What is the incidence and management of bilateral breast carcinoma with discordant immunohistochemistry (IHC) reports?

Incidence and Management of Bilateral Breast Carcinoma with Discordant Immunohistochemistry

Bilateral breast cancer occurs in approximately 4-6% of all breast cancer cases at initial diagnosis, and when discordant immunohistochemistry (IHC) is present between the two tumors, systemic therapy must be directed by the more aggressive tumor phenotype. 1

Incidence of Bilateral Breast Cancer

• The overall incidence of bilateral breast cancer at initial presentation is approximately 4-6% of all breast cancer diagnoses 2
• Among bilateral breast cancer cases, approximately 89% (16/18) present as synchronous disease, while 11% (2/18) present as metachronous disease 3
• Lobular carcinoma shows particular propensity for bilateral presentation, comprising 36% of bilateral breast cancer cases, with these patients tending to be younger and more likely to have simultaneous cancers 4

Incidence of Discordant Immunohistochemistry

Between Primary and Metastatic Sites

• ER discordance between primary and recurrent/metastatic disease ranges from 3.4-60% 5
• PR discordance ranges from 7.2-31% 5
• HER2 discordance between primary breast cancer and distant metastases ranges up to 50% in some studies 5

Between Bilateral Primary Tumors

• Discordant receptor status occurs in a clinically significant proportion of synchronous bilateral breast cancers, though exact incidence is not precisely quantified in the guidelines 6
• The biological heterogeneity reflects distinct tumor biology rather than metastatic spread 6

Interlaboratory and Technical Discordance

• Interlaboratory concordance for HER2 testing ranges from 74-92% for IHC, meaning discordance rates of 8-26% exist depending on the study 5
• IHC+/ISH- discordance occurs in 13.8% of cases, while IHC-/ISH+ discordance occurs in 3% of cases 7
• Overall IHC/ISH discordance constitutes approximately 4% of all cases and 5.4% of those with unequivocal IHC status 7

Management Algorithm for Bilateral Breast Cancer with Discordant IHC

Step 1: Independent Pathologic Confirmation

• Each breast lesion requires separate core needle biopsy before any surgical intervention 1
• Obtain complete pathologic assessment for both tumors including: histological type and grade, ER/PR status by IHC, HER2 status (with reflex ISH if IHC is 2+), and Ki67 proliferation markers 2, 1
• Stage each breast cancer independently using the TNM system 1

Step 2: Verify Discordance and Rule Out Technical Error

• When apparent discordance exists, order a new HER2 test if the initial result conflicts with histopathologic findings (e.g., grade 1 tumor testing HER2-positive, or grade 3 tumor testing HER2-negative) 2
• Consider retesting if there are concerns about specimen handling, fixation time, or suspected testing error 2
• For equivocal results (IHC 2+), perform both IHC and dual-probe ISH on the same tissue sample, reviewing slides together to guide area selection 2

Step 3: Determine Systemic Therapy Based on More Aggressive Phenotype

When tumors have discordant biology between breasts, treat according to the more aggressive phenotype 1

The hierarchy of aggressiveness for treatment selection:

1. Triple-negative disease (most aggressive): Requires chemotherapy as mainstay, with consideration of immunotherapy if PD-L1 positive 1
2. HER2-positive disease: Requires anti-HER2 therapy plus chemotherapy regardless of hormone receptor status 1
3. Hormone receptor-positive/HER2-negative disease (least aggressive): Endocrine therapy is mandatory, with chemotherapy added based on stage and risk factors 1

Step 4: Surgical Management

• Bilateral total mastectomy with removal of all breast tissue is the recommended surgical approach for most patients with bilateral malignant breast masses 1
• Perform sentinel lymph node biopsy for each breast separately when invasive cancer is present 1
• Bilateral breast conservation is feasible ONLY when ALL criteria are met: clear surgical margins achievable in both breasts, tumor size relative to breast volume allows adequate resection, absence of multicentric disease, no prior chest wall irradiation, and patient can tolerate mandatory bilateral whole breast radiation 1

Step 5: Radiation Therapy

• For bilateral breast conservation: postoperative whole breast radiation therapy is mandatory for both breasts, reducing local recurrence risk by two-thirds 1
• For bilateral mastectomy: post-mastectomy radiotherapy recommended for patients with four or more positive axillary nodes or T3 tumors with positive nodes 1

Step 6: Genetic Counseling

• Genetic counseling is mandatory given the bilateral presentation, particularly to assess for BRCA1/2 mutations 1
• BRCA1/2 carriers face a 25-31% 10-year risk of developing new breast cancer even after breast conservation, and should be counseled about bilateral mastectomy as a definitive risk-reducing option 1

Clinical Interpretation of Discordance

The Panel informal consensus for management when there is discordance of ER, PR, or HER2 results between primary and metastatic tissues (or between bilateral primaries) is to use the receptor status from the more aggressive lesion to direct therapy, if supported by the clinical scenario and the patient's goals for care 2

The rationale for this approach:

• Discordance may reflect tumor heterogeneity, biological evolution, or assay variability 2
• Retrospective data suggest inferior outcomes in discordant patients, possibly due to inappropriate treatment not adjusted for biomarker changes 2
• Treating the more aggressive phenotype ensures patients are not denied potentially beneficial targeted therapy 7

Critical Pitfalls to Avoid

• Never perform unilateral mastectomy when bilateral malignancy is confirmed—the risk is equal in both breasts 1
• Do not omit genetic counseling in bilateral breast cancer, as this presentation strongly suggests possible hereditary cancer syndrome 1
• Do not assume discordance is due to laboratory error without verification—it often reflects true biological heterogeneity 5, 7
• Never deny HER2-targeted therapy based solely on IHC-/ISH+ discordance—routinely performing both IHC and ISH may uncover cases where patients would benefit from targeted therapy 7
• Do not use the less aggressive tumor's biology to guide systemic therapy—this results in undertreatment and worse outcomes 2