High expression of phosphoglycerate dehydrogenase predicts poor outcome in patients with high-grade serous ovarian cancer

Abstract Introduction High-grade serous ovarian cancer (HGSOC) is characterized by high mortality and prevalent recurrences. This study investigates the prognostic value of phosphoglycerate dehydrogenase (PHGDH) in HGSOC which has been linked to metabolic reprogramming and recurrences in other cancers. Methods Data from 306 patients with advanced-stage HGSOC treated between 2008 and 2015 were analyzed. PHGDH expression levels were determined using immunohistochemistry and categorized as “low” or “high.” Results PHGDH-high was associated with higher FIGO stage and increased use of neoadjuvant chemotherapy. Patients with PHGDH-high tumors had significantly worse survival than PHDH-low, even after adjusting for confounding factors.


Introduction
Ovarian cancer is the deadliest gynecological malignancy in Western countries, 1 with high-grade serous (HGSOC) being the most prevalent subtype.Standard treatment is platinumbased chemotherapy combined with debulking surgery 2 ; however, the vast majority of patients develop recurrent disease.Metabolic reprogramming is linked to malignant proliferation and recurrent disease 3 and is emerging as a possible source of therapeutic targets.The de novo serine synthesis pathway (SSP; Figure 1) plays a crucial role in tumor metabolic adaptation and carcinogenesis and is mediated by phosphoglycerate dehydrogenase (PHGDH). 4The prognostic value of PHGDH has been shown in multiple cancers, 5 yet little is known about its role in HGSOC.In this study, we examined PHGDH as a prognostic biomarker of survival in HGSOC.

Methods
We included 322 women with FIGO stage 2b-4 HGSOC who received either primary debulking surgery followed by adjuvant chemotherapy or neoadjuvant chemotherapy and interval debulking (NACT-IDS), in one of 3 Dutch referral hospitals (Netherlands Cancer Institute (NKI-AVL), Maastricht University Medical Center and Amsterdam University Medical Center) between 2008 and 2015.Patient data were extracted from the Netherlands Cancer Registry (NCR).Pathological data and tumor blocks were obtained from the Dutch Nationwide Pathology Databank (PALGA).Institutional review board approval of the NCR (K19.074),PALGA (2019-169), and NKI-AVL (CFMPB297) was obtained.The dataset was anonymous and exempt from ethics review board approval.All cases underwent pathological review by 3 dedicated pathologists (K.V.d.V., H.H, and J.S.).PHGDH was detected by immunohistochemistry (HPA021241, Sigma Aldrich) and scored by multiplying staining intensity (0, no; 1, weak; 2, moderate; and 3, intense staining) with the percentage of positive cells (0%-100%).PHGDH was subgrouped into "low" and "high" based on the cutoff point with the most discriminative survival power (PHGDH≥210; Figure 2B, 2C).Pathologists were blinded to e1232 The Oncologist, 2024, Vol. 29, No. 9 patient characteristics.Characteristics are summarized using descriptive statistics and compared at PHGDH level using the chi-square test, t-tests, and Wilcoxon rank-sum tests.
Kaplan-Meier survival estimates, log-rank tests, and Cox regressions were used to assess survival differences between low and high PHGDH.Analyses were conducted using

Discussion
The biosynthesis of serine, mediated by PHGDH, has been linked to the development and malignant proliferation of multiple cancer types. 5Serine is either acquired through uptake or synthesized via the SSP (Figure 1).The glycine, one-carbon, serine network produces carbon units essential for various metabolic pathways, such as the anabolic metabolism, maintaining redox balance, and shaping the epigenetic landscape. 6Our data portray that high PHGDH levels in primary tumors at initial diagnosis are associated with worse survival in HGSOC.Interestingly, in a prior study, in which we investigated PHGDH levels in vivo and in vitro, we depicted that in a subgroup of HGSOC a downregulation of PHGDH occurred when the disease recurred after primary treatment and became platinum resistant. 7Taken together, a dynamic role of PHGDH could be hypothesized in which higher levels at diagnosis are associated with unfavorable prognosis and metabolic adaptation could result in lower PHGDH levels in platinum-resistant recurrences.The PHGDH pathway could reveal possible therapeutic targets in primary tumors, per instance by targeting enzymes involved in the PHGDH pathway in tumors with elevated PHGDH expression, as well as vulnerabilities in resistant recurrences.Nonetheless despite the completeness in patient data and large size, the current study is not without limitations.Such limitations are its historical nature, heterogenic patient group and lack of validation cohort.Therefore, PHGDH's role in HGSOC and possible influence on survival should be further validated.As new treatment options emerge, understanding underlying mechanisms of cancer progression and chemoresistance may assist in patient tailored treatment.

Figure 2 .
Figure 2. Survival analyses of patients with HGSOC, according to PHGDH levels.(A) Kaplan-Meier curves for overall survival according to PHGDH-high and PHGDH-low.P values were derived with the use of the log-rank statistic.(B) Immunohistochemical (IHC) staining of a patient with low PHGDH tumors.(C) IHC staining of a patient with high PHGDH tumors.

Table 1 .
Patient and tumor characteristics.