The WHG Weekly Brief: Issue 1

Stay informed. Stay ahead. Weekly clinical insights.

June 23, 2025 • Estimated Reading Time: 5 minutes

🌟 Editor's Note

Hello!

You’re reading The WHG — a sharp, no-fluff newsletter designed for busy clinicians and healthcare leaders. It’s built by someone who’s spent over a decade creating digital tools for MDs and deeply understands how overwhelming it is to stay on top of constantly evolving guidelines. Each issue cuts through the noise to bring you what’s actionable, relevant, and sometimes even surprising.

Let’s dive in.

— The WHG Team

Clinical Insight of the Week:
ACOG sets the floor, but NCCN moves the field forward. While ACOG’s guidelines on hereditary cancer testing haven’t been updated since 2017, NCCN has revised its criteria multiple times—most recently in March 2025. These updates expand testing access (e.g., breast cancer age threshold raised to 65), include additional genes like PALB2 and CHEK2, and tailor recommendations for gender-diverse patients. Crucially, insurers follow NCCN—not ACOG—when determining coverage. So even if you’re practicing within ACOG’s bounds, aligning with NCCN ensures your patients can access and afford the testing they need.

🔄 Key Update Snapshot: March 2025 NCCN Guidelines

✅ What's New:

  • 📈 Age Threshold Raised
    Breast cancer testing expanded to ≤ 65 years (previously 60).

  • 👩‍⚕️ Unaffected Patients Eligible
    Testing now recommended for unaffected individuals meeting risk criteria — not just those with personal diagnoses.

  • 🧬 More Genes, More Clarity

    • ATM: Now tied to colorectal risk

    • CHEK2: Bi-allelic risk clarified

    • PALB2: Updated breast + pancreatic risk range (32–53%)

  • 🩺 Pancreatic Surveillance Added
    Screening recommended for BRCA2 or ATM carriers starting at age 50, even without a family history.

  • ⚧ Inclusive Care
    New guidance added for transgender, non-binary, and gender-diverse individuals with hereditary risk.

What’s new in research?

April 2025

This multi-center study analyzed 967 patients with advanced or recurrent endometrial cancer to assess the impact of next-generation sequencing (NGS) and targeted therapies. Among those tested, 94% had at least one actionable genomic alteration, most commonly in PI3K, TP53, and PTEN genes. A subset of 233 patients received matched targeted therapies, with a median progression-free survival of 6.9 months and overall survival of 20.5 months. The study included a racially and geographically diverse population. The findings suggest that molecularly matched biologic therapies are associated with improved survival compared to standard chemotherapy, supporting the utility of genomic testing in guiding treatment decisions for this population.

June 2025

This study investigated the expression of TROP2 and the effectiveness of the TROP2-targeting antibody-drug conjugate sacituzumab govitecan (SG) in uterine carcinosarcoma (UCS), a rare and aggressive endometrial cancer. TROP2 protein and mRNA were detected in over 90% of archival UCS samples, with higher expression in tumors with predominant carcinomatous components. UCS patient-derived organoids (PDOs) maintained the genetic profiles of their primary tumors and showed dose-dependent responses to SG, with a median IC50 of 167.7pM. In xenograft models, SG treatment significantly reduced tumor volume regardless of TROP2 expression levels. The study concludes that TROP2 is a promising therapeutic target in UCS and supports further clinical investigation of SG for this disease.

🔥 Gene of the week: PALB2

Primary Breast Cancer

PALB2 (Partner and Localizer of BRCA2) is a tumor suppressor gene that works closely with BRCA2 to help repair damaged DNA through homologous recombination. Inherited mutations in PALB2 significantly increase the risk of breast cancer—with lifetime risk estimates ranging from 33–58%, depending on family history. It also confers moderate risk for pancreatic cancer, and there is emerging evidence of increased ovarian and prostate cancer risks. Because of its clinical relevance, PALB2 is now included in many multi-gene hereditary cancer panels, and carriers may qualify for enhanced cancer surveillance and preventive strategies similar to BRCA1/2 guidelines.

Absolute risk: A person with a PALB2 mutation has a 32% to 53% chance of developing breast cancer in their lifetime.

Till next time,

The WHG Team