What is the treatment for p53 mutated PAX8 (Paired Box 8) positive cancer?

Treatment of PAX8-Positive, p53-Mutated Cancer

For PAX8-positive cancers with p53 mutations, treatment should be directed by the specific cancer type, with the most common being high-grade serous ovarian cancer, endometrial cancer, and renal cell carcinoma—each requiring distinct therapeutic approaches based on stage and molecular profile.

Cancer Type Identification and Treatment Selection

High-Grade Serous Ovarian Cancer (Most Common PAX8+/p53-mutated Cancer)

For newly diagnosed advanced-stage disease, platinum-based chemotherapy with PARP inhibitor maintenance is the standard approach, with combined chemoradiotherapy showing particular benefit in p53-abnormal tumors. 1

• All patients with high-grade ovarian cancer should undergo germline and somatic BRCA1/2 mutation testing at diagnosis, as this determines eligibility for PARP inhibitor therapy 1
• HRD (homologous recombination deficiency) testing is recommended in advanced high-grade cancers to guide targeted therapy selection 1
• For stage III-IV disease, surgical cytoreduction followed by platinum-based chemotherapy (carboplatin/paclitaxel) is standard 1
• Molecular analysis from PORTEC-3 demonstrated that p53-abnormal tumors specifically benefit from combined chemoradiotherapy versus radiotherapy alone, with 5-year recurrence-free survival of 59% versus 36% 1, 2

Endometrial Cancer with p53 Abnormality

For high-risk endometrial cancer with p53 mutations, combined chemoradiotherapy (EBRT 48.6 Gy with concurrent cisplatin followed by carboplatin/paclitaxel) provides superior survival compared to radiotherapy alone. 1, 2

• PAX8 is expressed in 98% of endometrial adenocarcinomas and correlates with p53 expression and high-grade histology 3
• Stage I grade 3 with deep myometrial invasion or LVSI, stage II, or stage III disease warrants consideration for combined modality therapy 1, 2
• The PORTEC-3 molecular substudy specifically identified p53-abnormal tumors as deriving the greatest benefit from systemic chemotherapy addition to radiotherapy 1, 2
• For stage I-II disease without high-risk features, treatment algorithms should follow FIGO staging with consideration of adjuvant therapy based on risk factors 1

Clear Cell Renal Cell Carcinoma

For metastatic PAX8-positive renal cell carcinoma, VEGF and mTOR pathway inhibitors are standard, with PAX8 expression supporting renal origin when diagnosis is uncertain. 1

• PAX8 is expressed in 90% of renal cell carcinomas and 81% of renal oncocytomas, serving as a diagnostic marker 4
• For metastatic disease, agents targeting VEGF and mTOR pathways improve progression-free survival in both first-line and second-line settings 1
• Cytoreductive nephrectomy followed by sunitinib may be considered in select patients with optimally one IMDC risk factor 1
• PAX8 expression combined with diffuse CAIX expression supports clear cell renal origin when establishing metastatic disease diagnosis 1

Molecular Considerations for p53-Mutated Cancers

p53 Mutation Testing Requirements

• TP53 mutation analysis should include exons 4-10 at minimum, optimally exons 2-11, covering the DNA-binding domain and oligomerization domain 1
• Testing should be performed on peripheral blood with mononuclear cell separation when lymphocyte count is adequate (>60-70% lymphocytes) 1
• For chronic lymphocytic leukemia with TP53 mutations, BCR inhibitors (ibrutinib) or BCL2 inhibitors (venetoclax) are recommended over chemoimmunotherapy 1

Therapeutic Implications of p53 Status

• p53 mutations predict poor response to conventional chemotherapy but identify patients who benefit most from combined chemoradiotherapy in endometrial and ovarian cancers 1, 2
• Novel agents targeting mutant p53 (PRIMA-1MET) are in early clinical trials for high-grade serous ovarian cancer, triple-negative breast cancer, and squamous lung cancer 5
• MDM2/MDM4 antagonists (nutlins) are being evaluated for cancers with wild-type p53 where MDM2 is overexpressed 5

Common Pitfalls and Caveats

• PAX8 positivity alone does not determine treatment—the primary tumor site must be established through additional markers including TTF-1, RCC marker, and WT-1 1, 4
• PAX8 is expressed in 99% of high-grade serous ovarian carcinomas but also in 91% of thyroid tumors and 98% of endometrial adenocarcinomas, requiring clinical context for interpretation 4
• Unexpected PAX8 positivity occurs in thymic neoplasms (12 cases in one series), which should not be confused with Müllerian, renal, or thyroid primaries 4
• Low-burden p53 mutations (<10% variant allele frequency) have unclear clinical significance with targeted agents, though they predict clonal expansion with genotoxic chemotherapy 1
• For endometrial cancer, p53 overexpression correlates with high-grade histology but has not been validated as an independent prognostic parameter for survival 3