Insight

Armando Orlandi։ Redefining Who Should Consider Preventive Breast Surgery

Armando Orlandi/photos.asco.org

Aug 3, 2025, 20:42

Armando Orlandi։ Redefining Who Should Consider Preventive Breast Surgery

Armando Orlandi, Medical Director at the Agostino Gemelli University Hospital Foundation IRCCS, shared a post on LinkedIn about a paper by Xia Wei et al. published in JAMA Oncology:

“Breakthrough Research

Redefining Who Should Consider Preventive Breast Surgery

A groundbreaking economic analysis published in JAMA Oncology is reshaping how we think about risk-reducing mastectomy (RRM) for breast cancer prevention through sophisticated risk calculation methodology.

The Current Reality:

Preventive mastectomy is primarily offered only to BRCA1/BRCA2/PALB2 carriers, despite many other women facing similarly elevated risks through combined factors.

How Risk is Actually Calculated – The Multi-Factor Approach:

Genetic Components:

High-penetrance genes: BRCA1/BRCA2/PALB2 (50-80% lifetime risk)
Moderate-penetrance genes: ATM/CHEK2/RAD51C/RAD51D (20-40% risk)
Polygenic Risk Score: Hundreds of common variants contributing incremental risk

Integrated Factors:

Family history patterns and age at diagnosis
Reproductive history and hormone use
Mammographic density and benign lesions

Validated Models Used:

Tyrer-Cuzick: Genetics + family history + reproductive factors
CanRisk/BOADICEA: Multiple genes + PRS + density

Mathematical Framework:

UK baseline: 10.79% lifetime risk (ages 20-80)
Formula: Hazard ratio = ln(1-assumed risk) ÷ ln(1-baseline risk)
35% lifetime risk = 4.2x general population risk

Real-World Examples Reaching >35% Risk:

RAD51C carrier + first-degree relative + favorable PRS = ~35-40%
ATM carrier + strong family history + high PRS = ~41%
Multiple moderate factors without high-penetrance genes = 35%

The Game-Changing Findings

RRM becomes cost-effective at 35% lifetime risk regardless of how that threshold is reached. Age-adjusted thresholds range from 29-42%.

The Robust Methodology:

Markov Model: 100,000 UK women simulated over lifetime
NHS Economic Analysis: £20,000-30,000/QALY thresholds
Conservative Comparator: Intensive screening + medical prevention
Validation: 10,000 Monte Carlo simulations

Impact:
Expanded Access: ~3% of UK women (vs 0.5% BRCA carriers) could benefit
Prevention Potential: ~6,500 UK breast cancer cases preventable annually
Precision Medicine: Complete risk profile assessment, not just single mutations

Looking Forward:

This research provides evidence for truly personalized breast cancer prevention through integrated risk assessment. The methodology ensures accurate identification of high-risk women who could benefit from preventive surgery, regardless of traditional high-risk mutations.”

Title: Defining Lifetime Risk Thresholds for Breast Cancer Surgical Prevention

Journal: JAMA Oncology

Authors: Xia Wei, Lea Mansour, Samuel Oxley, Caitlin T. Fierheller, Ashwin Kalra, Jacqueline Sia, Subhasheenee Ganesan, Michail Sideris, Li Sun, Adam Brentnall, Stephen Duffy, D. Gareth Evans, Li Yang, Rosa Legood, Ranjit Manchanda

Read the full article.

Armando Orlandi

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