Long-term Safety of Nipple Sparing Mastectomy in Women With High Penetrance Breast Cancer Susceptibility Genes in Breast Cancer (NSM)

December 1, 2025 updated by: Stephanie Wong, Sir Mortimer B. Davis - Jewish General Hospital

Long-term Oncologic Safety of Nipple Sparing Mastectomy in Women With High Penetrance Germline Pathogenic Variants in Breast Cancer Susceptibility Genes

Patients with a germline pathogenic variant (GPV) in high-penetrance breast cancer susceptibility genes who are considering risk reducing mastectomy (RRM) often strongly desire to keep their nipple areola complex but inquire as to whether it is safe to do so. Relative to traditional or skin sparing mastectomy (SSM) techniques, nipple sparing mastectomy (NSM) is associated with improved psychosocial and sexual well-being and is significantly better for body image and reducing feelings of disfigurement.

Despite this, guidelines have yet to endorse the use of NSM over other RRM techniques, stating that more data and longer follow-up are needed to confirm it as a safe and effective strategy in GPV carriers. As NSM was not routinely adopted in high-risk patient populations undergoing RRM before 2010, there has been little data to inform the long-term oncologic safety of NSM. Well-designed studies have reported low to negligible rates of subsequent breast cancer in BRCA1/2 carriers following NSM, but have been limited by short median follow-up of less than 3 years. The current study is designed to confirm, with longer follow-up, prior findings on the oncologic safety of NSM in unaffected BRCA1/2 carriers. The investigators will also expand data to other high-penetrance GPV carriers, including PALB2, CDH1, PTEN, and TP53, for whom there is little-to-no data on outcomes following RRM.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Study Type

Observational

Enrollment (Estimated)

4700

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Australia
  • Belgium
      • Antwerp, Belgium, 2030
        • Active, not recruiting
        • Ziekenhuis Aan De Stroom
  • Canada
    • Alberta
    • Ontario
      • Hamilton, Ontario, Canada, L8L 2X2
        • Recruiting
        • Hamilton Health Sciences
        • Contact:
        • Principal Investigator:
          • Elena Parvez, MD
      • Toronto, Ontario, Canada
    • Quebec
      • Montreal, Quebec, Canada, H3T1E2
      • Québec, Quebec, Canada, G1S 4L8
  • Portugal
      • Lisbon, Portugal
  • United States
    • Connecticut
      • New Haven, Connecticut, United States, 06510
        • Recruiting
        • Yale University
        • Contact:
        • Principal Investigator:
          • Mehra Golshan, MD
    • Massachusetts
      • Boston, Massachusetts, United States, 02115
    • New York
      • New York, New York, United States, 10065
        • Not yet recruiting
        • Memorial Sloan Kettering Cancer Center (MSKCC)
        • Contact:
        • Principal Investigator:
          • Giacomo Montagna, MD
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104-6205

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Female patients aged 18-years or older with a confirmed GPV in BRCA1, BRCA2, PALB2, TP53, CDH1 or PTEN identified on pre-symptomatic genetic testing performed between January 1, 1994-June 30, 2024

Description

Inclusion Criteria:

  • Assigned female sex at birth
  • Age 18 years or older
  • Confirmed GPV in BRCA1, BRCA2, PALB2, TP53, CDH1 or PTEN identified on pre-symptomatic genetic testing

Exclusion Criteria:

  • History of breast cancer prior to genetic testing
  • History of ovarian cancer prior to genetic testing
  • History of bilateral mastectomy performed prior to genetic testing
  • Presence of a variant of uncertain significance (VUS) in the absence of another GPV in BRCA1, BRCA2, PALB2, TP53, CDH1 or PTEN.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Risk Reducing Mastectomy
Procedure: Nipple Sparing Mastectomy (NSM)
Nipple sparing mastectomy (NSM) is a surgical procedure which removes all macroscopic breast glandular tissue while retaining the skin as well as the nipple areola complex.
Procedure: Skin-Sparing Mastectomy (SSM)
Skin sparing mastectomy (SSM) is a procedure that removes the nipple and areola complex along with all visible macroscopic breast glandular tissue.
Procedure: Total (Simple) Mastectomy
Total (Simple) Mastectomy is a traditional mastectomy approach that removes the breast glandular tissue with a large overlying area of skin including the nipple and areola complex to allow for flat closure.
Active surveillance

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of breast cancer following RRM
Time Frame: 10 years
The primary outcome of interest is the incidence of breast cancer following RRM, defined as a histologically confirmed diagnosis of in situ or invasive breast cancer present within the nipple/areola, skin, subcutaneous tissue of the chest wall/reconstructed breast, or axillary lymph nodes. Patients with clinically occult invasive breast cancer diagnosed at the time of RRM (ie. on mastectomy pathology) will be excluded from the primary outcome analysis.
10 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incidence of RRM
Time Frame: 10 years
To evaluate uptake of RRM versus active surveillance amongst an international cohort of unaffected women with high-penetrance GPVs in BRCA1/2, PALB2, CDH1, PTEN, or TP53
10 years
Incidence of post-operative complications
Time Frame: 10 years
To evaluate post-operative complications and supplemental surgery following NSM, SSM, and total mastectomy in those undergoing RRM
10 years
Incidence of pathologic outcomes following NSM
Time Frame: 10 years
To evaluate pathologic outcomes following RRM, including the presence of high-risk lesions or occult in situ and/or invasive malignancy
10 years
Number of participants using endocrine prevention
Time Frame: 10 years
To explore the use of endocrine prevention in unaffected women with high-penetrance GPVs in BRCA1/2, PALB2, CDH1, PTEN, or TP53 who elect to undergo active surveillance
10 years
Number of participants who have undergone pre-mastectomy imaging and post-mastectomy surveillance
Time Frame: 10 years
To assess practices in pre-mastectomy imaging and post-mastectomy surveillance, including the number of participants who underwent preoperative MRI and mammography as well as post-mastectomy surveillance, including MRI, ultrasound and chest wall examination.
10 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sir Mortimer B. Davis - Jewish General Hospital

Collaborators

Quebec Breast Cancer Foundation
Cancer Research Society

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 1, 2025

Primary Completion (Estimated)

February 1, 2027

Study Completion (Estimated)

February 1, 2028

Study Registration Dates

First Submitted

March 15, 2025

First Submitted That Met QC Criteria

March 15, 2025

First Posted (Actual)

March 21, 2025

Study Record Updates

Last Update Posted (Actual)

December 8, 2025

Last Update Submitted That Met QC Criteria

December 1, 2025

Last Verified

December 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • MP-05-2025-4291 (MP)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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