Evaluating the Role of Folate Receptor Alpha Expression in Ovarian Cancer

The treatment landscape for ovarian cancer has rapidly progressed in recent years, particularly with the discovery of antiangiogenic agents and the emergence of PARP inhibitors. Despite these advances, high recurrence rates and low cure rates remain a significant challenge and new treatments are needed. One potential target that has emerged in recent years is folate receptor α (FRα), which is overexpressed in more than half of high-grade serous ovarian cancers. Multiple agents that target FRα have been developed and are currently under investigation for the treatment of ovarian cancer. This article explores the evolving ovarian cancer therapeutic spectrum, with an emphasis on FRα and its potential role among the current treatment options.

Epidemiology, Risk Factors, and Staging

Ovarian cancer is the most common cause of death associated with female reproductive cancers.¹ In 2019, an estimated 13,980 patients will die from ovarian cancer.¹ Of these cases, 90% to 95% are epithelial ovarian carcinomas; the remainder include sex cord-stromal and germ cell tumors.²

Family history is the strongest known risk factor for ovarian cancer, particularly when a hereditary cancer syndrome (eg, breast—ovarian cancer syndrome that is associated with a BRCA1 or BRCA2 mutation) is indicated.³ The presence of a BRCA1 mutation increases the lifetime risk of breast cancer up to 54% and ovarian cancer up to 39%.⁴ Similarly, the presence of a BRCA2 mutation increases the lifetime risk up to 45% and 16% for breast cancer and ovarian cancer, respectively.⁴ For female patients with hereditary nonpolyposis colorectal cancer (ie, Lynch syndrome), the lifetime incidence of all gynecological cancers is 32.5%.⁵ Infertility (odds ratio [OR], 2.67; 95% CI, 1.91-3.74), endometriosis (OR, 1.73; 95% CI, 1.10-2.71), and polycystic ovarian syndrome (OR, 2.52; 95% CI, 1.06-5.99) are each associated with increased risks of ovarian cancer.^6,7

Ovarian cancer is staged surgically,² using the International Federation of Gynecology and Obstetrics classification system (Table 1).⁸ The stage at diagnosis is associated with length of survival and recommended treatment options.⁹ Approximately 15% of ovarian cancers are diagnosed at stage I (cancer localized to primary site), with a 5-year survival rate of 92.3%.⁹ Approximately 59% of ovarian cancer cases are diagnosed when the cancer has metastasized to distant sites, with an estimated 5-year survival rate of 29.2%.⁹

Ovarian tumors exhibit a high degree of molecular and cellular heterogeneity. The 5 main histologic types, according to the 2014 World Health Organization criteria, are high-grade serous carcinoma, low-grade serous carcinoma, endometrioid carcinoma, clear cell carcinoma, and mucinous carcinoma.¹⁰ The most common epithelial ovarian cancers are serous histologic tumors (>50%), followed by endometrioid carcinomas (15%-20%), mucinous carcinomas (5%-10%), and clear cell adenocarcinomas (5%-10%).²

Current Treatment Options

Typically, epithelial ovarian tumors metastasize by exfoliation, releasing malignant cells into the peritoneal cavity.² Normal peritoneal fluid circulation allows malignant cells to develop into surface implants in various sites in the abdomen. Hence, aggressive surgical debulking, or cytoreduction, is typically attempted.² Although all intraperitoneal surfaces are at risk, the omentum is highly vascular and frequently supports metastatic disease.²

According to guidelines from the National Comprehensive Cancer Network (NCCN), the current standard treatment for women with stage IIIC or IV ovarian cancer is cytoreductive surgery followed by platinum-based combination chemotherapy (Table 2).¹¹ If a patient with stage I ovarian cancer wants to preserve fertility, NCCN guidelines suggest unilateral salpingo-oophorectomy in addition to comprehensive surgical staging to be performed.¹¹ If fertility preservation is not desired, a total abdominal hysterectomy and comprehensive staging and debulking should be performed regardless of the cancer stage.¹¹ Optimal surgical debulking is typically defined as complete tumor resection without gross residual disease.² In patients who are not surgical candidates, or who have bulky disease with residual lesions despite attempted debulking, neoadjuvant chemotherapy may be administered to shrink the disease prior to interval cytoreduction surgery.^2,11

Although most women with ovarian cancer achieve remission after surgery and platinum-based chemotherapy, up to 80% of patients will eventually relapse and die following disease progression.² Monitoring for relapse following primary treatment includes pelvic exams, CA-125 level measurements, and imaging as clinically indicated.¹¹ The duration of response to primary platinum-based chemotherapy is determined by a patient’s platinum sensitivity.¹² Recurrent ovarian cancer is classified based on time since treatment with a platinum agent, known as the platinum-free interval¹³:

• Refractory: progression during or within 4 weeks of completing platinum-based therapy.
• Primary resistant: relapse within 6 months of completing initial platinum-based therapy.
• Partially platinum-sensitive: relapse between 6 and 12 months of completing initial platinum-based therapy.
• Platinum-sensitive: relapse after 12 months of completing platinum-based therapy.

Therapy for disease recurrence depends on initial response to platinum-based therapy.¹¹ Patients with platinum-sensitive disease will likely respond to additional platinum-based treatment. However, virtually all patients will eventually develop acquired or secondary platinum resistance. Both primary and secondary platinum resistance carry a dismal prognosis because limited therapeutic options currently exist for this patient population.¹³

Platinum-Sensitive Relapsed Ovarian Cancer

For patients who achieve initial complete remission but relapse after 6 months of completing primary chemotherapy, NCCN category 1 guidelines suggest secondary cytoreduction surgery for radiographic or clinical relapse, followed by combination platinum-based chemotherapy for the first recurrence.¹¹ Although response rates to further platinum-based therapy range from 30% to 90% in women with platinum-sensitive recurrences, median overall survival (OS) is only 2 to 3 years.¹³

Platinum-Resistant Relapsed Ovarian Cancer

For recurrence therapy in patients with platinum-resistant relapsed ovarian cancer, a nonplatinum single agent is usually recommended, but limited evidence exists for particular regimens.^11,12 Ovarian cancer that does not respond to primary platinum-based chemotherapy or relapses within 6 months of chemotherapy completion generally has a low response rate (10%-25%) of short duration to further therapy.¹² Progression-free survival (PFS) in this population is only 3 to 4 months, and OS is less than a year.¹³

Recent Targeted Therapies

Given the dismal prognosis of relapsed ovarian cancer and limited treatment options, novel and effective therapies that improve clinical outcomes of these patients is an unmet clinical need. Increased understanding of the molecular complexity of ovarian cancer has led to the recent development of targeted therapies. Two new classes of targeted agents are now approved for ovarian cancer: angiogenesis inhibitors (eg, bevacizumab) and PARP inhibitors (niraparib, olaparib, and rucaparib).^14-17

Another recent approach is the combination of targeted agents with conventional chemotherapy. In the setting of platinum-sensitive disease, bevacizumab in combination with carboplatin—gemcitabine, as compared with carboplatin–gemcitabine alone, significantly increased median PFS (12.4 months vs 8.4 months; P <.0001) but did not affect median OS (33.3 months vs 35.2 months).^12,18 Similar findings were also reported with bevacizumab in combination with carboplatin—paclitaxel.^12,19 In an instance of platinum-resistant recurrence, bevacizumab combined with a nonplatinum therapy, such as paclitaxel, liposomal doxorubicin, or topotecan, administered weekly improved median PFS (6.7 vs 3.4 months), but the difference in median OS was not significant (16.6 vs 13.3 months; P <.17).^12,20

Another strategy that is designed to improve patient outcomes is the use of targeted therapies as maintenance agents. According to NCCN guidelines, patients who have been treated with bevacizumab in combination with chemotherapy at disease recurrence and have achieved complete response may continue bevacizumab as maintenance therapy; other options such as niraparib, olaparib, or rucaparib may also be considered.¹¹ Maintenance therapy with PARP inhibitors is also an option for this group of patients.^11,15-17 PARP inhibition is a recent approach to target deleterious BRCA-mutated ovarian cells.¹² Maintenance treatment with olaparib was evaluated following platinum-based chemotherapy in platinum-sensitive relapse. Although olaparib led to a longer PFS compared with placebo (8.4 vs 4.8 months; P <.001), OS was not significantly different.¹² Rucaparib and niraparib are similarly indicated for maintenance therapy after recurrence of ovarian cancer in a complete or partial response to platinum-based chemotherapy.^15,17

Folate and Folate Receptors in Ovarian Cancer

In addition to PARP and angiogenesis inhibitors, the search for other molecular targets for ovarian cancer continues. One target under active investigation that has gained significant momentum is FRα.²¹

Folate Biology

Folic acid metabolism sustains DNA synthesis and methylation and is critical for rapidly growing cells.^22,23 Under normal physiologic conditions, water-soluble B vitamins, which are reduced folates, are transported intracellularly through high-capacity, low-affinity, reduced folate carriers that are ubiquitously expressed. Once inside the cells, folates facilitate the biosynthesis of thymidine and purines needed for DNA synthesis, methylation, and repair.²²

In addition to the reduced folate carrier, folates can be transported into the cell through 2 other routes.²⁴ One possible route is the proton-coupled folate transporter, which mediates folate transport through the transmembrane proton gradient.²⁴ Folates can also be transported by high-affinity transmembrane folate receptors (FRs).²² There are 4 FR glycopolypeptide isoforms: FRα, FRβ, FRγ, and FRδ.^22,24 FRα, also known as folate-binding protein (FOLR1), binds with high affinity and transports the active form of folate, 5-methyltetrahydrofolate, unidirectionally into cells.^21,24

FRα Expression

In normal human tissue, FRα is expressed at low levels in a small number of polarized epithelia (eg, choroid plexus, lung, kidney, uterus, placenta) and its expression is restricted to the luminal/apical surface of polarized cells, avoiding contact with the circulation.²² Evidence suggests that FRα is overexpressed in the majority of ovarian, uterine, and ependymal brain tumors.²² FRα is also overexpressed in varying percentages of lung, breast, kidney, and colon carcinomas.²² In contrast to its expression in normal tissue, FRα’s cellular location in malignant tissues is no longer restricted to polarized areas, but instead covers the entire cell.²²

In ovarian cancer, FRα is expressed in more than 70% of primary tumors and more than 80% of recurrent tumors but is not commonly in normal ovarian epithelium.^25,26 Expression in ovarian cancer appears to depend on tumor histology. Some findings suggest that FRα is expressed most commonly in approximately 82% of serous tumors.^26,27 Results from 1 study suggest that endometrioid and clear cell histology also have FRα in more than 60% of cases, while the prevalence of expression is much lower in mucinous tumors (22.2%).²⁶ Notably, chemotherapy treatment does not change FRα expression in remaining tumor tissue or recurrent ovarian tumors.^27,28

Although not uniform across studies, preliminary evidence suggests that levels of FRα may be associated with stage of disease.²⁵ In a study that measured the soluble form of FRα, serum FRα (sFRα), higher levels of sFRα were significantly associated with advanced clinical stage (III/IV vs I/II) and higher tumor grade.²⁹

Folate Receptor Mechanisms in Ovarian Cancer

FRα overexpression in ovarian cancer may involve modulation of folate uptake, activating tumor growth signals, facilitating DNA synthesis, and supporting the proliferation of malignant cells.^22,25 Inhibition of FRα expression has been shown to suppress tumor growth in cell lines, according to in vivo studies.

FRα expression may also enhance tumor cells’ antiapoptotic ability, inducing drug resistance.^22,30 Increased FRα expression in serous ovarian tumors has been associated with chemotherapy resistance in patients with disease recurrence or progression within 6 months of discontinuing chemotherapy (OR, 13.96; 95% CI, 2.71-71.88; P = .001).³⁰ Elevated FRα expression has also been shown to be a poor predictor of a shortened disease-free interval (HR 2.45; 95% CI, 1.16-5.18; P = .02).³⁰ In addition to serous ovarian cancer, the relationship between FRα expression and poor response to chemotherapy has been observed in a study of various ovarian histologic subtypes.³¹

Prognostic Value of FRα

To date, not all studies have shown that FRα expression is associated with PFS or OS. In a study that examined ovarian cancer of various histologic subtypes, FRα expression was not independently associated with time to recurrence or OS.²⁶ Results of another study showing a lack of relationship between FRα expression and progression-free interval corroborated these early findings.²⁸

In a more recent study of various ovarian histologies, patients with lower FRα levels had a significantly longer PFS (P <.0001).²⁹ This finding was observed in both stage I and II patients (P = .04), as well as in patients with stage III and IV disease (P = .02). In patients with advanced-stage disease, PFS was 23 months in the lower sFRα group (<7004 pg/mL), compared with 15 months in patients with higher sFRα levels. However, sFRα levels were not prognostic for OS.²⁹ Of note, the duration of PFS was reported in only stage III/IV patients.

Several factors may contribute to such disparate results. Large sample sizes are needed to study independent associations with survival, as FRα expression is also associated with prognostic indicators, such as tumor grade and stage; the small samples of patients without elevated FRα expression may also complicate analyses; and quantification of FRα expression also depends on sufficient tumor sampling.²⁵

Targeting FRα in Ovarian Cancer

Because FRα is expressed on the surface of tumor cells, and it has limited expression in normal tissues, FRα-targeted therapeutics allow selective treatment delivery to the malignant tissues, potentially minimizing adverse events (AEs) to normal tissues.²² Specifically, in nontumor tissues, FRα is localized to the luminal surface of epithelial cells that are inaccessible to the circulation. In malignant tissues, FRα is expressed in the entire cell and is accessible through circulation. In addition, folic acid is a reasonably innocuous small molecule that can penetrate solid tumors rapidly and is suitable to chemical conjugation with other therapeutic molecules. When FRα binds to a drug conjugate, it is internalized into the cell, and FRα is quickly recovered using the endocytic pathway to the surface of the cell.²² Hence, targeting the FRα may have unique advantages as an anticancer treatment with limited toxicity.

Several agents with varying mechanisms that target FRα are in development. One of the earliest agents developed to target FRα is farletuzumab, a humanized monoclonal antibody with high affinity for FRα.³² Farletuzumab induces antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and cell death associated with autophagy.³²

Another method to target FRα is the conjugation of chemotherapeutic agents to folate itself, resulting in small-molecule drug conjugates (SMDCs), such as vintafolide.³³ Through its γ-carboxyl group, folate can be conjugated with other molecules without affecting its binding affinity to FRα. Because folate is a physiological compound, it is presumed to be nonimmunogenic. Folate’s low molecular weight also allows folate derivatives to be easily synthesized.³³ SMDCs that have been developed are able to target all FR isoforms. These include folate conjugates of platinum, fluorodeoxyuridine, paclitaxel, vinca alkaloid, mitomycin C, and a prodrug of thiolate histone deacetylase inhibitor.³³

More recently, antibody—drug conjugates (ADCs) have been investigated as a potential intervention for platinum-resistant ovarian cancer. ADCs are engineered molecules composed of highly cytotoxic compounds conjugated to antibodies that are directed toward tumor-associated antigens.³⁴ They have potentially favorable pharmacokinetic features and the specific tumor-targeting properties of an antibody, but with the potent cancer-killing effect of the attached small-molecule cytotoxic agent.³⁴ Several ADCs are already approved in the oncology space, including brentuximab vedotin for relapsed/refractory Hodgkin lymphoma and anaplastic large cell lymphoma; ado-trastuzumab emtansine for recurrent human EGFR2-positive breast cancer; inotuzumab ozogamicin, for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia; and gemtuzumab ozogamicin for the treatment of adults with newly diagnosed CD33-positive acute myeloid leukemia. In the ovarian cancer space, mirvetuximab soravtansine, an antibody—maytansinoid conjugate targeting FRα, is under development, with phase III data currently maturing.³⁴

The next article of this publication will review the mechanisms of FRα-targeting agents in development, as well as clinical trial data in advanced ovarian cancer.

Conclusions

Given the high risk of relapse in patients with ovarian cancer after surgery and platinum-based therapy, effective therapeutic interventions remain an essential unmet need for patients. Because FRα is expressed on the tumor cell surface in ovarian cancer, targeting FRα may allow the delivery of treatment agents to adhere selectively to the malignant tissue, while minimizing AEs to normal tissues.&ensp;

References

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7-34. doi: 10.3322/caac.2155
2. Epithelial ovarian cancer. In: Hoffman BL, Schorge JO, Bradshaw KD, et al. Williams Gynecology. 3rd ed. New York, NY: McGraw-Hill; 2016.
3. Kerlikowske K, Brown JS, Grady DG. Should women with familial ovarian cancer undergo prophylactic oophorectomy? Obstet Gynecol. 1992;80(4):700-707.
4. Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol. 2007;25(11):1329-1333. doi: 10.1200/JCO.2006.09.1066.
5. Barrow E, Robinson L, Alduaij W, et al. Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: a report of 121 families with proven mutations. Clin Genet. 2009;75(2):141-149. doi: 10.1111/j.1399-0004.2008.0112x.
6. Ness RB, Cramer DW, Goodman MT, et al. Infertility, fertility drugs, and ovarian cancer: a pooled analysis of case-control studies. Am J Epidemiol. 2002;155(3):217-224.
7. Chittenden BG, Fullerton G, Maheshwari A, Bhattacharya S. Polycystic ovary syndrome and the risk of gynaecological cancer: a systematic review. Reprod Biomed Online. 2009;19(3):398-405.
8. Prat J; FIGO Committee on Gynecologic Oncology. Staging classification for cancer of the ovary, fallopian tube, and peritoneum. Int J Gynaecol Obstet. 2014;124(1):1-5. doi: 10.1016/j.ijgo.2013.10.001.
9. Cancer stat facts: ovarian cancer. National Cancer Institute/Surveillance Epidemiology and End Results Program website. seer.cancer.gov/statfacts/html/ovary.html. Accessed January 12, 201
10. Peres LC, Cushing-Haugen KL, Anglesio M, et al. Histotype classification of ovarian carcinoma: a comparison of approaches. Gynecol Oncol. 2018;151(1):53-60. doi: 1016/j.ygyno.2018.08.016.
11. NCCN Clinical Practice Guidelines in Oncology: Ovarian Cancer, Including Fallopian Tube Cancer and Primary Peritoneal Cancer, version 2.2018. National Comprehensive Cancer Network website. nccn.org/professionals/physician_gls/pdf/ovarian.pdf. Published March 9, 2018. Accessed January 25, 2019.
12. Corrado G, Salutari V, Palluzzi E, et al. Optimizing treatment in recurrent epithelial ovarian cancer. Expert Rev Anticancer Ther. 2017;17(12):1147-1158. doi: 10.1080/14737140.2017.1398088.
13. Moore KN, Martin LP, O’Malley DM, et al. A review of mirvetuximab soravtansine in the treatment of platinum-resistant ovarian cancer. Futur Oncol. 2018;14(2):123-136. doi: 10.2217/fon-2017-0379.
14. Avastin [prescribing information]. South San Francisco, CA: Genentech, Inc; 2018. gene.com/download/pdf/avastin_prescribing.pdf. Accessed February 12, 2019.
15. Zejula [prescribing information]. Waltham, MA: Tesaro, Inc; 2019. zejula.com/prescribing-information. Accessed February 12, 2019.
16. Lynparza [prescribing information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2018. azpicentral.com/lynparza_tb/lynparza_tb.pdf#page=1. Accessed February 12, 2019.
17. Rubraca [prescribing information]. Boulder, CO: Clovis Oncology, Inc; 2018. clovisoncology.com/media/1094/rubraca-prescribing-info.pdf. Accessed February 12, 2019.
18. Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012;30(17):2039-2045. doi: 10.1200/JCO.2012.42.0505.
19. Coleman RL, Brady MF, Herzog TJ, et al. Bevacizumab and paclitaxel—carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18(6):779-791. doi: 10.1016/S1470-2045(17)30279-6.
20. Pujade-Lauraine E, Hilpert F, Weber B, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open- label randomized phase III trial. J Clin Oncol. 2014;32(13):1302-1308. doi: 10.1200/JCO.2013.51.4489.
21. Birrer MJ, Betella I, Martin LP, Moore KN. Is targeting the folate receptor in ovarian cancer coming of age? Oncologist [published online January 11, 2019]. doi: 10.1634/theoncologist.2018-0459.
22. Ledermann JA, Canevari S, Thigpen T. Targeting the folate receptor: diagnostic and therapeutic approaches to personalize cancer treatments. Ann Oncol. 2015;26(10):2034-2043. doi: 10.1093/annonc/mdv250.
23. Crider KS, Yang TP, Berry RJ, Bailey LB. Folate and DNA methylation: a review of molecular mechanisms and the evidence for folate’s role. Adv Nutr. 2012;3(1):21-38. doi: 10.3945/an.111.000992.
24. Cheung A, Bax HJ, Josephs DH, et al. Targeting folate receptor alpha for cancer treatment. Oncotarget. 2016;7(32):52553-52574. doi: 10.18632/oncotarget.9651.
25. Vergote IB, Marth C, Coleman RL. Role of the folate receptor in ovarian cancer treatment: evidence, mechanism, and clinical implications. Cancer Metastasis Rev. 2015;34(1):41-52. doi: 10.1007/s10555-014-9539-8.
26. Kalli KR, Oberg AL, Keeney GL, et al. Folate receptor alpha as a tumor target in epithelial ovarian cancer. Gynecol Oncol. 2008;108(3):619-6 doi: 10.1016/j.ygyno.2007.11.020.
27. Crane LM, Arts HJ, van Oosten M, et al. The effect of chemotherapy on expression of folate receptor-alpha in ovarian cancer [published correction appears in Cell Oncol (Dordr). 2012;35(3):229]. Cell Oncol (Dordr). 2012;35(1):9-18. doi: 10.1007/s13402-011-0052-6.
28. Despierre E, Lambrechts S, Leunen K, et al. Folate receptor alpha (FRA) expression remains unchanged in epithelial ovarian and endometrial cancer after chemotherapy. Gynecol Oncol. 2013;130(1):192-199. doi: 10.1016/j.ygyno.2013.03.024.
29. Kurosaki A, Hasegawa K, Kato T, et al. Serum folate receptor alpha as a biomarker for ovarian cancer: implications for diagnosis, prognosis and predicting its local tumor expression. Int J Cancer. 2016;138(8):1994-2002. doi: 10.1002/ijc.29937.
30. Chen YL, Chang MC, Huang CY, et al. Serous ovarian carcinoma patients with high alpha-folate receptor had reducing survival and cytotoxic chemo-response. Mol Oncol. 2012;6(3):360-369. doi: 10.1016/j.molonc.2011.11.010.
31. Toffoli G, Russo A, Gallo A, et al. Expression of folate binding protein as a prognostic factor for response to platinum-containing chemotherapy and survival in human ovarian cancer. Int J Cancer. 1998;79(2):121-126.
32. Sato S, Itamochi H. Profile of farletuzumab and its potential in the treatment of solid tumors. Onco Targets Ther. 2016;9:1181-1188. doi: 10.2147/OTT.S98242.
33. Marchetti C, Palaia I, Giorgini M, et al. Targeted drug delivery via folate receptors in recurrent ovarian cancer: a review. Onco Targets Ther. 2014;7:1223-1236. doi: 10.2147/OTT.S40947.
34. Ab O, Whiteman KR, Bartle LM, et al. IMGN853, a folate receptor-α (FRα)—targeting antibody–drug conjugate, exhibits potent targeted antitumor activity against FRα-expressing tumors. Mol Cancer Ther. 2015;14(7):1605-1613. doi: 10.1158/1535-7163.MCT-14-1095.