. 2022 Oct 4;19(1):35.

doi: 10.1186/s12014-022-09372-y.

Proteomic alterations associated with residual disease in neoadjuvant chemotherapy treated ovarian cancer tissues

Emily R Penick^#¹, Nicholas W Bateman^#^{1

2

3}, Christine Rojas^#¹, Cuauhtemoc Magana⁴, Kelly Conrads^{1

3}, Ming Zhou^{1

5}, Brian L Hood^{1

3}, Guisong Wang^{1

3}, Niyati Parikh^{1

3}, Ying Huang^{1

3}, Kathleen M Darcy^{1

2

3}, Yovanni Casablanca^{1

2}, Paulette Mhawech-Fauceglia⁴, Thomas P Conrads^{6

7

8}, G Larry Maxwell^{9

10

11}

Affiliations

¹ Women's Health Integrated Research Center, Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA.
² Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA.
³ Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., 6720A Rockledge Dr., Suite 100, Bethesda, MD, 20817, USA.
⁴ Department of Anatomic Pathology, Division of Gynecologic Pathology, University of Southern California, Los Angeles, CA, 9007, USA.
⁵ Women's Health Integrated Research Center, Women's Service Line, Inova Health System, 3289 Woodburn Rd, Falls Church, VA, 22003, USA.
⁶ Women's Health Integrated Research Center, Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA. conrads@whirc.org.
⁷ Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA. conrads@whirc.org.
⁸ Women's Health Integrated Research Center, Women's Service Line, Inova Health System, 3289 Woodburn Rd, Falls Church, VA, 22003, USA. conrads@whirc.org.
⁹ Women's Health Integrated Research Center, Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA. george.maxwell@inova.org.
¹⁰ Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA. george.maxwell@inova.org.
¹¹ Women's Health Integrated Research Center, Women's Service Line, Inova Health System, 3289 Woodburn Rd, Falls Church, VA, 22003, USA. george.maxwell@inova.org.

^# Contributed equally.

PMID: 36195845
PMCID: PMC9531351
DOI: 10.1186/s12014-022-09372-y

Proteomic alterations associated with residual disease in neoadjuvant chemotherapy treated ovarian cancer tissues

Emily R Penick et al. Clin Proteomics. 2022.

. 2022 Oct 4;19(1):35.

doi: 10.1186/s12014-022-09372-y.

Authors

Affiliations

¹ Women's Health Integrated Research Center, Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA.
² Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA.
³ Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., 6720A Rockledge Dr., Suite 100, Bethesda, MD, 20817, USA.
⁴ Department of Anatomic Pathology, Division of Gynecologic Pathology, University of Southern California, Los Angeles, CA, 9007, USA.
⁵ Women's Health Integrated Research Center, Women's Service Line, Inova Health System, 3289 Woodburn Rd, Falls Church, VA, 22003, USA.
⁶ Women's Health Integrated Research Center, Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA. conrads@whirc.org.
⁷ Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA. conrads@whirc.org.
⁸ Women's Health Integrated Research Center, Women's Service Line, Inova Health System, 3289 Woodburn Rd, Falls Church, VA, 22003, USA. conrads@whirc.org.
⁹ Women's Health Integrated Research Center, Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA. george.maxwell@inova.org.
¹⁰ Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA. george.maxwell@inova.org.
¹¹ Women's Health Integrated Research Center, Women's Service Line, Inova Health System, 3289 Woodburn Rd, Falls Church, VA, 22003, USA. george.maxwell@inova.org.

^# Contributed equally.

PMID: 36195845
PMCID: PMC9531351
DOI: 10.1186/s12014-022-09372-y

Abstract

Background: Optimal cytoreduction to no residual disease (R0) correlates with improved disease outcome for high-grade serous ovarian cancer (HGSOC) patients. Treatment of HGSOC patients with neoadjuvant chemotherapy, however, may select for tumor cells harboring alterations in hallmark cancer pathways including metastatic potential. This study assessed this hypothesis by performing proteomic analysis of matched, chemotherapy naïve and neoadjuvant chemotherapy (NACT)-treated HGSOC tumors obtained from patients who had suboptimal (R1, n = 6) versus optimal (R0, n = 14) debulking at interval debulking surgery (IDS).

Methods: Tumor epithelium was harvested by laser microdissection from formalin-fixed, paraffin-embedded tissues from matched, pre- and post-NACT treated tumors for twenty HGSOC patients and analyzed by quantitative mass spectrometry-based proteomics.

Results: Differential analysis of patient matched pre- and post-NACT treated tumors revealed proteins associated with cell survival and metabolic signaling to be significantly altered in post-NACT treated tumor cells. Comparison of pre-NACT treated tumors from suboptimal (R1) versus optimally (R0) debulked patients identified proteins associated with tumor cell viability and invasion signaling enriched in R1 patients. We identified five proteins altered between R1 and R0 patients in pre- NACT treated tumors that significantly correlated with PFS in an independent cohort of HGSOC patients, including Fermitin family homolog 2 (FERMT2), a protein elevated in R1 that correlated with disease progression in HGSOC patients (multivariate Cox HR = 1.65, Wald p = 0.022) and increased metastatic potential in solid-tumor malignancies.

Conclusions: This study identified distinct proteome profiles in patient matched pre- and post-NACT HGSOC tumors that correlate with NACT resistance and that may predict residual disease status at IDS that collectively warrant further pre-clinical investigation.

Keywords: Neoadjuvant chemotherapy; Ovarian cancer; Personalized medicine, Biomarkers; Proteomics; Residual disease.

PubMed Disclaimer

Conflict of interest statement

TPC is a ThermoFisher Scientific, Inc SAB member and receives research funding from AbbVie.

Figures

**Fig. 1**
Differential analysis of quantitative proteomic data generated from matched FFPE tissues collected from HGSOC patients (n = 20), post versus pre-neoadjuvant chemotherapy (NACT) treatment. A Volcano plot showing 97 proteins significantly altered between post and pre-NACT treated tissues (LIMMA p < 0.01). B Principal component (PC) analysis of the 97 altered proteins serves explain 34.5% and 8.6% of the variance between these post and pre-NACT treated tumors

**Fig. 2**
A Differential analysis of quantitative proteomic data generated from FFPE tissues collected pre-neoadjuvant chemotherapy (NACT) treatment from HGSOC patients with residual (R1, n = 6) or no/microscopic residual (R0, n = 14) disease at interval debulking surgery. Differential analyses of pre-NACT treated tissue revealed 140 proteins as significantly altered between these patient populations (LIMMA p-value ≤ 0.05). “R0” = none or microscopic, “R1” = macroscopic, i.e. < 1 cm disease

**Fig. 3**
Fermitin Family Member 2 (FERMT2) correlates with an increased risk of progression and is significantly elevated in HGSOC patients with high (> 1.1 cm) residual disease burden. A Kaplan–Meier curve illustrating the relationship between FERMT2 protein abundance and progression free survival (PFS) identified from a publicly available global proteomics data set of 154 HGSOC patient tissues (CPTAC Ovarian, 2016); high and low reflects median cut-point of FERMT2 protein abundance and Log-rank P reflects categorized, univariate log-rank testing. B FERMT2 protein abundance for patients exhibiting > 1.0 cm (> R1, n = 50), 0.1–1.0 cm (R1, n = 64) or no residual disease (R0, n = 24); * reflects Mann Whitney U P-value = 0.02

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Proteomic alterations associated with residual disease in neoadjuvant chemotherapy treated ovarian cancer tissues

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Proteomic alterations associated with residual disease in neoadjuvant chemotherapy treated ovarian cancer tissues

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