Neoadjuvant therapy

Neoadjuvant therapy (NAT) for early breast cancer (BC) refers to systemic treatment administered prior to definitive surgery. NAT was first introduced in the 1980s with the aim of downstaging large, inoperable tumors [1]. The NSABP-B18 trial was the first pivotal study to directly compare preoperative versus postoperative chemotherapy and demonstrated similar outcomes in terms of event-free survival (EFS) and overall survival (OS) between NAT and standard adjuvant treatment [2]. Despite a slightly higher local recurrence rate, a recent large meta-analysis from the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) confirmed that there is no relevant difference in distant recurrence, BC mortality, or all-cause mortality between neoadjuvant and adjuvant therapy [3]. Among systemic regimens, anthracycline-plus taxane-containing combinations remain the most effective in improving patient outcomes [4], particularly when administered in a dose-dense manner [5].

The extent of residual disease after NAT can be quantified using the residual cancer burden (RCB) method and has a major impact on patient prognosis [6]. In a pooled analysis of nearly 12,000 patients, achievement of pathologic complete response (pCR) was associated with improved EFS and OS, especially in aggressive BC subtypes, namely HER2-positive (HER2+) and triple-negative breast cancer (TNBC) [7]. However, the favorable prognostic impact of pCR appears to be restricted to the patient-level and does not necessarily translate into improved EFS and OS at a trial level [8]. Beyond pCR, high numbers of tumor-infiltrating lymphocytes (TILs) has also been linked to a survival benefit in both HER2+ and TNBC, and predicts response to NAT across all BC subtypes, including luminal disease [9]. The prognostic information provided by NAT enables optimization of adjuvant treatment strategies, with therapy escalation for patients with residual disease and de-escalation for those achieving pCR. Although initially developed to facilitate surgery, NAT has evolved into a pivotal tool not only for improving outcomes through pCR but also for guiding therapeutic decisions—even in patients with smaller, operable tumors.

The development of trastuzumab, the first HER2-directed monoclonal antibody, revolutionized the treatment landscape and substantially improved the prognosis of patients with HER2+ disease in both the early and advanced settings. The NOAH trial was the first study to demonstrate that the addition of trastuzumab—administered neoadjuvantly and continued adjuvantly for one year—to neoadjuvant chemotherapy (NACT) improves EFS, OS, and pCR [10]. The phase II studies NeoSphere and TRYPHAENA provided further insights, showing that the addition of pertuzumab to neoadjuvant trastuzumab and chemotherapy significantly increased pCR rates and improved long-term outcomes [11, 12], ultimately leading to the approval of pertuzumab in the neoadjuvant setting. Beyond demonstrating high pCR rates (45.3% to 51.9% depending on the treatment arm), the TRYPHAENA study importantly confirmed the cardiac safety of dual HER2-blockade with trastuzumab and pertuzumab, even when administered concomitantly with anthracycline-containing regimens [12]. While dual HER2-blockade with trastuzumab and pertuzumab is incontrovertible, the optimal chemotherapy backbone remains under debate. In the NeoSphere trial, indeed, anthracyclines were administered exclusively in the adjuvant phase; nevertheless, pCR was achieved in nearly 50% of patients given pertuzumab, trastuzumab, and docetaxel [11]. Consistently, in the phase III TRAIN-2 study, no relevant difference in pCR was observed between anthracycline-containing and anthracycline-free regimens (67% vs. 68%, respectively; p = 0.95). Therefore, in the context of dual HER2-blockade, anthracyclines may be omitted, particularly if carboplatin is administered [13]. However, the necessity of neoadjuvant carboplatin in the presence of dual HER2-blockade has recently been questioned by the phase III NeoCARHP trial. In this study, no difference in pCR rates was observed among patients with stage II–III HER2+ early BC treated with a taxane plus trastuzumab and pertuzumab, with or without carboplatin. EFS data are eagerly awaited to determine the feasibility of this de-escalated treatment approach [14]. In contrast to TNBC, the addition of immune checkpoint inhibitors (ICIs) to NACT and HER2-blockade has, to date, failed to improve pCR rates [15]. Even if the combination of chemotherapy and dual HER2-blockade represents the current standard NAT for most patients with stage II–III HER2+ early BC, the omission of NAT and de-escalated adjuvant therapy is a reasonable option in patients with small, node-negative HER2+ tumors. At the 10-year follow-up of the APT trial, patients with small (most of the tumors were < 2 cm), node-negative HER2+ early BC who received adjuvant therapy with weekly paclitaxel for 12 weeks and trastuzumab every 3 weeks to complete 1 year demonstrated an excellent invasive disease-free survival (iDFS) of 91.3% and an OS of 94.3% at 1 year [16]. Other findings suggest that some patients may have an excellent prognosis and could potentially be cured with HER2-blockade alone: in the NeoSphere trial, 16% of patients treated with neoadjuvant trastuzumab plus pertuzumab alone achieved a pCR [10], whereas in the NeoALTTO trial, 51.3% of patients achieved a pCR with neoadjuvant HER2-blockade using trastuzumab plus lapatinib [17]. Conversely, patients with residual disease after NAT have poorer prognosis. In this setting, post-neoadjuvant treatment with the antibody–drug conjugate trastuzumab emtansine (T-DM1) significantly improved iDFS (7-year iDFS: 80.8% vs. 67.1%; hazard ratio [HR] = 0.54; 95% confidence interval [CI] 0.44–0.66) and OS (7-year OS: 89.1% vs. 84.4%; HR = 0.66; 95% CI 0.51–0.87; P = 0.003) compared with adjuvant trastuzumab. However, treatment escalation with T‑DM1 did not prevent central nervous system (CNS) recurrences as the first invasive disease event [18].

The main challenge in the treatment of early breast cancer lies in optimizing patient selection and balancing treatment de-escalation and escalation. Prognostic and predictive tools are essential to guide clinical decision-making and help tailor treatment intensity. Among these is HER2DX, a 27-gene multianalyte genomic test capable of predicting both long-term risk of relapse after neoadjuvant trastuzumab and the probability of achieving pCR following anti-HER2-based therapy. In a large meta-analysis including 2518 patients, HER2DX was significantly associated with EFS, both as a continuous score and as a risk group, independently of and beyond classical clinicopathological variables [19].

Triple-negative breast cancer (TNBC) is biologically, pathologically, and molecularly a heterogeneous entity. By definition, TNBC lacks both hormone receptor (HR)- and HER2-expression. However, the cut-off for estrogen receptor (ER) positivity (1% vs. 10%) remains a matter of debate [20]. TNBC may also display low HER2-expression; however, this does not affect the response to NAT or outcomes in early stage disease [21]. Recently, the minimal tumor size justifying neoadjuvant or adjuvant chemotherapy in TNBC was challenged: in a large retrospective, population-based study investigating the role of adjuvant chemotherapy in stage IA TNBC, patients with T1c tumors derived the greatest benefit, whereas no clear survival advantage was observed for T1a or T1b tumors [22]. Despite growing evidence that stage I TNBC with high TILs-expression (≥ 50%) has an excellent prognosis even without chemotherapy [23], current guidelines still recommend NAT for patients with tumors larger than 1 cm (≥ T1c), primarily due to the strong association between pCR and long-term outcomes in TNBC [7]. Standard NACT for TNBC consists of sequential anthracyclines and taxanes, administered in either sequence [24]. The role of platinum-based chemotherapy has long been debated. A recent Cochrane meta-analysis demonstrated that the addition of carboplatin in early-stage TNBC is associated with improved pCR and EFS and with a significant survival benefit (n = 1973, HR 0.69; 95% CI 0.55–0.86; p = 0.0001) [25]. Younger patients (< 50 years) appeared to benefit most from carboplatin-containing regimens [26]. Therefore, carboplatin should be considered for all patients with T2 or node-positive TNBC, particularly those of younger age. The ICI pembrolizumab has recently revolutionized NAT for patients with stage II–III TNBC. In the phase III Keynote-522 trial, neoadjuvant pembrolizumab plus carboplatin-containing chemotherapy followed by adjuvant pembrolizumab versus NACT alone led to higher pCR rates (63.4% vs 56.2%), and, overall, a shift towards lower RCB categories [27]. Most importantly, pCR translated into improved EFS (5-year EFS 81.2% vs 72.2%; HR 0.65; 95% CI 0.51–0.83; P < 0.001) and OS (5-year OS 86.6% vs 81.7%; HR 0.66; 95% CI 0.50–0.87; P = 0.0015) [28]. The benefit of pembrolizumab was independent of programmed death-ligand 1 (PD-L1) expression, and in a broad exploratory biomarker analysis, only high tumor mutational burden appeared to be associated with improved EFS in the pembrolizumab group [29]. Whether pembrolizumab should be continued after achieving pCR is currently under investigation. The optimal therapeutic approach for patients with residual disease after NAT remains even more debated. Current post-neoadjuvant strategies include adjuvant continuation of pembrolizumab, capecitabine, and the PARP-inhibitor olaparib for patients with germline BRCA mutations. Adaptive treatment strategies are urgently needed to balance treatment escalation and de-escalation, with the goal of not only avoiding harm but further improving patient outcomes in this poorly prognostic BC subtype.

HR-positive/HER2-negative (HR+/HER2−) tumors represent the most common BC subtype. While genomic tests in the adjuvant setting enable risk-adapted treatment decisions, the use of NAT in patients with HR+/HER2− disease is still primarily guided by clinical and pathological features [30]. Given the lower pCR rates and their limited association with long-term outcomes in luminal disease [31], together with the availability of escalated adjuvant endocrine treatments—such as extended endocrine therapy and CDK4/6 inhibitors—NAT is mainly reserved for patients with large, inoperable tumors or extensive nodal involvement. NAT options for HR+/HER2− BC include both NACT and neoadjuvant endocrine therapy (NET). While evidence on NET in premenopausal women remains scarce, multiple studies comparing NACT and NET in postmenopausal women have demonstrated similar clinical responses, but with lower toxicities in favor of NET [32]. Despite numerous ongoing studies investigating SERDs and CDK4/6 inhibitors as NET options, aromatase inhibitors are currently still the most effective agents [30]. In luminal tumors, the prognostic role of pCR is replaced by Ki-67 dynamics and the preoperative endocrine prognostic index (PEPI) score. High Ki-67 and higher PEPI scores after NET may help to identify patients with poorer prognosis [33, 34] who may be candidates for treatment escalation. Escalation strategies also include combining immunotherapy with NACT. Although luminal tumors are considered the least immunogenic among all BC subtypes, new evidence from phase III trials showed that the addition of the ICI pembrolizumab (Keynote-756 study) or nivolumab (Checkmate-7FL study) to standard chemotherapy in high-risk, high-grade early HR+/HER2− BC increased and almost doubled pCR rates, with the highest benefit seen in patients with high PD-L1 or low ER expression (1–9%) [35, 36]. In conclusion, NACT is indicated for patients with large, inoperable tumors or extensive nodal involvement. Although still considered experimental, NET represents an effective and well-tolerated de-escalated treatment option to consider for older patients with comorbidities that contraindicate NACT. New evidence suggests that there is at least a subgroup of patients with high-risk HR+/HER2− BC, who may benefit from immunotherapy.

The increased pCR rates observed in patients with HER2+ and TNBC following NAT raise the question of whether patients achieving pCR can be identified preoperatively and spared surgery. Conventional imaging modalities such as mammography and ultrasound have limited accuracy in predicting response to NAT [37]. Despite higher sensitivity, magnetic resonance imaging (MRI) has also failed to reliably predict pCR [38, 39]. Furthermore, several studies have reported high false-negative rates with image-guided biopsy alone [40]. In contrast, a small phase II study of 50 patients with HER2-positive and TNBC demonstrated no local or distant recurrences after omission of surgery in cases where pCR was confirmed by image-guided biopsy [41]. Nevertheless, although larger needles and MRI-guided biopsies have shown promising results [42, 43], pCR cannot yet be reliably predicted by imaging or biopsy. Therefore, surgery after NAT remains standard of care. Further studies are required to establish reliable strategies for identifying patients with pCR who may safely omit surgery. Given the curative intent of NAT, the greatest challenge is to find the optimal balance between treatment efficacy and long-term toxicity. Escalated approaches aim to improve the chance to cure without increasing treatment-related harm, whereas de-escalated strategies aim to reduce avoidable toxicity without compromising therapeutic efficacy or patient outcomes. Adaptive clinical trial designs and predictive biomarkers are needed to allow more accurate patient selection and guide treatment choices, particularly to decide whether treatment de-escalation, including foregoing surgery, can be safely applied.