Neoadjuvant Chemotherapy: Practice and Thinking for Chinese Patients with Early Breast Cancer
The role of neoadjuvant chemotherapy (NAC) in the management of early breast cancer (EBC) remains a topic of global debate. While some hypothesize that NAC could improve prognosis by initiating systemic treatment earlier, large randomized controlled trials have not confirmed differences in disease-free survival (DFS) or overall survival (OS) between patients receiving NAC and adjuvant chemotherapy. Meta-analyses, including those from the Early Breast Cancer Trialists’ Collaborative Group, reinforce this conclusion, showing no survival advantage for NAC over adjuvant therapy. However, clinical practices vary widely, particularly in China, where the application of NAC for EBC requires careful consideration of its benefits, limitations, and context-specific challenges.
Controversies Surrounding Prognostic Impact
A central controversy emerged from a 2017 study by Karagiannis et al., which suggested that NAC might promote breast cancer micrometastasis to blood vessels and lungs in mouse models and human xenografts. This finding raised concerns about the systemic effects of NAC, though its clinical relevance in humans remains unproven. Despite such debates, consensus exists on certain benefits of NAC: tumor downsizing to facilitate surgery, improved resection rates for locally advanced breast cancer, and increased breast-conserving surgery (BCS) opportunities for larger tumors. For inoperable or locally advanced cases, NAC is indispensable. Conversely, disadvantages include prolonged tumor presence, delayed surgery, elevated local recurrence risks, diagnostic errors from limited biopsy sampling, and potential overtreatment of low-risk patients.
Clinical Guidelines and Discordant Perspectives
The 2017 St. Gallen Consensus strongly endorsed NAC for stage II/III HER2-positive (HER2+) and triple-negative breast cancer (TNBC), particularly when de-escalation of surgery or radiotherapy is possible. Over 90% of experts preferred NAC for these subtypes, reflecting its high pathological complete response (pCR) rates. However, this enthusiasm is not universal. Critics, including Vaidya et al., caution against indiscriminate NAC use, emphasizing that rapid progression during treatment may deprive patients of curative surgery. In China, variable practices highlight the need for nuanced decision-making, balancing tumor biology, patient preferences, and institutional capabilities.
pCR: A Surrogate Endpoint with Limitations
While pCR—defined as the absence of invasive cancer in the breast and lymph nodes after NAC—correlates with improved prognosis in studies like NSABP B-18 and B-27, it remains an imperfect surrogate for survival. The CREATE-X and Katherine trials demonstrated that non-pCR patients may benefit from post-NAC therapies, such as capecitabine or trastuzumab emtansine. However, pCR rates vary by subtype: approximately 30–60% in TNBC and HER2+ tumors, compared to <10% in hormone receptor-positive (HR+) cancers. Crucially, pCR does not guarantee cure, nor does its absence preclude long-term survival. Thus, pursuing pCR as a primary treatment goal is misguided, especially in EBC, where overtreatment risks harming patients with favorable prognoses.
Molecular Subtypes and NAC: A Double-Edged Sword
TNBC and HER2+ breast cancers, characterized by aggressive biology and high NAC sensitivity, are frequently cited as ideal candidates for NAC. For example, dual HER2-targeted therapies in the NeoSphere and TRYPHAENA trials achieved pCR rates exceeding 60%, prompting some to advocate universal NAC for these subtypes. However, no prospective studies compare NAC to adjuvant therapy in TNBC or HER2+ EBC. Notably, 10–30% of TNBC patients experience rapid progression during NAC, losing surgical opportunities. Similarly, HER2+ tumors may develop resistance, underscoring the importance of careful patient selection. The National Comprehensive Cancer Network (NCCN) guidelines stress the need to weigh progression risks during NAC, particularly in resource-limited settings where salvage therapies are unavailable.
Timing of Systemic Therapy: Survival Equipoise
Proponents argue that NAC initiates systemic therapy earlier than adjuvant regimens. However, the interval between NAC and adjuvant therapy is marginal—typically 1–2 weeks for biopsy-to-NAC initiation versus 2 weeks for postoperative adjuvant therapy. Over a 3–6 month NAC course, tumors may progress, metastasize, or develop resistance. For instance, 15–20% of NAC patients in Chinese cohorts experienced disease progression, rendering them inoperable. This contrasts with adjuvant therapy, where upfront surgery removes the primary tumor, eliminating the risk of progression during chemotherapy.
The Myth of “In Vivo Drug Sensitivity Testing”
A theoretical advantage of NAC is the ability to assess tumor response and tailor therapy. However, clinical evidence contradicts this. The GeparTrio trial evaluated switching non-responders from taxane-based NAC to capecitabine/vinorelbine, revealing no survival benefit. Similarly, the Aberdeen study found that docetaxel improved pCR only in initial responders (15% to 31%), while non-responders remained refractory (2% pCR). These studies debunk the notion of NAC as a reliable “drug sensitivity test,” as cross-resistance and clonal heterogeneity limit its predictive value. Furthermore, 30% of initial responders later developed resistance, highlighting the dynamic nature of tumor evolution during NAC.
Balancing Benefits and Risks in Clinical Practice
In China, NAC utilization for EBC reflects both overtreatment and missed opportunities. While NAC is justified for locally advanced or borderline-operable tumors, its routine use in small, node-negative HER2+ or TNBC cases is contentious. For example, a 2 cm TNBC tumor amenable to BCS may benefit more from immediate surgery and adjuvant therapy, avoiding NAC-related delays and progression risks. Conversely, a 5 cm HER2+ tumor requiring mastectomy could achieve BCS after NAC. Key considerations include:
- Tumor Stage and Operability: NAC is essential for downstaging inoperable or borderline-resectable tumors.
- Molecular Subtype: High pCR rates in TNBC and HER2+ cancers support NAC, but rapid progression necessitates vigilant monitoring.
- Patient Preferences: Cultural values around breast preservation and chemotherapy side effects influence decision-making.
- Healthcare Infrastructure: Access to advanced imaging, genomic profiling, and targeted therapies determines NAC feasibility.
Future Directions and Unmet Needs
Prospective trials comparing NAC and adjuvant therapy in TNBC/HER2+ EBC are urgently needed. Biomarkers predicting NAC resistance (e.g., residual cancer burden index, stromal tumor-infiltrating lymphocytes) could refine patient selection. Additionally, integrating NAC with immunotherapy or novel targeted agents may enhance pCR rates while mitigating progression risks. In China, standardized NAC protocols and multidisciplinary tumor boards are critical to harmonizing practices and optimizing outcomes.
Conclusion
Neoadjuvant chemotherapy offers distinct advantages for specific subgroups of early breast cancer patients, particularly those with locally advanced or biologically aggressive tumors. However, its indiscriminate use risks harming patients through delayed surgery, overtreatment, and disease progression. Clinicians must weigh tumor biology, stage, and patient-specific factors to individualize NAC decisions. Ongoing research into predictive biomarkers and novel therapeutic combinations will further refine NAC’s role in the precision medicine era.
doi.org/10.1097/CM9.0000000000000940
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