Abstract
Background
The majority of HR+/HER2-breast cancer patients can also achieve long-term survival despite not attaining pCR, indicating limited prognostic value of pCR in this population. This study aimed to identify novel pathologic end points for predicting long-term outcomes in HR+/HER2-breast cancer after neoadjuvant chemotherapy.
Methods
We analyzed HR+/HER2-breast cancer patients with stage II-III tumors who underwent curative surgery after neoadjuvant chemotherapy from three hospitals. Major pathologic response (MPR), defined as the presence of Miller-Payne grades 3–5 and positive lymph node ratio of ≤10 %, was used as a pathological evaluation indicator. We assessed the association between MPR and event-free survival (EFS) and performed Multivariable Cox regression to identify independent factors associated with EFS.
Results
From January 2010 to December 2020, 386 patients were included in the final analysis. 28 patients (7.3 %) achieved pCR and 118 patients (30.6 %) achieved MPR. The median duration of follow-up was 54.4 months,5-year EFS was 87 % in the MPR group vs. 68 % in the non-MPR group. Multivariate analysis showed that low PR expression, high clinical stage, lower Miller–Payne grades and Positive lymph node ratio were independent poor prognostic factors for EFS (all P values < 0.05). The prognostic effect of MPR remained in multivariable models (hazard ratio (HR), 0.45; 95 % confidence interval (CI), 0.26–0.76; P = 0.008), In non-pCR patients, those who achieved MPR exhibited a similar EFS compared with pCR patients (HR, 2.25; 95 % CI, 0.51–9.84; P = 0.28).
Conclusion
MPR may be a novel pathologic end point in HR+/HER2-breast cancer after neoadjuvant chemotherapy, holding greater applicability in the prognosis evaluation than pCR.
Keywords: Major pathologic response, Neoadjuvant chemotherapy, Hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer, Prognostic factors
Highlights
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Major pathologic response (MPR) predicts long-term survival in HR+/HER2-breast cancer.
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MPR is defined by Miller-Payne grades 3–5 and positive lymph node ratio of ≤10 %.
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MPR achieved in 30.6 % of patients after neoadjuvant chemotherapy.
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5-year event-free survival (EFS) was 87 % in the MPR group vs. 68 % in the non-MPR group.
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MPR shows greater prognostic utility than pathological complete response (pCR).
1. Introduction
Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer accounts for approximately 68 % of all invasive breast cancer cases [1]. Neoadjuvant therapy is now being used more widely in early-stage breast cancer patients and has been recognized as the standard of care for patients with locally advanced and/or inoperable breast cancer [2]. For patients with locally advanced HR+/HER2− breast cancer, neoadjuvant therapy can downstage the tumor, rendering tumors operable, enabling breast-conserving surgery, and offer clinicians the opportunity for early observation and assessment of tumor response to therapy, thereby guiding subsequent adjuvant treatments [3,4]. Postoperative pathological examination is the most reliable method for evaluating the efficacy of neoadjuvant therapy [5]. Pathological complete response (pCR), defined as the absence of invasive tumor in the breast (ypT0/is) and in the lymph nodes (N0), is strongly associated with excellent long-term survival outcomes, serving as the primary end point in most neoadjuvant clinical trials [6,7]. A pooled analysis, the CTNeoBC study, encompassing 12 randomized controlled trials with a total of 11,955 patients, demonstrated that patients who attained pCR after neoadjuvant treatment had improved survival compared to patients who did not achieve pCR (event-free survival (EFS): hazard ratio (HR) = 0.48, 95 % CI: 0.43–0.54) [6].
The probability of achieving a pCR varies considerably across distinct molecular subtypes of breast cancer. Patients with HR + HER2-breast cancer tend to exhibit notably lower pCR rates in comparison to those with HER2-positive or those with triple-negative breast cancer (TNBC). In neoadjuvant chemotherapy trials involving unselected HR + breast cancer, pCR rates range from 7 % to 11 % [4]. While HR + breast cancer patients with pCR also tend to have improved long-term prognosis compared to non-pCR cases, the prognostic value appears to be relatively modest within this specific population, [6,7]. Among HR + tumors, pCR rates demonstrated a decrease and the association with long-term outcomes was weaker within grade 1–2 tumors (HR = 0.63, 95 % CI, 0.38–1.04) as opposed to grade 3 tumors (HR = 0.27, 95 % CI, 0.14–0.50) [6]. In a Comprehensive Meta-analysis comprising 27895 patients, only a trend towards significance was observed in EFS for HR + breast cancer (HR = 0.15; 95 % probability intervals (PI), 0.02–1.10; n = 3385), different from the statistically significant improvement of EFS observed in patients with TNBC (HR = 0.18; 95 % PI, 0.10–0.31; n = 2039) or HER2 positive breast cancer (HR = 0.31; 95 % PI, 0.21–0.50; n = 5711) [7]. Moreover, some HR+/HER2-breast cancer patients can also achieve long-term survival despite not attaining pCR, further illustrating that the prognostic value of pCR may be limited for HR+/HER2-breast cancer. Considering that the binary outcome of pCR does not adequately distinguish between patients with varying degrees of residual disease, the residual cancer burden (RCB) method was developed to assess and quantify the extent of residual disease in breast and axillary lymph nodes after neoadjuvant chemotherapy [8]. In a multicenter pooled analysis of 5161 patients, higher RCB scores were associated with worse EFS in patients with unselected HR + breast cancer. Unlike other subtypes, where EFS is superior with RCB-0 (indicating pCR) compared to any degree of residual disease, patients with RCB-0 and RCB-I exhibited similar EFS in HR+/HER2-breast cancer [3]. Currently, these two mainstream assessment methods are of limited value in assessing the prognosis of HR+/HER2-breast cancer, alternative end points for predicting long-term outcome of these patients are necessary. This could help select or identify people with a better prognosis in non-pCR patients and guide the de-escalation and escalation in HR+/HER2-breast cancer adjuvant treatment. This study aimed to identify novel pathologic end points reflecting long-term prognosis in HR+/HER2-breast cancer patients undergoing neoadjuvant therapy.
2. Methods
2.1. Study population
Data on breast cancer patients undergoing neoadjuvant chemotherapy were collected at three hospitals (Cancer Hospital, Chinese Academy of Medical Sciences; Beijing Chaoyang District Sanhuan Cancer Hospital; Cancer Hospital of Huanxing) from January 2010 to December 2020. Inclusion criteria: (1) patients pathologically diagnosed with invasive breast cancer and classified as HR+/HER2-subtype; (2) those who underwent surgical resection following neoadjuvant chemotherapy; (3) postoperative pathological results were available; (4) patients with complete medical records and follow-up information. Exclusion criteria: (1) de novo metastatic breast cancer; (2) combined with other tumors within 5 years, excluding thyroid carcinoma; (3) bilateral invasive breast cancer; (4) only treated with neoadjuvant endocrine therapy before surgery; (5) missing clinicopathological information. Patients with cM1 disease were exclude in this present study. Distant metastases were ruled out with ultrasound, computed tomography (CT), bone scintigraphy, or positron emission tomography (PET)scans. Among 1259 patients receiving surgical treatment after neoadjuvant therapy between January 2010 and April 2021, 386 patients with HR+/HER2-breast cancer were finally included for final analysis. Fig. 1 illustrates the flowchart for the selection of eligible patients.
Fig. 1.
Selection of patients.
2.2. Study definitions and endpoints
In our study, estrogen receptor (ER), progesterone receptor (PR) and HER2 status were determined through immunohistochemical (IHC) analysis. HR positivity was defined as ER and/or PR positive. A positive status for ER and PR was indicated when nuclear staining in tumor cells was equal to or exceeded 1 %. HER2 IHC scores of 0/1+ or 2+ with fluorescence in situ hybridization (FISH) negative were classified as HER2 negative. The pathological response of breast to neoadjuvant chemotherapy was evaluated was assessed using the Miller-Payne grading system, which estimates the percent reduction in tumor cells compared to pretreatment core biopsy samples [9]. Miller–Payne system, commonly used in clinical practice, is a five-point scale and higher grade can indicate greater therapeutic efficacy. Grade 1: no significant reduction in malignant cells; Grade 2: a minor loss of tumor cells (≤30 %); Grade 3: reduction in tumor cells between 30 % and 90 %; Grade 4: A marked disappearance of tumor cells >90 %; Grade 5: no malignant cells identifiable, but DCIS may be present. To enhance reproducibility, each pathological slide underwent confirmation by two expert pathologists. Miller-Payne grades 1–2 were grouped into a non-responder category, while Miller-Payne grades 3–5 were classified as a responder group based on preliminary findings (Fig. S1) a nd references to prior studies [10,11]. pCR was defined as the absence of invasive tumor in the breast (ypT0/is) and in the lymph nodes (N0). To assess the lymph node status, we calculated the lymph node ratio (LNR), which is defined as the ratio of the number of positive lymph nodes to the total number of lymph nodes that were evaluated. Notably, patients with ypN1 or ypN2 demonstrated similar prognoses, suggesting a limited prognostic value of postoperative pathologic N stage in HR+/HER2-breast cancer receiving neoadjuvant chemotherapy in our analysi s (Fig. S2). In this study, LNR was calculated to evaluate lymph node metastasis status after neoadjuvant chemotherapy. To identify a lower-risk population, the cut-off value for LNR was established at 10 % based on the three-class outcomes derived from X-tile software (Fig. S3 and S4). Furthermore, we propose a novel pathologic end point termed major pathologic response (MPR). MPR is defined as the presence of Miller-Payne grades 3–5 and positive lymph node ratio of ≤10 %. Similar to the definition of pCR, MPR evaluates the extent of residual invasive carcinoma in both the breast and axillary lymph nodes following neoadjuvant therapy.
The primary endpoint was event-free survival (EFS), measured as time from start of neoadjuvant chemotherapy to the occurrence of locoregional recurrence, distant recurrence, or death from any cause [3]. Overall survival (OS) was calculated from the date of initial diagnosis to the date of death for any cause.
2.3. Statistical analysis
The relationship between baseline characteristics and different MPR statuses was assessed using the Chi-square test and Fisher's exact test. To identify independent prognostic factors for EFS, multivariate Cox regression models were employed through the forward conditional method (Table S1 and S2). Hazard ratios (HRs) and 95 % confidence interval (CI) were estimated for these factors. The survival difference was compared by Kaplan-Meier curves using log-rank test. All reported P-values are two-sided and statistical significance was established at P < 0.05. Analyses were performed using SPSS version 26.0 and R software version 4.3.1.
3. Results
3.1. Baseline characteristics of patients
A total of 386 patients diagnosed with HR+/HER2-breast cancer, who underwent neoadjuvant chemotherapy followed by surgical intervention, were retrospectively enrolled for this study from three different hospitals. These patients were categorized into two groups: a non-MPR group (69.4 %, N = 268) and an MPR group (30.6 %, N = 118). Baseline characteristics of the overall population and the divided groups were summarized in Table 1. In the overall population analyzed, the median age was 46 years. Most of the patients were less than or equal to 60 years old (85.8 %), with 244 patients (63.2 %) were premenopausal. The majority of patients exhibited high levels of ER (>10 %, 86.8 %, N = 335) and PR (≥20 %, 71.5 %, N = 276) expression while 299 patients showed high Ki-67 index (≥20 %, 77.5 %). Most patients had later clinical stage, with 271 patients (70.2 %) diagnosed with stage III disease. The predominant neoadjuvant chemotherapy regimen administered was a combination of anthracycline and taxane (79.3 %), with 355 patients (92 %) completing at least four cycles of neoadjuvant chemotherapy. There were 33 patients (8.5 %) that underwent taxane and platinum combination neoadjuvant chemotherapy, which was likely to be due to low-ER expression group (≤10 %, 13.2 %, N = 51). After neoadjuvant chemotherapy, mastectomy was performed in 88.3 % of patients while 11.7 % of patients received breast conserving surgery. Among the entire population, only 28 (7.3 %) achieved pCR, while 118 patients (30.6 %) achieved MPR. When compared with the non-MPR group, the MPR group exhibited a higher incidence of low ER and PR expression, II stage disease, utilization of platinum and taxane combination therapy, and completion of 4–6 cycles of neoadjuvant chemotherapy, suggesting that these factors may have a significant impact on the likelihood of achieving MPR.
Table 1.
Baseline characteristics of HR+/HER2-breast cancer patients for the overall cohort and by MPR.
| Total N = 386 |
Non-MPR N = 268 |
MPR N = 118 |
P value | |
|---|---|---|---|---|
| Age, years | 46 (23–74) | 46 (25–74) | 45 (23–70) | |
| Age at initial diagnosis, years | ||||
| <40 | 103 (26.7 %) | 66 (24.6 %) | 37 (31.4 %) | 0.184 |
| 40-60 | 228 (59.1 %) | 159 (59.3 %) | 69 (58.5 %) | |
| >60 | 55 (14.2 %) | 43 (16.0 %) | 12 (10.2 %) | |
| Menopausal status | ||||
| Pre-menopausal | 244 (63.2 %) | 164 (61.2 %) | 80 (67.8 %) | 0.191 |
| Post-menopausal | 142 (36.8 %) | 104 (38.8 %) | 38 (32.2 %) | |
| ER expression | ||||
| ≤10 % | 51 (13.2 %) | 19 (7.1 %) | 32 (27.1 %) | <0.001 |
| >10 % | 335 (86.8 %) | 249 (92.9 %) | 86 (72.9 %) | |
| PR expression | ||||
| <20 % | 110 (28.5 %) | 67 (25.0 %) | 43 (36.4 %) | 0.027 |
| ≥20 % | 276 (71.5 %) | 201 (75.0 %) | 75 (63.6 %) | |
| HER2 status | ||||
| 0 | 99 (25.6 %) | 60 (22.4 %) | 39 (33.1 %) | 0.084 |
| 1+ | 156 (40.4 %) | 112 (41.8 %) | 44 (37.3 %) | |
| 2+ | 131 (33.9 %) | 96 (35.8 %) | 35 (29.7 %) | |
| Ki-67 expression | ||||
| <20 % | 87 (22.5 %) | 66 (24.6 %) | 21 (17.8 %) | 0.148 |
| ≥20 % | 299 (77.5 %) | 202 (75.4 %) | 97 (82.2 %) | |
| Clinical stage | ||||
| II | 115 (29.8 %) | 61 (22.8 %) | 54 (45.8 %) | <0.001 |
| III | 271 (70.2 %) | 207 (77.2 %) | 64 (54.2 %) | |
| Regimens of neoadjuvant chemotherapy | ||||
| Anthracycline and taxane | 306 (79.3 %) | 221 (82.5 %) | 85 (72.0 %) | 0.004 |
| taxane and platinum | 33 (8.5 %) | 14 (5.2 %) | 19 (16.1 %) | |
| Anthracycline or taxane | 32 (8.3 %) | 21 (7.8 %) | 11 (9.3 %) | |
| Other | 15 (3.9 %) | 12 (4.5 %) | 3 (2.5 %) | |
| Cycles | ||||
| <4 | 31 (8.0 %) | 27 (10.1 %) | 4 (3.4 %) | 0.030 |
| 4-6 | 311 (80.6 %) | 207 (77.2 %) | 104 (88.1 %) | |
| >6 | 44 (11.4 %) | 34 (12.7 %) | 10 (8.5 %) | |
| Surgery | ||||
| Mastectomy | 341 (88.3 %) | 251 (93.7 %) | 90 (76.3 %) | <0.001 |
| Breast conserving surgery | 45 (11.7 %) | 17 (6.3 %) | 28 (23.7 %) | |
| Miller–Payne grades | ||||
| 1 | 19 (4.9 %) | 19 (7.1 %) | 0 | <0.001 |
| 2 | 119 (30.8 %) | 119 (44.4 %) | 0 | |
| 3 | 175 (45.3 %) | 106 (39.6 %) | 69 (58.5 %) | |
| 4 | 44 (11.4 %) | 23 (8.6 %) | 21 (17.8 %) | |
| 5 | 29 (7.5 %) | 1 (0.4 %) | 28 (23.7 %) | |
| Pathological reaction | ||||
| pCR | 28 (7.3 %) | 0 | 28 (23.7 %) | <0.001 |
| Non-pCR | 358 (92.7 %) | 268 (100.0 %) | 90 (76.3 %) | |
| ypT | ||||
| 0 | 29 (7.5 %) | 1 (0.4 %) | 28 (23.7 %) | <0.001 |
| 1 | 161 (41.7 %) | 102 (38.1 %) | 59 (50.0 %) | |
| 2 | 160 (41.5 %) | 130 (48.5 %) | 30 (25.4 %) | |
| 3 | 27 (7.0 %) | 27 (10.1 %) | 0 | |
| 4 | 9 (2.3 %) | 8 (3.0 %) | 1 (0.8 %) | |
| ypN | ||||
| 0 | 97 (25.1 %) | 25 (9.3 %) | 72 (61.0 %) | <0.001 |
| 1 | 97 (25.1 %) | 53 (19.8 %) | 44 (37.3 %) | |
| 2 | 75 (19.4 %) | 74 (27.6 %) | 1 (0.8 %) | |
| 3 | 117 (30.3 %) | 116 (43.3 %) | 1 (0.8 %) | |
| LNR | ||||
| ≤10 % | 161 (41.7 %) | 43 (16.0 %) | 118 (100.0 %) | <0.001 |
| >10 % | 225 (58.3 %) | 225 (84.0 %) | 0 | |
Abbreviation: MPR, major pathologic response; ER, estrogen receptor, PR, progesterone receptor; HER2, human epidermal growth factor receptor 2; pCR, pathological complete response; LNR, lymph node ratio.
3.2. MPR and survival analysis
The final follow-up was conducted in September 2023, with a median follow-up duration of 54.4 months (ranging from 3.2 to 153.3 months). Kaplan-Meier analysis demonstrated that a significant improvement in EFS among patients with stage II disease, those who responded to treatment (Miller-Payne grades 3–5), and those with a LNR of ≤10 % (Fig. 2). In multivariable analysis using a forward conditional procedure, higher clinical stage and LNR were found to be significantly associated with worse EFS (HR, 2.14 for stage III, P = 0.013; HR, 1.89 for LNR >10 %, P = 0.013). Conversely, high PR expression and Miller–Payne grades were strongly associated with favorable EFS (PR ≥ 20 %: HR, 0.62; 95 % CI 0.41–0.94; P = 0.024, Miller–Payne grades 3–5: HR, 0.56; 95 % CI 0.38–0.84; P = 0.005) (Table 2).
Fig. 2.
Event-free survival curves plotted by Kaplan-Meier method according to PR expression (A), clinical stage (B), Miller–Payne grades (C) and Positive lymph node ratio (D).
Table 2.
Factors associated with Event-free survival outcomes.
| Univariate |
Multivariate |
|||
|---|---|---|---|---|
| HR (95 % CI) | P Value | HR (95 % CI) | P Value | |
| PR expression | ||||
| <20 % | Reference | Reference | ||
| ≥20 % | 0.67 (0.45–1.02) | 0.060 | 0.62 (0.41–0.94) | 0.024 |
| Clinical stage | ||||
| II | Reference | Reference | ||
| III | 2.96 (1.74–5.05) | <0.001 | 2.14 (1.18–3.88) | 0.013 |
| Miller–Payne grades | ||||
| I-2 (non-responder group) | Reference | Reference | ||
| 3-5 (responder group) | 0.56 (0.38–0.82) | 0.003 | 0.56 (0.38–0.84) | 0.005 |
| LNR | ||||
| ≤10 % | Reference | Reference | ||
| >10 % | 2.69 (1.71–4.23) | <0.001 | 1.89 (1.13–3.16) | 0.016 |
Abbreviation: PR, progesterone receptor; LNR, lymph node ratio; HR, hazard ratio. CI confidence interval.
MPR, defined as Miller-Payne grades 3–5 and positive lymph node ratio of ≤10 %, was established based on two independent prognostic factors. When compared to the prognostic value of pCR, there were also significant differences in EFS and OS between MPR and non-MPR group (Fig. 3A, B and 3D). EFS estimates for patients within the MPR group were 87 % at 3 years and 87 % at 5 years, in contrast to 79 % and 68 % for MPR group (Table 3 and Fig. 2B). Furthermore, association between MPR and EFS remained significant (HR, 0.45; 95 % CI 0.26–0.76; P = 0.008) in the overall population when we adjusted for PR expression and clinical stage at baseline, which differs from the findings for pCR (Table 3). In non-pCR patients, those who achieved MPR exhibited a similar EFS compared with pCR patients (HR, 2.25; 95 % CI, 0.51–9.84; P = 0.28) (Table S3 and Fig. 3C). Of notable importance, prognosis appeared to be closer to that of patients with pCR if additional T1 staging criteria was introduced on the basis of MPR (Table S4 and Fig. 3D).
Fig. 3.
Event-free survival curves plotted by Kaplan-Meier method according to pCR (A), MPR (B), pCR vs. MPR (C), pCR vs. MPR + T1 (D). Overall survival curves plotted by Kaplan-Meier method according to MPR (E), pCR vs. MPR (F).
Table 3.
Multivariate analysis of MPR and event-free survival of patients.
| Multivariate |
Event free survival |
|||
|---|---|---|---|---|
| HR (95 % CI) | P Value | 3-year | 5-year | |
| PR expression | ||||
| <20 % | Reference | 73 % | 66 % | |
| ≥20 % | 0.64 (0.42–0.97) | 0.036 | 85 % | 77 % |
| Clinical stage | ||||
| II | Reference | 93 % | 92 % | |
| III | 2.40 (1.39–4.13) | 0.002 | 76 % | 65 % |
| MPR | ||||
| Non-MPR | Reference | 79 % | 68 % | |
| MPR | 0.45 (0.26–0.76) | 0.008 | 87 % | 87 % |
Abbreviation: PR, progesterone receptor; MPR, major pathologic response; HR, hazard ratio. CI confidence interval.
4. Discussion
Our results showed that MPR had a strong association with improved EFS in HR+/HER2-breast cancer, even after adjusting for pretreatment clinical stages and PR expression levels. Considering that the clinical utility of pCR or RCB as prognostic markers for predicting long-term prognosis in HR+/HER2-breast cancer appears to be limited, there is a pressing need for surrogate endpoints that can reliably predict long-term survival in this specific population. To our knowledge, this is the first study to specifically explore the prognostic role of MPR. In our study, approximately one third of patients (30.6 %) achieved MPR, whereas only a minority (7.3 %) attained pCR. Intriguingly, despite the majority of patients failing to attain pCR, those who reached MPR demonstrated a comparable EFS to patients who achieved pCR. Consequently, MPR emerges as a potentially more applicable and informative pathologic end point for HR+/HER2-breast cancer patients compared to pCR.
As previously mentioned, the association between pCR and survival outcomes is notably weaker in HR+/HER2-subgroup [6,7]. A pooled analysis from Germany also revealed that pCR did not serve as a prognostic factor in patients with luminal A or luminal B/HER2-positive breast cancer [12]. Similarly, the log relative hazard rate remained close to zero until an RCB score of approximately 1.5, indicating the presence of residual disease may not carry the same degree of prognostic significance for these patients in contrast to the other subtypes [3]. The chemosensitivity of HR+/HER2-breast cancer is not as robust as biologically aggressive subtypes, namely HER2+ breast cancer or TNBC. Accordingly, it has a relatively favorable long-time outcome despite lower pCR rates. Another potential reason for this observation is that the survival of some HR+/HER2-breast cancer patients may not depend primarily on their response to neoadjuvant chemotherapy, but rather on the crucial role of adjuvant endocrine therapy. Furthermore, the distinctiveness of this type of cancer can be attributed to unique biological characteristics and a certain degree of heterogeneity of this subtype. HR+/HER2-breast cancer is enriched with PAM50 luminal A subtype with the relatively indolent biologic behavior of this subtype resulted in less responsiveness to chemotherapy [13]. Additionally, IHC-based intrinsic subtype were not entirely consistent with intrinsic subtype using PAM50 gene expression assay. For instance, IHC-defined Luminal B tumors may include intrinsic subtypes with basal-like (21.4 %) and HER2-enriched (10.7 %) based on gene expression profiling [14,15]. Some HR+/HER2-breast cancer can present as low positivity for hormone receptors or high risk gene expression signatures [16,17]. Interestingly, tumors displaying a luminal B or basal intrinsic subtype, low expression of hormone receptor (<10 %), and high-risk gene expression score are more likely to achieve a pCR following neoadjuvant chemotherapy [[14], [15], [16], [17]].
Similarly, it was difficult to achieve pCR in neoadjuvant chemotherapy of lung cancer in the era of chemotherapy and the low rates of a pCR restricted its use as a surrogate endpoint [18]. In the context of lung cancer, a concept known as major pathological response (MPR) has emerged, termed as ≤10 % residual viable tumor after neoadjuvant chemotherapy. MPR has demonstrated a robust association with improved survival and has been recommended as a surrogate endpoint for survival in neoadjuvant trials involving resectable lung cancers [18]. A systematic review and meta-analysis fifty-three trials have further supported the use of neoadjuvant chemo-immunotherapy achieved higher MPR (53.8 %) in resectable nonsmall-cell lung cancers patients and there was a potential association between increased MPR rates and improved survival [19]. Given the observed lower pCR rates of HR+/HER2-breast cancer, this study introduces the concept of MPR and used a completely new definition of MPR as a pathologic end point for predicting long-term outcome.
Other than pCR, several evaluation systems have been proposed and may provide more information (Table S5). The RCB index was calculated as a continuous index incorporating pathologic measurements of primary tumor bed (size, cellularity and the proportion of carcinoma in situ) and lymph node metastases (number and size), and therefore provided additional information for patients with residual disease following neoadjuvant therapy [8,20]. While RCB index or class is highly prognostic in all subtypes of breast cancer, the association between RCB and survival was weakest in patients with HR+/HER-breast cancer, among whom the RCB-0 and RCB-1 groups had similar EFS [3]. The Miller and Payne grading system, a five-point histological grading system, was based on assessing a reduction in tumor cellularity in comparison with a pretreatment core biopsy specimens [9]. It serves as a tool to evaluate treatment response and predict prognosis. However, this system only described the response of the primary breast tumor site to neoadjuvant treatment regardless of axillary involvement. The CPS + EG system, including all clinical and pathologic substages before and after neoadjuvant therapy, as well as tumor markers (grade and ER status), can result in a total of seven distinct subgroups, offer refined prognostic information and assist in the selection of appropriate patients for clinical trials [21]. In OlympiA trial, patients receiving neoadjuvant chemotherapy were required to have not had a pCR with a CPS + EG score of 3 or higher, with higher scores indicating worse survival [22]. However, the complex and detailed prognostic stratification restricted its use. In our study, we introduced the concept of MPR, which combines Miller-Payne grades and axillary lymph node metastases. MPR serves as a straightforward and reliable tool to assess the response to neoadjuvant chemotherapy and predict prognosis.
In this study, patients were administered different neoadjuvant regimens based on physician's choice, and the specific type or duration of chemotherapy was not standardized, which may demonstrate the generalizability of MPR across different treatment scenarios. Notably, the I-SPY 2 trial also supports the robust prognostic significance of both pCR and RCB score, regardless of the specific type of chemotherapy-based treatment [23,24]. Furthermore, our study observed a 5-year EFS rate of 87 % for the MPR group, which was higher than the 68 % EFS rate for the non-MPR group. It's worth mentioning that these figures differ somewhat from a previous study, which reported a 5-year EFS of 97 % for those with pCR and 88 % for those without pCR in HR + subgroup [7]. The variance in outcomes could potentially be attributed to factors such as the high proportion of stage III patients (70.2 %) in our cohort and the relatively limited sample size.
Nevertheless, our study has several limitations that warrant consideration. Firstly, it was retrospective study with the possibility of selection bias. Secondly, postoperative adjuvant treatment of early breast cancer has evolved tremendously over the extended timeframe from 2010 to 2022. Both adjuvant Abemaciclib (monarchE trial) and adjuvant olaparib (OlympiA trial, gBRCA-mutated patients) improving prognosis of HER2 negative patients with residual disease after neoadjuvant treatment and both drugs are the current standard care for such patients [25,26]. Thirdly, the Miller–Payne system cannot be used as a continuous variable but use a semiquantitative method to assess the loss of tumor cells, in which grade 3 covers a wide range from 30 % to 90 % regardless of size or volume of tumor in the breast [4].Consequently, the best cut-offs for tumor cellularity and diameter were not able to be identified. Additionally, the median follow-up time for the overall study was less than 5 years, which may be considered relatively short in the context of the natural history of HR+/HER2-breast cancer.
5. Conclusions
In conclusion, MPR can predict long-term survival in HR+/HER2-breast cancer patients after neoadjuvant chemotherapy. This finding suggests that MPR may offer greater practical utility than pCR in clinical settings. Moreover, the use of MPR as a prognostic marker can provide valuable guidance for the design and assessment of neoadjuvant trials specifically tailored to HR+/HER2-breast cancer patients. These findings have important implications for tailoring treatment strategies and improving prognostic assessments in HR+/HER2-breast cancer patients.
Funding
This research received no external funding.
Ethical approval
Ethical approval was provided by the independent ethics committees of Cancer Hospital, Chinese Academy of Medical Sciences.
Data availability statement
The datasets of our study were available on request from the corresponding author.
Conflicts of interest
The authors have declared no potential conflicts of interest.
CRediT authorship contribution statement
Lei Ji: Writing – original draft, Methodology, Formal analysis, Conceptualization. Xi Chen: Writing – original draft, Methodology, Formal analysis, Conceptualization. Xiaoyan Qian: Data curation. Min Xiao: Data curation. Qing Li: Resources. Qiao Li: Resources. Jiayu Wang: Resources. Ying Fan: Resources. Yang Luo: Resources. Shanshan Chen: Resources. Fei Ma: Resources. Binghe Xu: Resources. Pin Zhang: Writing – review & editing, Validation, Supervision, Resources, Data curation, Conceptualization.
Acknowledgments
We acknowledge Lei Cheng for guidance in data analysis.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.breast.2024.103792.
Appendix ASupplementary data
The following are the Supplementary data to this article.
Event-free survival curves plotted by Kaplan-Meier method according to Miller-Payne grades.
Event-free survival curves plotted by Kaplan-Meier method according to ypN.
The optimal cut-off value for LNR based on the dichotomous outcomes derived from X-tile software.
The optimal cut-off value for LNR based on the three-class outcomes derived from X-tile software.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Event-free survival curves plotted by Kaplan-Meier method according to Miller-Payne grades.
Event-free survival curves plotted by Kaplan-Meier method according to ypN.
The optimal cut-off value for LNR based on the dichotomous outcomes derived from X-tile software.
The optimal cut-off value for LNR based on the three-class outcomes derived from X-tile software.
Data Availability Statement
The datasets of our study were available on request from the corresponding author.