DNA strand with HER2 receptor

Decoding Breast Cancer: How BRCA Mutations and IGF-1R Expression Impact Treatment

Mira Elwood in Health & Wellness December 2025 • 4 min read.

"Unlocking the link between genetic mutations, protein expression, and Trastuzumab sensitivity in HER2-positive breast cancer patients."

Breast cancer is a complex disease, and its treatment often requires a personalized approach. One area of intense research focuses on understanding how genetic mutations and protein expression within cancer cells can influence the effectiveness of targeted therapies. A recent study delved into the interplay between BRCA mutations and the expression of insulin-like growth factor receptor-1β (IGF-1Rβ) in HER2-positive breast cancer patients.

HER2-positive breast cancer is characterized by an overabundance of the HER2 protein, which promotes cancer cell growth. Trastuzumab, a monoclonal antibody, is a standard treatment that targets HER2. However, not all patients respond equally to Trastuzumab, prompting scientists to investigate factors that might affect its efficacy.

The study aimed to assess the combined impact of BRCA mutations (specifically BRCA1/2) and IGF-1Rβ expression on Trastuzumab sensitivity in patients with HER2-positive breast cancer. Researchers also sought to unravel the relationships between HER2 overexpression, BRCA mutations, and IGF-1R expression through pathway reconstruction analysis.

BRCA Mutations, IGF-1R Expression, and Trastuzumab Response: What the Study Revealed

The study analyzed data from 35 patients with HER2-positive breast cancer who were treated with Trastuzumab, either as an adjuvant/neoadjuvant therapy (82.9%) or after the development of metastasis (17.1%). The researchers performed immunohistochemistry to assess the expression of HER2, ER/PR, Ki67, and IGF-R1β. Bioinformatic analysis was then used to identify potential correlations between HER2 overexpression, BRCA mutations, and IGF-1Rβ expression.

Key findings from the study include:

High Prevalence of BRCA Mutations: 19 tumors (54%) presented BRCA mutations, with 11 (57.9%) being pathogenic.
IGF-1Rβ Expression and BRCA Status: Patients with BRCA mutations showed significantly higher IGF-1Rβ expression compared to those without (78.6% vs. 26.7%, p = 0.027).
Progression-Free Survival (PFS): The median PFS was 15.1 months in the overall population but shorter (9.7 months) in patients harboring BRCA mutations.
Disease-Free Survival (DFS): Patients with HER2-positive tumors and BRCA mutations had a median DFS of 60.3 months, while those without BRCA mutations had not reached that point (p = 0.018). A trend toward longer DFS was observed in HER2+ BRCA2 vs BRCA1 mutated patients.
IGF-R1β Expression and DFS: Patients with IGF-R1β-positive tumors treated with adjuvant/neoadjuvant Trastuzumab had a median DFS of 92.4 months, compared to those with IGF-R1β-negative tumors (p = 0.234).

The study also reconstructed the signaling pathways involved, revealing that BRCA1 mutations may lead to IGF-1R overexpression and increased phosphorylation of AKT. This, in turn, affects the transcription factor YB-1, which translocates to the nucleus, binds to the HER2 promoter, and increases HER2 and EGFR expression.

Implications for Personalized Treatment

These findings suggest that BRCA mutational status and IGF-1R expression are linked to Trastuzumab sensitivity in HER2-positive breast cancer. This highlights the potential for personalized treatment strategies based on a patient's unique genetic and protein expression profile.

For example, patients with BRCA mutations and high IGF-1R expression may benefit from alternative treatment approaches or combination therapies that target both HER2 and IGF-1R pathways. Further research is needed to validate these findings and explore the clinical utility of assessing BRCA and IGF-1R status in HER2-positive breast cancer.

By understanding the complex interplay between genetic mutations, protein expression, and treatment response, healthcare professionals can move closer to tailoring breast cancer treatments to individual patients, ultimately improving outcomes and quality of life.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.1093/annonc/mdw337.19, Alternate LINK

Title: Brca Mutations And Igf-R1 Expression In Modulating Sensitivity To Trastuzumab In Patients With Her2-Positive Breast Cancer

Subject: Oncology

Journal: Annals of Oncology

Publisher: Elsevier BV

Authors: M. Pistelli, A. Santinelli, M. Santoni, F. Piva, F. Bianchi, T. Biscotti, L. Belvederesi, Z. Ballatore, G. Occhipinti, M. De Lisa, A. Pagliacci, N. Battelli, R. Bracci, E. Maccaroni, L. Bastinelli, L. Cantini, R. Berardi, S. Cascinu

Published: 2016-09-01

Everything You Need To Know

What role do BRCA mutations play in treating HER2-positive breast cancer?

BRCA mutations, specifically BRCA1/2, are genetic alterations that can affect the response to cancer treatments. In the context of HER2-positive breast cancer, the study found that a significant portion of patients (54%) had BRCA mutations. These mutations were associated with higher expression of IGF-1Rβ and shorter progression-free survival when treated with Trastuzumab, a medication used to treat HER2-positive breast cancer. The presence of BRCA mutations can impact the effectiveness of the treatment and, thus, influence the course of the disease.

How does IGF-1R expression affect treatment outcomes?

IGF-1R, or Insulin-like Growth Factor Receptor-1β, is a protein that can influence cancer cell behavior. The study revealed a link between IGF-1Rβ expression and BRCA status in patients with HER2-positive breast cancer. Patients with BRCA mutations exhibited higher IGF-1Rβ expression. This is significant because the level of IGF-1Rβ expression was associated with how well patients responded to Trastuzumab. The study suggests that high IGF-1Rβ expression may be related to decreased sensitivity to Trastuzumab, potentially due to the signaling pathways that IGF-1Rβ activates.

What is the role of Trastuzumab in the treatment of HER2-positive breast cancer?

Trastuzumab is a monoclonal antibody used to treat HER2-positive breast cancer. It works by targeting the HER2 protein, which is overexpressed in these types of cancers and promotes cell growth. While Trastuzumab is an effective treatment, not all patients respond in the same way. The research showed that patients with BRCA mutations and/or high IGF-1Rβ expression had a different response to Trastuzumab compared to those without these characteristics. The study looked at Progression-Free Survival (PFS) and Disease-Free Survival (DFS) as indicators of Trastuzumab's effectiveness. Understanding the impact of BRCA mutations and IGF-1R expression on Trastuzumab response is vital for personalizing treatment plans.

Why is personalized treatment important based on the findings of this study?

The study's findings point towards the importance of personalized treatment strategies in HER2-positive breast cancer. This means that treatment plans should be tailored to each patient's unique genetic and protein expression profile. The results showed that patients' BRCA mutational status and IGF-1R expression are linked to their response to Trastuzumab, a key medication for this type of cancer. This information enables doctors to make more informed decisions about the most appropriate course of treatment, potentially improving outcomes by using therapies tailored to the patient's specific cancer.

How are BRCA mutations, HER2 expression, and IGF-1R expression connected in this context?

The study reconstructed signaling pathways, suggesting how BRCA mutations, HER2, and IGF-1R are interconnected. BRCA1 mutations may lead to increased IGF-1R expression and activation of the AKT pathway. This, in turn, can affect the transcription factor YB-1, which then binds to the HER2 promoter, boosting HER2 and EGFR expression. This provides a mechanistic explanation for how BRCA mutations might lead to resistance to Trastuzumab, as they can influence the expression of HER2, the target of the drug. These findings are important for understanding how different factors interplay in cancer progression and treatment resistance.