Rapid development and use of patient-specific ctDNA biomarkers to avoid a "rash decision" in an ovarian cancer patient

Abstract

Epithelial ovarian cancer (OvCa) is the most lethal female reproductive tract malignancy. A major clinical hurdle in patient management and treatment is that when using current surveillance technologies 80% of patients will be clinically diagnosed as having had a complete clinical response to primary therapy. In fact, the majority of women nonetheless develop disease recurrence within 18 mo. Thus, without more accurate surveillance protocols, the diagnostic question regarding OvCa recurrence remains framed as "when" rather than "if." With this background, we describe the case of a 61-yr-old female who presented with a 3-mo history of unexplained whole-body rash, which unexpectedly led to a diagnosis of and her treatment for OvCa. The rash resolved immediately following debulking surgery. Nearly 1 yr later, however, the rash reappeared, prompting the prospect of tumor recurrence and requirement for additional chemotherapy. To investigate this possibility, we undertook a genomics-based tumor surveillance approach using a targeted 56-gene NGS panel and biobanked tumor samples to develop personalized ctDNA biomarkers. Although tumor-specific TP53 and PTEN mutations were detectable in all originally collected tumor samples, pelvic washes, and blood samples, they were not detectable in any biosample collected beyond the first month of treatment. No additional chemotherapy was given. The rash spontaneously resolved. Now, 2 yr beyond the patient's original surgery, and in the face of continued negative ctDNA findings, the patient remains with no evidence of disease. As this single case report suggests, we believe for the first time that ctDNA can provide an additional layer of information to avoid overtreatment.

Keywords: ovarian neoplasm.

Figure 1.

Pruritic whole-body rash of unexplained origin. (A) Evidence of marked dermatographism and eczematous dermatitis on back (1), shoulder (2), and thigh (3). (B) Histologic findings of rash biopsied prior to OvCa diagnosis and treatment. (1) (H&E; 10×) Low-power view of right upper thigh excoriation with extensive parakeratosis. (2) (H&E; 40×) High-power view demonstrating acute and chronic inflammation surrounding a blood vessel. (C) Similar histologic findings of rash 1 yr following initial OvCa surgery and chemotherapy. (1) (H&E; 10×) Punch biopsy from the right lateral upper thigh demonstrating both deep and superficial dermatitis. (2) (H&E; 40×) Deep dermal blood vessels surrounded by inflammatory cells. The endothelial cells are rounded and consistent with a generalized reactivity phenotype.

Figure 2.

Stage IIIC ovarian cancer. High-grade serous nuclei displaying significant pleomorphism, prominent nucleoli, and apoptosis (H&E; 20×).

Figure 3.

Timeline of patient clinical history, testing, and results. Schematic demonstrating the patient's overall presentation and clinical course highlighted with both traditional and precision medicine–directed molecular results. The patient developed a whole-body rash of unexplained origin that was resistant to multiple topical and systemic treatments 3 mo prior to her diagnosis of ovarian cancer. The original rash disappeared within days of tumor debulking at the time of primary surgery and initiation of chemotherapy. The rash reappeared ∼1 yr later and suggested the possibility of cancer recurrence. Results of serum CA125 levels, CT and PET scans, and ultrasound (US) throughout her care are shown. The patient's tumor was sequenced at the timepoint shown (green arrowhead), with the express intent to identify somatic mutations and develop patient-specific ctDNA biomarkers. These tumor-specific mutations were simultaneously screened for in blood samples, second-look biopsies, and a pelvic wash sample (purple), all of which had been previously collected in real time and biobanked. In the upper and lower panels, the clinical presentation, surgical history, and chemotherapy events are shown as well as the clinical and molecular results including both next-generation sequencing (NGS) and droplet digital polymerase chain reaction (ddPCR) assay results, respectively. Results are shown as positive (+) or negative (−).