufficient sensitivity and specifi city. Therefore, the development of additional diagnostic biomarkers for OC is needed.49

Biomarkers of Interest for the Future

In preliminary studies, circulating tumor DNA (ctDNA) was detected in blood and cervical secretions from 55% of patients with early-stage OC, including in cases missed by CA125 testing alone. A more concentrated sample of ctDNA can be obtained from cervical material than from the peripheral blood, which may be critical for the detection of tumors less than 1 cm in diameter.31,51 The recent development of a repetitive element aneuploidy sequencing system (RealSeq) to detect aneuploidy in ctDNA from as little as 3 pg of DNA in relatively small amounts of plasma may improve sensitivity for early-stage high-grade OCs with copy number abnormalities.52 Additionally, 2 clinical trials have further investigated biomarkers for OC (NCT01466049 and NCT00854399).53,54


“Biomarker testing results, including HRD, BRCA, and defi cient MMR/MSI status, can help predict the potential magnitude of a therapeutic effect in patients with ovarian cancer,” Monk said. “Patient counseling is an important component of biomarker testing and is recommended as a fundamental aspect of care for women with ovarian cancer.”

In an interview with Targeted Therapies in Oncology™, Robert L. Coleman, MD, FACOG, FACS, chief scientifi c offi cer for US Oncology Research and codirector of GOG Partners, summarized the main takeaways from the past few years of OC biomarker research.

“The last provocative clinical trial to inform treatment [decision-making] for patients with OC was PAOLA-1,” Coleman said. “I have recommended and used bevacizumab as primary adjuvant therapy for several years, but the availability of olaparib [for] these patients whose tumors harbor HRD detected by a test changed my approach to maintenance therapy and to genomic testing. Previously my testing approach was to obtain tumor and germline testing for BRCA. Now I add HRD.

“I would also mention that the failure of immune checkpoint inhibitor trials in both primary and recurrent setting has removed that option except for those patients with MSI high or the rare case with high tumor mutational burden.”


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