Abstract
Background:
Neoadjuvant chemotherapy (NAC) is increasingly used to treat node positive (N+) breast cancer. Predictors of nodal pathological complete response (pCR) in Asian women are poorly described and variety in the management of the axilla after NAC exists. We evaluated predictors of nodal pCR and axillary management in a cohort of Asian N+ patients.
Methods:
Consecutive biopsy proven N+ patients treated with NAC were identified from the Shanghai Ruijin Hospital in China. Axillary nymph node dissection was performed in all patients, irrespective of the nodal response to NAC.
Results:
323 patients were included. Nodal pCR was achieved in 105 (33%) patients, 15% of HR+/HER2− tumors, 38% of HR+/HER2+ tumors, 49% of HR−/HER2+ tumors, and 42% of HR−/HER2− tumors (p < 0.001). Factors associated with nodal pCR were receptor status (HR+/HER2− (referent): OR 3.42, 95% CI 1.43–8.16, p = 0.006 for HR+/HER2+; OR 4.19, 95% CI 1.85–9.50, p = 0.001 for HR−/HER2+; and OR 2.94, 95% CI 1.11–7.74, p = 0.029 for HR−/HER2−), breast pCR (no pCR (referent): OR 15.22, 95% CI 6.29–36.79, p < 0.001) and absence of LVI (LVI (referent): OR 9.04, 95% CI 2.09–39.18, p = 0.003).
Conclusion:
This study confirmed expected predictors of nodal pCR in Asian women and the benefit of NAC in downstaging the axilla independently of ethnicity.
Introduction
Neoadjuvant chemotherapy (NAC) increases the likelihood of breast conservation [1-3] and decreases the chances of finding nodal metastases [4-6]. Indications for NAC have evolved over time, and downstaging of the axilla in patients who present with nodal metastases has become a common indication for NAC [7-9]. While in node-negative patients, sentinel lymph node biopsy (SLNB) after NAC is a feasible and accurate procedure [5,10], in node-positive patients who downstage to cN0 after NAC, the false negative rate (FNR) of SLNB exceeds the 10% threshold considered clinically acceptable [11-13]. Different techniques for reducing the FNR in this setting have been developed [8,14-17], and great variety in the management of the axilla across and within countries still exists [18-21].
Nodal response to NAC strongly depends on tumor biology, with higher rates of nodal pathological complete response (pCR) in triple negative (TN) and human epidermal growth factor receptor 2 (HER2) positive tumors and lower rates in hormone receptor (HR) positive tumors [8,22-24]. Most of the studies that evaluated nodal response to modern NAC were performed in Western populations [8,22,25]. However, ethnic differences in response to common chemotherapeutic and targeted agents used to treat early breast cancer exist [26,27] and data on nodal downstaging in Asian women are sparse [28-30].
In this study we sought to describe predictors of nodal pCR and axillary management in a large cohort of Asian women.
Methods
We retrospectively reviewed all consecutive patients, with stage II-III breast cancer and biopsy proven nodal metastases, treated with NAC and subsequent surgery at the Comprehensive Breast Health Center, Shanghai Ruijin Hospital, Shanghai, China, from January 2009 to May 2019. Axillary lymph node dissection (ALND) was performed regardless of nodal response to NAC. Clinicopathological features and treatment recommendation made after discussion at the multidisciplinary meeting (MDT) were prospectively recorded in the Shanghai Jiao Tong University Breast Cancer Database (SJTU-BCDB) and on an internet-based MDT platform (MDT4BC).
The majority (78%) of patients received anthracycline and taxane based chemotherapy regimens, 2% received concomitant platinum salts, 10% received a taxane based regimen +/− carboplatin, and 10% received other chemotherapeutic agents. Of the HER2+ patients, 96% received trastuzumab and 4% received trastuzumab and pertuzumab.
Statistical analysis
Clinical characteristics between patients who achieved nodal pCR and those with residual nodal disease were compared in univariate analysis using Student’s t-test or the Wilcoxon rank sum test for continuous variables, and the Fisher’s exact test for categorical variables. Multivariable logistic regression analysis was used to study the association between the odds of achieving nodal pCR and the clinicopathologic pathological features found to be significant in univariate analysis, while retaining clinically relevant variables. The final list of variables for the multivariable model was obtained by stepwise selection, using a p-value of < 0.05 as being eligible for inclusion from the model. The type 1 error rate (α) was set to 0.05 for all the statistical tests. Presented p-values are nominal and were not corrected for multiple testing. All statistical analyses were performed using SAS version 9.2 (SAS Institute, Cary, NC, USA).
Results
Three hundred twenty-three patients met the inclusion criteria. All patients were Asian, median age was 51 years (IQR 41, 60) and the majority of them (52%) were postmenopausal. Tumor biology was HR+/HER2− in 127 cases (39.3%), HR+/HER2+ in 58 cases (18%), HR−/HER2+ in 83 cases (25.7%), and HR−/HER2− in 55 cases (21.7%) (Table 1).
Table 1.
Clinicopathological features of patients stratified by residual nodal burden
| Overall cohort (n = 323) |
ypN0 (n = 105) |
ypN+ (n = 218) |
p value | |
|---|---|---|---|---|
| Age, years | 51 (41, 60) | 51 (42, 60) | 50.5 (41, 60) | 0.365 |
| Ethnicity | ||||
| Asian | 323 (100%) | 105 (100%) | 218 (100%) | NA |
| Palpable node at presentation | 0.407 | |||
| No | 77 (23.8%) | 28 (26.7%) | 49 (22.5%) | |
| Yes | 246 (76.2%) | 77 (73.3%) | 169 (77.5%) | |
| Suspicious node on imaging at presentation | 0.212 | |||
| No | 12 (3.7%) | 6 (5.7%) | 6 (2.8%) | |
| Yes | 310 (96%) | 98 (93.3%) | 212 (97.2%) | |
| Missing | 1 (0.3%) | 1 (1.0%) | 0 (0.0%) | |
| Clinical T at presentation | 0.128 | |||
| 1 | 51 (15.8%) | 17 (16.2%) | 34 (15.6%) | |
| 2 | 205 (63.58%) | 68 (64.8%) | 137 (62.8%) | |
| 3 | 34 (10.5%) | 6 (5.7%) | 28 (12.8%) | |
| 4 | 21 (6.5%) | 7 (6.7%) | 14 (6.4%) | |
| x | 12 (3.7%) | 7 (6.7%) | 5 (2.3%) | |
| Clinical N at presentation | 0.502 | |||
| 1 | 196 (60.7%) | 68 (64.7%) | 128 (58.7%) | |
| 2 | 105 (32.5%) | 31 (29.5%) | 74 (33.9%) | |
| 3 | 21 (6.5%) | 5 (4.8%) | 16 (7.3%) | |
| Missing | 1 (0.3%) | 1 (1.0%) | 0 (0.0%) | |
| Receptor status | <0.001 | |||
| HR+/HER2− | 127 (39.3%) | 19 (18.1%) | 108 (49.5%) | |
| HR+/HER2+ | 58 (18%) | 22 (21.0%) | 36 (16.5%) | |
| HR−/HER2+ | 83 (25.7%) | 41 (39.0%) | 42 (19.3%) | |
| HR−/HER2− | 55 (217%) | 23 (21.9%) | 32 (14.7%) | |
| Histology | 0.030 | |||
| Ductal | 293 (90.7%) | 98 (93.3%) | 195 (89.4%) | |
| Lobular and mixed | 7 (2.2%) | 3 (2.9%) | 4 (1.8%) | |
| Micropapillary and mixed | 13 (4.0%) | 0 (0.0%) | 13 (6.0%) | |
| Other | 10 (3.1%) | 4 (3.8%) | 6 (2.8%) | |
| LVI | <0.001 | |||
| Yes | 60 (18.6.9%) | 2 (1.9%) | 58 (26.6%) | |
| No | 263 (81.4.1%) | 103 (98.1%) | 160 (73.4%) | |
| Grade | 0.737 | |||
| I | 7 (2.2%) | 1 (1.0%) | 6 (2.8%) | |
| II | 114 (33.3%) | 32 (30.5%) | 82 (37.6%) | |
| III | 172 (53.3%) | 53 (50.5%) | 119 (54.6%) | |
| Missing | 30 (9.3%) | 19 (18.1%) | 11 (5.1%) | |
| Breast pCR | <0.001 | |||
| Yes | 70 (21.7%) | 55 (52.4%) | 15 (6.9%) | |
| No | 253 (78.3%) | 50 (47.6%) | 203 (93.1%) |
Frequency (column percent) reported for categorical variables and median (Q1, Q3) reported for continuous variables. Results from Fisher’s exact test for categorical variables and Wilcoxon’s rank-sum test for continuous variables. Missing values are not taken into account. ypN+, residual nodal disease; ypN0, nodal pathological complete response; pCR, pathological complete response; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; LVI, lymphovascular invasion.
The mean number of lymph nodes removed was 16.5 (SD 5.8) in those who achieved nodal pCR and 18.1 (SD 6.7) in those with nodal residual disease (p = 0.035).
Overall, 105/323 (33%) patients achieved nodal pCR. Patients with ductal and lobular tumors were more likely to achieve nodal pCR compared to micropapillary tumors (33% and 43% vs. 0%, respectively; p = 0.030). Nodal pCR occurred in 15% of HR+/HER2− tumors, 38% of HR+/HER2+ tumors, 49% of HR−/HER2+ tumors, and 42% of HR−/HER2− tumors (p < 0.001). LVI was more often present in patients with residual disease than in those who achieve nodal pCR (26.6% vs. 1.9%; p < 0.001). Breast pCR on the other hand was more often present in patients who achieved nodal pCR than in those with nodal residual disease (52.4% vs. 6.9%; p < 0.001) (Table 1).
On multivariable analysis, factors that remained independently associated with achieving nodal pCR were receptor status (HR+/HER2− (referent): OR 3.42, 95% CI 1.43–8.16, p = 0.006 for HR+/HER2+; OR 4.19, 95% CI 1.85–9.50, p = 0.001 for HR−/HER2+; and OR 2.94, 95% CI 1.11–7.74, p = 0.029 for HR−/HER2−), achievement of breast pCR (no breast pCR (referent): OR 15.22, 95% CI 6.29–36.79, p < 0.001) and the absence of LVI (LVI (referent): OR 9.04, 95% CI 2.09–39.18, p = 0.003) (Table 2).
Table 2.
Association between clinicopathological factors and the odds of achieving nodal pCR using stepwise selection
| Multivariable | ||
|---|---|---|
| odds ratio (95% CI) | p value | |
| Subtype (Ref.: HR+/HER2−) | ||
| HR+/HER2+ | 3.42 (1.43; 8.16) | 0.006* |
| HR−/HER2+ | 4.19 (1.85; 9.50) | 0.001* |
| HR−/HER2− | 2.94 (1.11; 7.74) | 0.029* |
| No LVI (Ref.: LVI) | 9.04 (2.09; 39.18) | 0.003* |
| Breast pCR (Ref.: no pCR) | 15.22 (6.29; 36.79) | <0.001 |
Discussion
Surgical management of the axilla has changed dramatically over the last decades and is continuing to evolve. In this study, all patients had ALND irrespective of their nodal response, with a mean number of lymph nodes removed of 18.1 and 16.5 in ypN+ and ypN0, respectively. The use of SLNB in patients who present with nodal disease and downstage to cN0 after NAC is still debated and current guidelines do not categorically recommend SLNB in this group [31]. Although four prospective studies have demonstrated that modifications of the standard SLNB technique, such as use of dual tracer and retrieval of ≥ 3 sentinel nodes, result in an acceptable false negative rate [10-13], until recently, data on the oncological safety of SLNB after NAC in node positive patients at presentation were limited [32].
New studies have shown that N1 patients who achieve nodal pathological response after NAC and are treated with SLNB alone have excellent locoregional control, with similar disease-free and overall survival as those who receive complete axillary dissection [33-36]. In a study from Memorial Sloan Kettering Cancer Center (MSKCC) in which 234 biopsy-proven N1 patients underwent NAC and had ≥ 3 negative sentinel nodes removed with no further axillary surgery, the crude 5-year rate of regional recurrence was 1/234 (0.43%) [33]. In another study with longer follow-up (median follow up: 9.2 years) from the European Institute of Oncology, of 123 initially cN1/2 patients treated with SLNB alone, axillary failure occurred in 2/123 (1.8%) [35].
The advantage of minimally invasive techniques such as SLNB or targeted axillary surgery is to reduce the number of lymph nodes removed and to limit the surgical sequalae related to ALND (i.e. lymphedema, chronic pain and sensitivity disorders) which negatively impact quality of life [16,37-39]. Given the recent reassuring data on the oncological safety of these approaches, their use in the future is likely to continue to increase [9,34].
The 33% rate of nodal pCR found in this study is in line with the results of several other studies, conducted mainly in western populations, which reported rates ranging between 25% and 52% [8,11-13,22,40]. It’s important to note the great majority of HER2+ patients were treated only with Trastuzumab with only 4% receiving additional Pertuzumab, which may have influenced the rate of pCR (45%) in this group [41]. In multivariable analysis, factors associated with nodal pCR were tumor molecular subtype, the presence of LVI and breast pCR. The role of tumor biology in nodal response is well known [8,22,25], but the role of LVI is less well characterized. A previous study from MSKCC found a similar inverse association between LVI and nodal downstaging. In that study, Montagna et al. found that LVI was associated with a 54% decrease in the odds of finding ≥ 3 sentinel nodes and with a 76% decrease in the odds of achieving nodal pCR [8]. In the present study, the absence of LVI was associated with a significant increase in the odds of achieving nodal pCR (OR 9.04 (2.09; 39.18)). The poor nodal response to NAC when LVI is present is in line with previous studies demonstrating that LVI indicates more aggressive tumor biology associated with poorer prognosis [42]. Previous studies have shown that breast pCR is highly correlated with nodal status after NAC [43]. Tadros and colleagues found that 95.9% of TN and HER2+ patients who achieved breast pCR also had a nodal pCR [44]. In our study, including all BC subtypes, the rate on nodal pCR among patients who successfully downstaged in the breast was 79% (55/70).
Identification of patients who are likely to successfully respond to NAC, such as those who achieve breast pCR, is the pillar on which ongoing trials to eliminate breast surgery are based [45].
In this study the rate of nodal pCR in Asian woman treated with modern NAC was 33%. This rate is likely to increase over the next years due to the combination of new target agents to standard chemotherapy [46] and the development of new biomarker-driven therapeutic strategies [47,48].
Strengths and Limitations
To the best of our knowledge this is the first study that directly investigated nodal pCR rate in an Asian population. Strengths of the study include the large and homogenous sample and the fact that all patients had complete axillary dissection. Limitations include its retrospective nature, and the fact that the majority of HER2+ patients were treated with a single anti-HER2 agent.
Conclusion
Predictors of nodal pCR in Asian women do not seem to differ from those in non-Asian populations. The results of this study, combined with the recently published data on the oncological safety of omitting ALND in cN1 patients who achieve nodal pCR, support the use of minimal invasive techniques in this subgroup of patients.
Footnotes
Statement of Ethics
Subjects (or their parents or guardians) have given their written informed consent. The study was approved by the independent Ethical Committee of the Ruijin Hospital, Shanghai Jiaotong University School of Medicine. All procedures involving human participants were in accordance with the ethical standards of the committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Conflict of Interest Statement:
Dr. Giacomo Montagna was supported by the Ticino Cancer League, the Hanne Liebermann Foundation, the Fondation Ancrage, the Bangerter-Rhyner Stiftung and the HEMMI-Stiftung. No other authors have conflict of interest disclosures to report.
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