Post-Frontline Recurrence-Prevention Strategy

Post-Frontline Recurrence-Prevention Strategy for Stage IV High-Grade Serous Tubo-Ovarian Carcinoma

A Personalized Mechanistic Analysis

Patient: Claire Gribbin | DOB: February 26, 1967 (Age 59) | Date: May 14, 2026 Oncologist: Dr. Amy BonDurant, Swedish Cancer Institute Gynecologic Oncology

Section 1: Executive Summary

Patient Profile

A 59-year-old woman with newly diagnosed Stage IV high-grade serous carcinoma of tubo-ovarian origin (HGSOC). Tumor genomics reveal a distinctive profile: HRD-negative (HRDsig 0.14), BRCA1/2 wildtype, PIK3CA H1047L activating kinase domain mutation (VAF 63.1%), TP53 M1K (start-loss), HER2 IHC 2+, FOLR1=0, microsatellite stable, TMB 5 mut/Mb (low), and PD-L1 CPS 0. Disease distribution includes peritoneal implants, ascites, retroperitoneal lymphadenopathy, sigmoid tethering, colon mesentery involvement, bladder peritoneum, diaphragmatic nodules, and right pleural effusion. She is currently receiving neoadjuvant carboplatin/paclitaxel/bevacizumab with interval debulking surgery planned after cycle 3. Germline testing (Ambry 77-gene panel) revealed only a POLE R1324H VUS in the C-terminal domain (non-actionable). Clinical considerations include emerging paclitaxel neuropathy, neutropenia approaching severe after cycle 2, A1c 5.8% (borderline prediabetes), B12 deficiency (177 pg/mL), and bilateral patellofemoral arthroplasty (2024, healed).

Core Biological Narrative

This cancer occupies a challenging but not hopeless molecular niche. It is HRD-negative — meaning PARP inhibitors provide minimal benefit and expected median PFS with bevacizumab maintenance alone is approximately 16–18 months. However, the near-clonal PIK3CA H1047L mutation (unusual in HGSOC, typically found at 3–7% frequency) creates both a therapeutic vulnerability and metabolic target that can be exploited through next-generation mutant-selective PI3Kα inhibitors, metabolic optimization, and future combination strategies. The immune-cold profile (MSS, TMB-low, PD-L1=0) makes standard checkpoint immunotherapy ineffective, but macrophage/innate immune targeting and intraperitoneal approaches represent emerging opportunities. Bevacizumab is especially rational given the VEGF-dependent phenotype evidenced by ascites and pleural effusion.

Section 2: Biological Interpretation — What Makes This Case Typical vs. Atypical

Typical HGSOC Features

TP53 mutation (>96% of HGSOC harbor TP53 alterations): The M1K start-loss mutation is consistent with TP53 loss of function, confirmed by abnormal p53 overexpression on IHC.
Peritoneal/transcoelomic dissemination pattern: Ascites, peritoneal implants, omental/mesenteric involvement, and diaphragmatic nodules represent the classic HGSOC spread pattern.
Stage IV with low-volume pleural disease: Right-sided pleural effusion with diaphragmatic nodules is the most common mechanism of Stage IV upstaging in HGSOC (transdiaphragmatic lymphatic drainage).
WT1+/PAX8+ immunophenotype: Confirms müllerian serous lineage.
CA-125 elevation (464 U/mL): Typical for advanced HGSOC.

Atypical Features

PIK3CA H1047L (VAF 63.1%): Highly atypical for HGSOC. PIK3CA activating mutations occur in only 3–7% of HGSOC versus 33–50% of clear cell and 20–40% of endometrioid ovarian carcinoma. The near-clonal VAF (63.1%) indicates this is a truncal/founding event, not a late subclonal acquisition. This raises the question of whether this tumor has "clear-cell-like" molecular features embedded within morphologic HGSOC — sometimes called "molecular mixed biology." The WT1+ staining argues against pure clear cell, but additional IHC (HNF1β, Napsin A, ARID1A, ER/PR) at debulking surgery would clarify. European Journal of Translational and Clinical Medicine

HRD-negative status (HRDsig 0.14): While ~40% of HGSOC are HRD-negative, this profoundly low score indicates fully intact homologous recombination repair — the strongest predictor of lack of benefit from PARP inhibitor maintenance. It also predicts shorter platinum-free interval (median PFS ~16–18 months with bevacizumab). The clinical challenges of HRP in ovarian cancer

HER2 IHC 2+ in HGSOC: Not commonly tested or reported. ~28% of ovarian cancers show HER2 IHC 2+. Notably, PIK3CA mutations are more prevalent in HER2 2+/3+ ovarian tumors, suggesting biological co-occurrence. FISH/ISH should be completed. Zhang et al., Sci Rep 2024

FOLR1=0: Approximately 35–40% of HGSOC are FRα-high; this patient's FOLR1-negative status excludes mirvetuximab soravtansine unless expression changes at recurrence.

Immune-cold profile (MSS, TMB 5, CPS 0): While not uncommon in HGSOC, the combination of all three negative biomarkers plus HRD-negative status creates a quadruple-negative immunotherapy profile with essentially no evidence base for standard checkpoint inhibitor benefit.

Synthetic Interpretation

This tumor represents a PI3K-driven, HR-proficient, immune-cold HGSOC — a molecular subtype that is resistant to both PARP inhibitors and checkpoint immunotherapy, but potentially vulnerable to:

1. PI3K pathway-directed therapy (the mutation itself is targetable)

2. Anti-angiogenic therapy (VEGF-driven effusions predict bevacizumab benefit)

3. Replication stress exploiters (WEE1/ATR inhibitors given TP53 loss + intact HR)

4. Metabolic intervention (PI3K-driven glucose addiction)

5. Innate immune approaches (macrophage-targeting bypasses T-cell coldness)

Section 3: Mechanisms of Recurrence (Ranked by Plausibility)

Rank

Mechanism

Plausibility

Key Evidence

Biomarkers to Confirm

Mapped Interventions

1	Peritoneal niche-protected residual disease	Very High	Extensive peritoneal/mesenteric/diaphragmatic disease creates multiple sanctuary sites; microscopic submesothelial deposits survive R0 surgery	CRS score at surgery (low CRS = more viable residual); post-op ctDNA positivity	Bevacizumab (anti-VEGF disrupts niche), HIPEC (investigational), IP therapy trials
2	PI3K-driven platinum tolerance	Very High	PIK3CA H1047L (63.1% VAF) confers universal anti-apoptotic/pro-survival signaling (BAD phosphorylation, NF-κB), reducing platinum kill fraction across all residual cells	PIK3CA ctDNA persistence post-chemo; organoid platinum sensitivity testing	PI3K inhibitors (STX-478, alpelisib), metformin (AMPK/mTOR opposition), PI3Ki+PARPi combinations
3	Drug-tolerant persister cells (ATF3+/partial EMT)	High	HRp biology + PI3K activation creates ideal conditions for non-genetic persistence; ATF3+ DTPs confirmed in all HGSOC scRNA-seq datasets	Organoid re-challenge assays; EMT marker expression (vimentin, ZEB1) on surgical IHC	Epigenetic therapies, ferroptosis inducers (FZD7+ persisters), PI3K inhibition
4	Cancer stem cells enriched by platinum	High	Ascites + IL-6 + PI3K activation synergistically drive CSC enrichment; ALDH+ spheroid formation confirmed by ascites presentation	ALDH1A1 IHC on surgical specimen; flow cytometry of ascites for CD133+/ALDH+	Anti-CSC trials, Wnt inhibitors, IL-6 blocking, metformin (reduces CSC markers)
5	Ascites-associated anoikis-resistant spheroids	High	Active ascites at presentation confirms this compartment exists and regenerates after drainage	Ascites volume at surgery; tumor spheroid count in washings	Bevacizumab (reduces VEGF/permeability), CSF1R inhibition (reverses vascular leakage)
6	HRp-mediated efficient DNA repair	Moderate-High	Intact HR directly reduces platinum-induced cell death; HRDsig 0.14 predicts reduced platinum efficacy	Platinum-free interval post-treatment; CRS on surgical specimen	WEE1/ATR inhibitors (exploit replication stress despite intact HR); ATRi+AKTi synergy
7	Lymphatic micrometastases	Moderate	Established retroperitoneal LN involvement means residual intranodal disease persists beyond surgical field	Lymph node status at surgery; retroperitoneal recurrence pattern on surveillance	Surveillance imaging of retroperitoneum; systemic (not IP) therapy at recurrence
8	Transdiaphragmatic/pleural dormant deposits	Moderate	Diaphragmatic and pleural disease confirms this dissemination axis is active; micro-deposits in pleural recesses are surgically inaccessible	Pleural recurrence on CT; ctDNA positivity from pleural clone	Systemic therapy; bevacizumab (addresses effusion biology)
9	Immune evasion (CPS 0, MSS, TMB-low)	Moderate	No immune pressure to control residual disease; recurrence proceeds unchecked by adaptive immunity	CD8 TIL density at surgery; immune gene expression	Macrophage-targeting (SL-172154, CD47/CD24), IP CAR-T, oncolytic virus
10	Replication-stress-driven clonal evolution	Moderate	Ongoing CIN generates heterogeneity enabling selection of fully resistant clones	Emergence of new mutations on serial ctDNA; CCNE1 amplification	WEE1i (azenosertib), PKMYT1i+WEE1i (lunresertib+zedoresertib)

Section 4: Ranked Post-Frontline Courses of Action

Summary Table

Rank

Strategy

Evidence

Expected Benefit

Toxicity

Detailed Narrative

1. Bevacizumab Maintenance (15 Months)

Biological rationale: This patient's ascites and pleural effusion are direct evidence of VEGF-dependent vascular permeability. The NRG Oncology/GOG analysis of GOG-0218 demonstrated that patients WITH ascites derived significant PFS (HR 0.71, p<0.001) AND OS (HR 0.82, p=0.014) benefit from bevacizumab, while patients without ascites did not. The ICON7 high-risk subgroup (Stage IV) showed OS improvement of 7.8 months (36.6 vs 28.8 months, HR 0.64, p=0.002). The KELIM biomarker analysis further identifies HRD-negative patients with poor chemosensitivity as deriving the greatest bevacizumab benefit. NRG/GOG Ascites Analysis Evidence level: Phase III, Level I. Standard of care per NCCN/ESMO for Stage IV HRD-negative HGSOC. Expected benefit: Median PFS ~16-18 months with bevacizumab maintenance (vs. ~10-12 without); possible OS benefit in Stage IV. Risks: Hypertension (20-40%), proteinuria, GI perforation (elevated risk 5-11% given sigmoid tethering), thromboembolism. Requires 4-6 week surgical washout. Key management: Hold bevacizumab ≥4-6 weeks before IDS; resume ≥4 weeks post-surgery with confirmed wound healing. Surgeon should plan for possible segmental sigmoid resection. Prior PFA (2024) is NOT a wound-healing concern (fully healed). AGO-OVAR 17 BOOST showed no benefit from extending beyond 15 months.

2. Mutant-Selective PI3Kα Inhibitor Trial (STX-478)

Biological rationale: PIK3CA H1047L is the identical kinase-domain hotspot position as H1047R, constitutively activating PI3Kα. STX-478 is a first-generation mutant-selective allosteric PI3Kα inhibitor that spares wild-type enzyme — dramatically reducing the hyperglycemia, rash, and diarrhea that limited alpelisib. ESMO 2024 data: 44% ORR in gynecologic cancers (monotherapy), tumor reductions in 72% of all patients, ctDNA decline in 86%. No treatment discontinuations due to adverse events. Scorpion/BioSpace 2024 Evidence level: Phase 1/2 with exceptional early signal. The most promising agent for this specific mutation. Expected benefit: 44% response rate; durable responses; well-tolerated. Feasibility: Currently enrolling at MD Anderson, Dana-Farber, UI Health Care. Not yet at a Seattle site but expansion cohorts include gynecologic cancers. RLY-2608 (zovegalisib) is an alternative mutant-selective PI3Kα inhibitor (NCT05216432) available at multiple sites. Timing: At first recurrence. Bank tissue at surgery to confirm PIK3CA H1047L and establish molecular eligibility.

3. ctDNA Monitoring (Signatera)

Biological rationale: Signatera tracks 16 patient-specific clonal variants via ultra-deep PCR (sensitivity ~0.01% VAF). For this patient, both TP53 M1K and PIK3CA H1047L would be tracked. Validated in ovarian cancer: 100% sensitivity and specificity for recurrence detection with 10-month lead time over imaging, compared to only 1 month for CA-125. Medicare-covered since February 2024. Natera Signatera Ovarian Validation, 2023 Expected benefit: Prognostic stratification (MRD-positive within 2.5 months = 7.6× recurrence risk); may enable earlier trial enrollment. Key caveat: No RCT proves intervention based on ctDNA positivity improves OS (the OV05 lesson). Use for risk stratification and trial eligibility, not automatic treatment trigger. Logistics: Submit tumor tissue from initial biopsy NOW to Natera for bespoke panel design (4-6 week turnaround). Post-surgery draw establishes baseline.

4. Metabolic Optimization Package

Biological rationale: PIK3CA H1047L creates a constitutively active PI3K→AKT→mTOR axis. Metformin activates AMPK, which directly opposes mTORC1. Preclinical data specific to H1047R (functionally equivalent to H1047L) showed >80% tumor growth inhibition with metformin — PIK3CA-mutant tumors are paradoxically more metformin-sensitive than wild-type because constitutive PI3K makes them independent of insulin but dependent on mTOR, which AMPK suppresses. Cufí et al., Oncotarget 2013 Components:

Metformin 500→1000 mg daily (discuss with Dr. BonDurant): addresses prediabetes (A1c 5.8%) + anti-cancer mechanism
CGM during chemotherapy: quantify dexamethasone hyperglycemia, guide dietary interventions, preserve PI3Ki trial eligibility (STX-478 excludes HbA1c ≥8%)
Exercise (150 min/week aerobic + 2-3× resistance): reduces IGF-1 by ~20 ng/ml, activates AMPK, improves insulin sensitivity
Atorvastatin continuation: mevalonate pathway inhibition has synergistic rationale with PI3K biology + mutant p53 mevalonate dependence

Evidence classification: Biologically plausible with mutation-specific preclinical support; no Phase III efficacy data in ovarian cancer. Low toxicity. Reasonable to implement.

5. Tissue Banking + Molecular Tumor Board (Fred Hutch/UW)

Rationale: Interval debulking surgery is the single best opportunity to collect diverse biospecimens. Fresh tissue for organoid culture enables future drug sensitivity testing (platinum, PI3K inhibitors, novel agents). Fred Hutch/UW molecular tumor board can review the PIK3CA/TP53 profile, POLE VUS, and guide trial strategy. Key actions: Coordinate ≥1 week pre-surgery with pathology and Fred Hutch organoid lab; request CRS scoring, expanded IHC, fresh-frozen tissue, ascites collection; refer for molecular tumor board review.

6. WEE1/PKMYT1 Inhibitor Trial

Biological rationale: TP53 M1K (loss of function) eliminates the G1 checkpoint, making this tumor dependent on the G2/M checkpoint (WEE1-mediated) for DNA repair. WEE1 inhibition forces cells with unrepaired DNA into mitosis → mitotic catastrophe. This mechanism is independent of HRD status. The MYTHIC trial (lunresertib + zedoresertib: PKMYT1i + WEE1i) showed 50% ORR in ovarian cancer and 60% in CCNE1-amplified tumors, receiving FDA Fast Track Designation (April 2026). MYTHIC AACR 2026 Timing: Platinum-resistant recurrence. Test for CCNE1 amplification on surgical tissue — if present, this becomes a top-priority trial.

7. ADC Strategy (T-DXd or Trop-2 ADC)

Biological rationale: HER2 IHC 2+ enables T-DXd (ORR ~27% in IHC 2+ solid tumors per DESTINY-PanTumor02); Trop-2 is expressed in >80% of epithelial ovarian cancers. Datopotamab deruxtecan (Dato-DXd) showed 42.9% ORR in ovarian cancer at ESMO 2024. All topoisomerase-I based ADCs avoid neuropathy — critical given this patient's emerging paclitaxel neuropathy precludes taxane rechallenge. Oaknin et al., ESMO 202402295-6/fulltext) Timing: Platinum-resistant recurrence (where ORR for standard chemo is only 10-15%). Consider earlier if neuropathy prevents taxane use at first recurrence.

8. Macrophage/Innate Immune Therapy

Biological rationale: This immune-cold tumor (CPS 0, MSS, TMB-low) is dominated by immunosuppressive M2 macrophages in the peritoneal microenvironment. Standard checkpoint inhibitors have failed (IMagyn050, JAVELIN 200, NINJA all negative). The CD47/SIRPα axis (SL-172154) and CD24/Siglec-10 axis represent targetable innate immune checkpoints. SL-172154 simultaneously blocks CD47 and agonizes CD40, bridging innate to adaptive immunity. Phase I showed acceptable safety with pharmacodynamic evidence of macrophage activation. SL-172154 Phase I, J Immunother Cancer 2025 Timing: At recurrence. Request CD47 and CD24 IHC at surgery to confirm target expression.

Section 5: Clinical Trial Strategy

Commercial (Medicare-covered)

[ ] NOW: Submit tumor from initial biopsy to Natera for Signatera panel design
[ ] 1 week pre-surgery: Meeting with surgical team + pathology to confirm specimen routing
[ ] 1 week pre-surgery: Arrange organoid transport with Fred Hutch/UW lab
[ ] 1 week pre-surgery: Obtain research consent if enrolling in Fred Hutch tissue banking protocol
[ ] Day of surgery: Fresh tissue in transport media → organoid lab; ascites on ice → research lab
[ ] Post-surgery: Request CRS, expanded IHC, FOLR1 Ventana re-test, CCNE1 status

Section 7: Surveillance Plan After Frontline Therapy

Integrated Surveillance Calendar

Months 0-24 Post-Completion of Frontline (High-Risk Period)

Modality

Frequency

Evidence Level

Action Threshold

Physical exam + pelvic	Every 3 months	NCCN Category 2A (proven)	New mass, ascites, adenopathy
CA-125	Every 3 months	NCCN Category 2A (caveat: bev suppresses CA-125)	Confirmed doubling from nadir; correlate with imaging
CT chest/abdomen/pelvis	Every 4-6 months (or as indicated)	Moderate (not routine per NCCN but rational for Stage IV)	RECIST progression
ctDNA (Signatera)	Every 3 months	Validated (10-mo lead time) — informational	MRD positivity → intensified imaging + trial eligibility discussion
Metabolic markers (A1c, fasting insulin, CRP, vitamin D)	Every 6 months	Observational; modifiable risk	Manage per targets

Months 25-60

Modality

Frequency

Notes

Physical exam + CA-125	Every 4-6 months	Standard
CT	Annually or as indicated	Reduce frequency if ctDNA persistently negative
ctDNA	Every 6 months	Consider stopping if negative through year 3

Key Interpretive Caveats

CA-125 on bevacizumab: Bev independently suppresses CA-125 via anti-permeability effects. A CA-125 rise at bev cessation (month 15) is expected and does NOT automatically indicate progression. Confirm with imaging.
ctDNA as prognostic, not prescriptive: MRD positivity post-surgery predicts recurrence (7.6× risk) but no RCT proves acting on it improves OS. Use for: (1) intensified surveillance, (2) trial eligibility, (3) maintenance duration discussion.

Section 8: Quality-of-Life & Longevity Optimization

URGENT Actions (Before Cycle 3)

Action

Rationale

Exercise Program

Category: Standard clinical recommendation (Level I evidence)

During chemo: 150 min/week moderate aerobic (cycling, swimming — ideal with bilateral PFA) + 2-3× resistance training
Prehab before IDS: Structured exercise 3-6 weeks pre-surgery reduces complications 20-50%
Avoid: Deep squats, lunges >90° knee flexion, plyometrics, running on hard surfaces
Specific benefits with PI3K biology: Exercise activates AMPK (opposes mTOR), reduces IGF-1 by ~20 ng/ml, improves insulin sensitivity
CIPN benefit: ECHO trial (JAMA Network Open 2023) showed exercise significantly reduces CIPN severity in ovarian cancer

Neuropathy Management

Current status: Grade 1-2 (fingertip numbness, thumb/index) after cycle 2
B12 correction: URGENT — compounds taxane neuropathy
Cryotherapy: Start cycle 3 (frozen gloves/socks 15 min before, during, 15 min after paclitaxel)
Consider duloxetine 30 mg prophylactically (2024 RCT shows prevention benefit)
Dose modification threshold: If symptoms progress to Grade 2 (functional impairment) → reduce paclitaxel to 135 mg/m²
Pharmacogenomics: CYP2C83 carriers have slower paclitaxel clearance → higher cumulative nerve exposure

Nutrition & Metabolic

Intervention Recommendation Category

Protein 1.2-1.5 g/kg/day 84-105g/day for muscle preservation; leucine-rich sources Standard

Mediterranean diet pattern Anti-inflammatory; reduces CRP, IL-6 Reasonable adjunctive

Vitamin D supplementation (4000-5000 IU/day) Target 40-60 ng/mL (was 39.4, prior 23.7) Standard

B12 5000 mcg methylcobalamin daily Target >500 pg/mL; urgent given 177 + neuropathy Standard

CGM during chemo cycles Quantify dexamethasone hyperglycemia; guide diet Reasonable adjunctive

Metformin 500→1000 mg/day Discuss with oncologist: A1c 5.8% + PIK3CA H1047L rationale Biologically plausible

Fasting-mimicking (modified: 24-48h low-cal around infusion) Differential stress resistance; immune rejuvenation Trial-level evidence

Integrative Oncology

Modality Best Evidence For Category

Acupuncture Nausea (Cochrane), fatigue (meta-analysis), CIPN (NMA: superior to usual care) Reasonable adjunctive

CBT-I for insomnia 2:30 AM wake pattern; superior to medications Standard recommendation

Mindfulness/MBSR Anxiety, depression, QOL Standard recommendation

Melatonin 3-5 mg Sleep; may synergize with chemo Reasonable adjunctive

Magnesium glycinate 200-400 mg Sleep + nerve function (cofactor) Reasonable adjunctive

Evidence Tier Classification Key

Tier Definition Examples

Standard clinical recommendation Level I/II evidence; guideline-supported G-CSF, B12, exercise, bevacizumab maintenance

Reasonable low-risk adjunctive Moderate evidence; favorable risk-benefit Cryotherapy, CGM, acupuncture, Mediterranean diet

Biologically plausible / off-label Preclinical + mechanistic rationale; no Phase III Metformin for PIK3CA-mutant, statin anti-cancer effect

Trial-based Early-phase clinical data; requires enrollment STX-478, WEE1i, SL-172154

Speculative Theoretical; should not drive care decisions Acupuncture for myeloprotection, interstitium targeting

Questions for Dr. BonDurant (Oncologist) Before Surgery

1. Neuropathy management: Can we implement frozen gloves/socks for cycle 3? Should we consider prophylactic duloxetine given emerging symptoms at cycle 2?

2. Neutropenia: Given approaching-severe neutropenia after cycle 2, should pegfilgrastim be added starting cycle 3?

3. B12 deficiency: B12 is 177 (below normal) — this compounds paclitaxel neuropathy. Can we start high-dose supplementation immediately?

4. Bevacizumab washout: What is the planned washout duration before IDS? (Minimum 4-6 weeks recommended)

5. Bowel perforation risk: Given sigmoid tethering/stricture, has the surgical team planned for possible segmental sigmoid resection?

6. Metformin: Given A1c 5.8% and PIK3CA H1047L biology (preclinical data showing H1047-mutant tumors are metformin-sensitive), is there rationale to start metformin 500 mg?

7. CRS scoring: Will Chemotherapy Response Score be explicitly requested on the surgical pathology?

8. Signatera timing: Can we submit existing tumor tissue to Natera NOW for bespoke ctDNA panel design (4-6 week lead time)?

9. PARP inhibitor: To confirm — bevacizumab alone (not olaparib or niraparib) is the planned maintenance, given HRDsig 0.14?

10. Fred Hutch referral: Would you support a molecular tumor board referral and/or tissue routing to Fred Hutch for organoid culture?

Questions for Pathology Before Surgery

1. CRS scoring: Please score per Böhm criteria (3-tier CRS system) on the surgical specimen.

2. Expanded IHC: Can the following be ordered on the debulking specimen?

- Immune: CD8, FOXP3, CD68, CD163, CD47, MHC-I/HLA-ABC

- Biology: HNF1β, Napsin A, ARID1A (BAF250a), ER, PR

- Targets: HER2 (repeat on solid tissue), FOLR1 (Ventana FOLR1-2.1 RxDx assay)

3. Fresh tissue routing: Can fresh tumor from ≥2 sites be routed to: (a) liquid nitrogen for fresh-frozen, (b) transport media for organoid lab?

4. Ascites collection: If ascites is present at surgery, can a sterile aliquot be collected on ice for research processing?

5. FFPE from multiple sites: Please archive blocks from all distinct anatomic sites (ovary, peritoneum, mesentery, diaphragm, LNs, bowel if resected).

6. CCNE1 amplification: Can this be assessed on the repeat NGS panel?

Questions for Fred Hutch / UW Molecular Tumor Board

1. PIK3CA H1047L in HGSOC: This is atypical (3-7% frequency). Does the molecular tumor board recommend any additional characterization or reclassification consideration?

2. Trial matching: Given PIK3CA H1047L + TP53 M1K + HRD-negative, what trials are currently accessible through Fred Hutch/SCCA? Specifically: STX-478 (expanding to gyn cancers), ComboMATCH, or any PI3K pathway trials?

3. Organoid feasibility: Can Fred Hutch organoid core receive fresh tissue from IDS at Swedish? What is the logistics protocol?

4. POLE R1324H VUS: This is in the C-terminal domain. Do you concur it is non-actionable? Any new reclassification data?

5. 23andMe pharmacogenomics: Would the UW Medical Genetics team be willing to provide a focused pharmacogenomic interpretation of the 23andMe raw data (CYP2C8, ABCB1, GSTP1) for clinical record?

6. BRCA1 promoter methylation: Should this be tested on the surgical specimen to assess for epigenetic HRD that might expand PARPi eligibility?

7. CCNE1 status: If CCNE1 amplification is found, does this change the recurrence strategy (WEE1i/PKMYT1i trials)?

8. Mother's tissue: Would it be useful to request her pathology blocks from OSU for comparative genomics or POLE VUS segregation?

Evidence Classification Key

Symbol Meaning

⭐⭐⭐ Phase III / Level I evidence; guideline-supported standard of care

⭐⭐ Phase II or strong Phase I data; rational off-label or active enrollment

⭐ Preclinical or observational; biologically plausible but not clinically validated

🔬 Research/translational only; no current clinical application

This report synthesizes findings from 8 parallel research tracks conducted May 14, 2026, incorporating the patient's FoundationOne CDx report, surgical pathology, Ambry 77-gene germline panel, 23andMe genome (546,603 SNPs), health records, and published medical literature (2020-2026). It is intended to support clinical discussion and does not constitute medical advice. All treatment decisions should be made in consultation with the treating oncology team.

ADDENDUM — Updated Data Integration & Frontier Possibilities

Added May 14, 2026, after review of additional source documents

A. Additional Source Documents Reviewed

Document Key Findings

CT Chest w Contrast (March 23, 2026) Bilateral pleural nodularity, small right pleural effusion, subcarinal LN 12mm, right paratracheal LN 10mm, 2mm and 5mm groundglass pulmonary nodules, perihepatic peritoneal fluid

CA-125 Trends (Swedish MyChart) Mar 20: 464 → Apr 9: 816.5 → Apr 29: 507.7 U/mL

CMP Trends (Feb 2023 – Apr 29, 2026) Glucose 92-97 (normal during chemo), creatinine 0.58-0.80, eGFR 85-104, albumin 4.5, all electrolytes normal

B12 + Folate (Mar 20, 2026) B12: 262 pg/mL (low-normal), Folate: 17.3 (normal)

CEA (Mar 20, 2026) 1.6 ng/mL (normal — rules out GI primary)

Chemo Tracking Spreadsheet Paclitaxel 339mg, Carboplatin 714mg, Bevacizumab 1200mg (from cycle 2). Dexamethasone 8mg x3-4 days per cycle. Detailed supplement tracking, sleep, nutrition, exercise data

B. CA-125 Kinetics — Critical Update

Date CA-125 (U/mL) Context

Dec 2023 5.2 Baseline (normal)

Oct 2020 5.8 Prior baseline (normal)

Mar 20, 2026 464 Pre-treatment (diagnostic)

Apr 9, 2026 816.5 Day 1 of Cycle 1 (pre-infusion draw)

Apr 29, 2026 507.7 Day 1 of Cycle 2 (with bevacizumab added)

Interpretation:

The rise from 464 → 816.5 between March 20 and April 9 (20 days) likely represents continued tumor growth in the interval before chemotherapy began. This is NOT a treatment failure — it is the natural trajectory before therapy took effect.

The decline from 816.5 → 507.7 (38% drop) after just one cycle of carboplatin/paclitaxel is a favorable early response signal. The KELIM model (CA-125 elimination kinetics) uses early CA-125 slope to predict chemosensitivity. A >50% decline after 2 cycles is considered favorable; this patient is tracking toward that threshold.
Bevacizumab caveat: Bev was added at cycle 2 (Apr 29). Bevacizumab can independently suppress CA-125 through anti-VEGF effects on vascular permeability, making it harder to distinguish true tumor kill from bev-mediated CA-125 suppression in subsequent readings. The post-cycle-3 CA-125 will be more interpretable. No change to report recommendations: Early CA-125 response is encouraging and consistent with platinum sensitivity. This reinforces bevacizumab maintenance as the rational backbone strategy.

C. CT Chest (March 23, 2026) — Baseline Thoracic Disease
Key findings:
Subtle bilateral pleural nodularity (mm-scale, along fissures and pleural surfaces)

Small dependent right pleural effusion

Subcarinal lymph nodes up to 12mm, right paratracheal up to 10mm

2mm and 5mm groundglass pulmonary nodules (may be inflammatory or metastatic)

Perihepatic peritoneal fluid

Left periaortic retroperitoneal LN 13mm

Impression per radiology: "Suspicious for early pleural and mediastinal metastatic disease, potentially early thoracic lymphangitic carcinomatosis." Implications for report: This confirms the Stage IV designation via pleural involvement and validates the report's emphasis on diaphragmatic/pleural migration pathways as a recurrence mechanism. The low-volume thoracic disease is encouraging — it suggests the "pleural seeding" is early and may respond well to systemic therapy + bevacizumab (which specifically targets VEGF-mediated effusions). Post-cycle-3 chest imaging will be critical for response assessment.

D. Chemo Tracking — Treatment Tolerance & Metabolic Insights

Chemotherapy Doses:

Paclitaxel 339 mg (consistent with 175 mg/m² for BSA ~1.94)

Carboplatin 714 mg (consistent with AUC 5-6 for normal renal function)

Bevacizumab 1200 mg (consistent with 15 mg/kg for ~80 kg body weight)

Dexamethasone Exposure (Hyperglycemia Context):

Cycle 1: Dexamethasone 8mg × 3 days (Apr 9-11)

Cycle 2: Dexamethasone 8mg × 4 days (Apr 29 – May 2)

Glucose on chemo days: 97 mg/dL (Apr 9 and Apr 29) — normal despite dexamethasone

This is reassuring: steroid-induced hyperglycemia is NOT currently manifest in fasting labs. However, dexamethasone causes postprandial spikes that fasting glucose may miss — this is exactly where CGM would provide additional data.

Supplement Regimen (Already Taking):

✅ B12 1000 mcg daily (started Apr 9; doubled to 2000 mcg from May 4)

✅ Vitamin D3 110 mcg (4,400 IU) daily

✅ Omega-3 2000mg daily

✅ Magnesium glycinate 400mg (sleep)

✅ Magnesium threonate 288mg (neuropathy/brain) — discontinued after cycle 1

✅ Alpha Lipoic Acid 600mg (neuropathy, blood sugar) — started cycle 2

✅ L-Glutamine 5g (GI, neuropathy) — intermittent

✅ Lipitor 10mg daily (cholesterol)

✅ Melatonin 10mg nightly

Update to report: The patient is already implementing many recommended supplements. B12 supplementation began at cycle 1 (1000 mcg) and was increased. Alpha Lipoic Acid (600mg) was added for neuropathy at cycle 2 — this has some evidence for CIPN prevention. The supplement strategy is well-designed.
Exercise Tracking:

Strength training: 30 min sessions, ~3-4x/week consistently through both cycles

Steps: 4,500-13,000/day (averaging ~6,500) — remarkably active during chemo

HRV: 20-41 ms (low range typical during chemo; trending slightly up toward end of cycle 2)

Sleep: 7-10 hours/night, quality 63-95% (excellent adherence to sleep hygiene)

Nutrition:

Calories: 500-1850/day (low day 1 post-infusion, recovering by day 3-4)

Protein: 37-120g/day (averaging ~80g — good; target is ≥1.2 g/kg = ~96g for ~80kg)

Fiber: 6-44g/day (variable)

No change to recommendations — the patient is already executing the exercise and nutrition strategy at a high level. Consider pushing protein slightly higher (aim for 95-100g/day consistently) on days appetite allows.

E. Clinical Observation: Increased Stool Diameter — Possible Sigmoid Response
Patient-reported: Stool diameter increased from ~1 cm (pre-treatment) to ~2 cm (after 2 cycles).
Clinical Interpretation:

The initial CT (March 18, 2026) documented tumor tethering/adherence to the sigmoid colon causing stricture. A narrowed sigmoid lumen would compress stool into a thinner caliber — exactly what was observed pre-treatment.
The doubling of stool diameter is a plausible functional indicator that:
1. The tumor mass is shrinking and releasing extrinsic compression on the sigmoid

2. Peritumoral inflammation/edema is resolving (bevacizumab reduces VEGF-mediated swelling)

3. The sigmoid lumen is re-opening
Clinical significance:
Supports chemotherapy response — consistent with the CA-125 decline

Favorable for surgical planning — if the sigmoid is no longer tethered, bowel resection may be avoidable at interval debulking (significant QOL difference)

Relevant to bevacizumab safety — bowel that has been invaded/tethered by tumor is the primary site of bev-associated perforation risk. If the tumor is releasing, this risk may decrease (though the area of prior involvement remains a site of vulnerability)

Recommendation: Report this observation to Dr. BonDurant before surgery. It informs the surgical approach and bowel perforation risk assessment.

F. B12 Status — Corrected Data

Date B12 (pg/mL) Status

Jan 19, 2026 177 🔴 Deficient

Mar 20, 2026 262 🟡 Low-normal (suboptimal for neuroprotection)

Apr 9 onward Supplementing 1000-2000 mcg/day ✅ Correction in progress

The report's recommendation for B12 supplementation remains correct but the urgency is reduced — the patien

[Truncated for app. Full version in Word doc.]*

1	Bevacizumab maintenance (15 months)	Standard of care	Immediately post-frontline
2	Mutant-selective PI3Kα inhibitor trial (STX-478)	Trial-based	At first recurrence (establish eligibility now)
3	ctDNA monitoring (Signatera) for MRD/recurrence	Guideline-supported (Medicare-covered)	Post-surgery baseline, then Q3 months
4	Metabolic optimization (metformin, CGM, exercise, statin continuation)	Biologically plausible / low-risk	Immediately
5	Tissue banking + molecular tumor board referral (Fred Hutch/UW)	Clinical preparation	Before/at surgery
6	WEE1/PKMYT1 inhibitor trial (azenosertib)	Trial-based	At platinum-resistant recurrence
7	Trastuzumab deruxtecan (T-DXd) or Trop-2 ADC	Off-label / trial-based	At platinum-resistant recurrence
8	Macrophage-targeting immunotherapy (SL-172154, CD47/CD24 axis)	Trial-based	At recurrence (Fred Hutch)

1	Bevacizumab maintenance (15 mo)	Phase III (GOG-0218, ICON7)	PFS +3.8 mo; OS +5 mo in Stage IV	HTN, proteinuria, bowel perf risk (5-11% with sigmoid involvement)	Standard of care	Immediately
2	STX-478 (mutant-selective PI3Kα inhibitor) trial	Phase 1/2 (44% ORR in gyn cancers)	Durable responses; ctDNA decline 86%	Minimal hyperglycemia; well-tolerated	Trial-based	First recurrence
3	Signatera ctDNA surveillance	Validated (100% sensitivity, 10-mo lead time)	Earlier recurrence detection; prognostic stratification	Anxiety of early detection; no RCT for intervention	Guideline-supported	Post-surgery
4	Metabolic optimization (metformin + CGM + exercise + statin)	Preclinical (H1047R-specific data); Phase II clinical	Biologically plausible recurrence delay; QOL improvement	Minimal (GI for metformin)	Biologically plausible	Immediately
5	Fred Hutch/UW molecular tumor board + tissue banking	Clinical preparation	Ensures trial readiness; organoid drug testing	None	Clinical standard	Before surgery
6	WEE1 inhibitor (azenosertib) trial	Phase 2/3 (ASPENOVA, DENALI)	50-60% ORR with PKMYT1i in CCNE1+	Myelosuppression, GI	Trial-based	Platinum-resistant recurrence
7	T-DXd or Trop-2 ADC	Phase II/III (ORR 27-43% in ovarian)	Meaningful responses without neuropathy	ILD (rare), GI, cytopenias	Off-label / trial	Platinum-resistant recurrence
8	Macrophage/innate immune therapy	Phase I/Ib (SL-172154, CD47/CD24 axis)	Novel mechanism for immune-cold tumors	TBD (early data shows safety)	Trial-based	Recurrence (Fred Hutch)

Correct B12 deficiency (methylcobalamin 5000 mcg/day sublingual)	B12=177 compounds paclitaxel neuropathy; correctable cause of nerve damage	Standard clinical recommendation
Implement cryotherapy (frozen gloves/socks during paclitaxel infusion)	Reduces Grade ≥2 CIPN by 42-50% (2025 meta-analysis)	Reasonable low-risk adjunctive
Add G-CSF prophylaxis (pegfilgrastim, cycle 3 onward)	Neutropenia approaching severe after cycle 2; expected worsening	Standard clinical recommendation
*Check 23andMe for CYP2C83 (rs10509681) and ABCB1* (rs1045642)	CYP2C83 carriers have 2.1× neuropathy risk + 2.1× neutropenia risk on carbo/taxol	Reasonable low-risk adjunctive

Protein 1.2-1.5 g/kg/day	84-105g/day for muscle preservation; leucine-rich sources	Standard
Mediterranean diet pattern	Anti-inflammatory; reduces CRP, IL-6	Reasonable adjunctive
Vitamin D supplementation (4000-5000 IU/day)	Target 40-60 ng/mL (was 39.4, prior 23.7)	Standard
B12 5000 mcg methylcobalamin daily	Target >500 pg/mL; urgent given 177 + neuropathy	Standard
CGM during chemo cycles	Quantify dexamethasone hyperglycemia; guide diet	Reasonable adjunctive
Metformin 500→1000 mg/day	Discuss with oncologist: A1c 5.8% + PIK3CA H1047L rationale	Biologically plausible
Fasting-mimicking (modified: 24-48h low-cal around infusion)	Differential stress resistance; immune rejuvenation	Trial-level evidence

Acupuncture	Nausea (Cochrane), fatigue (meta-analysis), CIPN (NMA: superior to usual care)	Reasonable adjunctive
CBT-I for insomnia	2:30 AM wake pattern; superior to medications	Standard recommendation
Mindfulness/MBSR	Anxiety, depression, QOL	Standard recommendation
Melatonin 3-5 mg	Sleep; may synergize with chemo	Reasonable adjunctive
Magnesium glycinate 200-400 mg	Sleep + nerve function (cofactor)	Reasonable adjunctive

Standard clinical recommendation	Level I/II evidence; guideline-supported	G-CSF, B12, exercise, bevacizumab maintenance
Reasonable low-risk adjunctive	Moderate evidence; favorable risk-benefit	Cryotherapy, CGM, acupuncture, Mediterranean diet
Biologically plausible / off-label	Preclinical + mechanistic rationale; no Phase III	Metformin for PIK3CA-mutant, statin anti-cancer effect
Trial-based	Early-phase clinical data; requires enrollment	STX-478, WEE1i, SL-172154
Speculative	Theoretical; should not drive care decisions	Acupuncture for myeloprotection, interstitium targeting

⭐⭐⭐	Phase III / Level I evidence; guideline-supported standard of care
⭐⭐	Phase II or strong Phase I data; rational off-label or active enrollment
⭐	Preclinical or observational; biologically plausible but not clinically validated
🔬	Research/translational only; no current clinical application

CT Chest w Contrast (March 23, 2026)	Bilateral pleural nodularity, small right pleural effusion, subcarinal LN 12mm, right paratracheal LN 10mm, 2mm and 5mm groundglass pulmonary nodules, perihepatic peritoneal fluid
CA-125 Trends (Swedish MyChart)	Mar 20: 464 → Apr 9: 816.5 → Apr 29: 507.7 U/mL
CMP Trends (Feb 2023 – Apr 29, 2026)	Glucose 92-97 (normal during chemo), creatinine 0.58-0.80, eGFR 85-104, albumin 4.5, all electrolytes normal
B12 + Folate (Mar 20, 2026)	B12: 262 pg/mL (low-normal), Folate: 17.3 (normal)
CEA (Mar 20, 2026)	1.6 ng/mL (normal — rules out GI primary)
Chemo Tracking Spreadsheet	Paclitaxel 339mg, Carboplatin 714mg, Bevacizumab 1200mg (from cycle 2). Dexamethasone 8mg x3-4 days per cycle. Detailed supplement tracking, sleep, nutrition, exercise data

Dec 2023	5.2	Baseline (normal)
Oct 2020	5.8	Prior baseline (normal)
Mar 20, 2026	464	Pre-treatment (diagnostic)
Apr 9, 2026	816.5	Day 1 of Cycle 1 (pre-infusion draw)
Apr 29, 2026	507.7	Day 1 of Cycle 2 (with bevacizumab added)

Jan 19, 2026	177	🔴 Deficient
Mar 20, 2026	262	🟡 Low-normal (suboptimal for neuroprotection)
Apr 9 onward	Supplementing 1000-2000 mcg/day	✅ Correction in progress

Medical Intelligence

Chemo Tracker v2

Daily Metrics

Sleep & Activity

Nutrition & Wellness

CA-125

Medications

Custom Symptoms

Notes

Recent Entries

Medication Adherence

Social & Engagement

USDA API Key

Search Foods

Daily Food Log