This comprehensive review analyzed the effects of breast cancer treatments given before (neoadjuvant) or after (adjuvant) surgery. Researchers found that most treatments reduce breast cancer deaths by 10-25% without increasing other health risks. However, anthracycline chemotherapy and radiotherapy increased deaths from heart disease, lung cancer, or leukemia, while taxanes raised leukemia risk. These findings help patients and doctors balance treatment benefits against potential long-term health risks.

Understanding the Benefits and Risks of Breast Cancer Treatments Before and After Surgery

Table of Contents

• Background/Introduction
• Study Methods
• Key Findings: Systemic Therapies
• Key Findings: Radiotherapy
• Clinical Implications
• Limitations
• Recommendations
• Source Information

Background/Introduction

Breast cancer treatments given before surgery (neoadjuvant) or after surgery (adjuvant) can lower the risk of cancer returning or causing death. However, these treatments might also increase the risk of dying from other health problems like heart disease. Currently, information about these benefits and risks is scattered across many research studies. This creates challenges for patients and doctors when making treatment decisions.

To solve this problem, researchers gathered the highest-quality evidence from clinical guidelines and scientific studies. They focused on treatments recommended between 2016 and 2021 for early-stage invasive breast cancer (stages I-IIIA). This comprehensive review analyzed how different treatments affect:

• Breast cancer mortality (death from breast cancer)
• Non-breast-cancer mortality (death from other causes)
• Specific risks like heart disease or secondary cancers

The team used a special statistical measure called rate ratios (RRs) to compare treatment effects. RRs show how much a treatment changes the risk of an outcome. For example, an RR of 0.75 means a 25% lower risk, while an RR of 1.20 means a 20% higher risk. These ratios help patients understand both benefits and potential harms of treatments.

Study Methods

Researchers followed a strict process to collect and analyze data:

1. Guideline Selection: They reviewed breast cancer guidelines from 6 major organizations in the US, Europe, and UK published between 2016-2021. Only guidelines with clear methods and conflict-of-interest policies were included.
2. Treatment Identification: From these guidelines, they listed all recommended adjuvant and neoadjuvant treatments for early invasive breast cancer. This included chemotherapy, anti-HER2 therapies, endocrine therapies, bisphosphonates, and radiotherapy.
3. Evidence Search: For each treatment, they searched medical databases to find the strongest evidence. They prioritized:
   • Meta-analyses combining data from multiple randomized trials
   • Large randomized trials when meta-analyses weren't available
4. Data Extraction: For each study, they recorded:
   • Number of patients (ranging from under 1,000 to over 10,000)
   • Follow-up time (minimum 3 years)
   • Rate ratios (RRs) for breast cancer mortality and non-breast-cancer mortality
   • Specific causes of increased risk
5. Radiotherapy Risk Analysis: For radiation treatments, they conducted extra searches to:
   • Find dose-response relationships (how radiation dose affects risk)
   • Determine typical modern radiation doses to organs like the heart and lungs

Two oncologists independently extracted all data, with two additional oncologists and a breast surgeon checking for accuracy. Any disagreements were resolved through discussion.

Key Findings: Systemic Therapies

The study examined 4 main categories of drug treatments:

Chemotherapy

Chemotherapy options reduced breast cancer mortality but had varying risks:

• Anthracycline-based chemo: Reduced breast cancer death by 11% (RR 0.89) but increased non-breast-cancer death by 30% (RR 1.30). This extra risk came mainly from heart disease and leukemia.
• Taxane + anthracycline combo: Lowered breast cancer death by 19% (RR 0.81) but increased leukemia risk. The exact increase couldn't be measured directly because no trials compared taxane-only to no treatment.
• Platinum-based chemo (neoadjuvant): Increased pathological complete response (no detectable cancer after treatment) but long-term mortality data isn't yet available.
• Capecitabine (adjuvant): Reduced overall death risk by 41% (RR 0.59) in patients with residual cancer after neoadjuvant chemo, though breast cancer-specific data wasn't reported.

Giving chemotherapy before surgery (neoadjuvant) instead of after (adjuvant) didn't affect breast cancer mortality overall but increased local recurrence by 37% (RR 1.37).

Anti-HER2 Therapies (for HER2+ cancer)

• Trastuzumab: Reduced breast cancer death by 34% (RR 0.66) with no increase in other mortality causes.
• Pertuzumab: Showed a trend toward reduced breast cancer death (RR 0.85) but results weren't statistically conclusive.
• Trastuzumab emtansine: Similarly showed a non-significant reduction in breast cancer death (RR 0.75).
• Neratinib: Reduced recurrence risk but had no mortality data available.

Endocrine Therapies (for ER+ cancer)

• 5 years of tamoxifen: Reduced breast cancer death by 31% (RR 0.69).
• Extended tamoxifen (10 years): Further reduced breast cancer death by 25% (RR 0.75) compared to 5 years.
• Aromatase inhibitors (AIs) vs tamoxifen: In postmenopausal women, AIs reduced breast cancer death by 15% (RR 0.85). In premenopausal women using ovarian suppression, AIs reduced recurrence but not significantly for mortality.
• Ovarian suppression/ablation: Added to tamoxifen, reduced recurrence but not significantly for mortality (RR 0.94).

Bisphosphonates (for postmenopausal women)

Reduced breast cancer death by 18% (RR 0.82) with no increase in other mortality causes.

Key Findings: Radiotherapy

Radiotherapy after surgery reduced breast cancer mortality but increased some long-term risks:

Benefits by Surgery Type

• After breast-conserving surgery: Whole breast radiation reduced breast cancer death. Adding a tumor bed boost or regional node radiation provided extra benefit.
• After mastectomy: Chest wall radiation significantly reduced breast cancer death in node-positive patients but not in node-negative patients.

Specific Risks and Dose Relationships

Radiotherapy increased deaths from:

• Heart disease: Risk increased by 4.2% per gray (Gy) of radiation to the heart. Modern techniques average 4 Gy heart dose.
• Lung cancer: Risk increased by 8.5% per Gy to the lungs. Modern techniques average 5 Gy lung dose.
• Esophageal cancer: Risk increased by 4.5% per Gy to the esophagus. Modern techniques average 4 Gy esophageal dose.

These risks persist for decades after treatment but are lower today due to more precise radiation techniques that reduce organ exposure.

Clinical Implications

This research provides crucial information for treatment decisions:

• Most treatments reduce breast cancer death by 10-25% without increasing other mortality risks, meaning their benefits generally outweigh risks.
• Anthracycline chemotherapy and radiotherapy require special consideration for patients with existing heart problems due to their cardiac risks.
• Radiotherapy benefits vary significantly:
  • Highly beneficial after mastectomy for node-positive patients
  • Less beneficial for node-negative mastectomy patients
• Modern radiation techniques reduce but don't eliminate long-term risks. Patients should ask about:
  • Estimated heart, lung, and esophagus doses
  • Advanced techniques like deep inspiration breath hold

The rate ratios (RRs) from this study can be used in decision-making tools to calculate personalized benefit-risk profiles based on a patient's age, cancer characteristics, and overall health.

Limitations

While comprehensive, this review has important limitations:

• Timing of evidence: Newer treatments like pembrolizumab and abemaciclib weren't fully evaluated as they were only recommended in US guidelines during the study period.
• Data gaps: For some treatments (platinum chemo, capecitabine, neratinib), only recurrence data was available, not mortality data.
• Radiotherapy challenges:
  • Direct risk estimates from older trials don't apply to modern techniques
  • Organ-specific dose data wasn't available in most trials
• Population specifics: Findings mainly apply to standard regimens. Effects might differ for:
  • Unconventional dosing schedules
  • Patients with multiple health conditions
• Follow-up duration: Some risks (like secondary cancers) take decades to appear and may be underestimated in newer treatments.

Recommendations

Based on these findings, patients and doctors should:

1. Discuss benefit-risk balance: For each recommended treatment, ask:
   • "How much will this reduce my risk of breast cancer recurrence or death?"
   • "What are the specific risks of other health problems?"
2. Request organ dose estimates: If having radiotherapy, ask your radiation oncologist for:
   • Estimated heart, lung, and esophagus doses
   • Options to further reduce these doses
3. Consider cardiac monitoring: If receiving anthracyclines or left-breast radiotherapy:
   • Discuss baseline heart function tests
   • Ask about long-term monitoring plans
4. Use decision aids: Request tools that incorporate:
   • Your specific cancer characteristics (stage, hormone receptors, HER2 status)
   • Your age and overall health
   • The rate ratios from this study
5. Inquire about newer techniques: For radiotherapy, ask about:
   • Deep inspiration breath hold (reduces heart dose)
   • 3D conformal or proton therapy

Source Information

Original Article Title: Adjuvant and neoadjuvant breast cancer treatments: A systematic review of their effects on mortality
Authors: Amanda J. Kerr, Gurdeep Mannu, David Dodwell, Paul McGale, Francesca Holt, Fran Duane, Sarah C. Darby, Carolyn W. Taylor
Journal: Cancer Treatment Reviews
Publication Details: Volume 105, 2022, Article 102375
Note: This patient-friendly article is based on peer-reviewed research from the original publication. It preserves all key data, findings, and limitations while translating medical language for broader accessibility.