Abstract

Methods

Results

The study population consisted of 2377 patients; all were women. The median patient age was 50 years (range, 21-87 years). The ER status was lower than 1% in 28.9% of the patients, 1% to 9% in 8.3%, and 10% or higher in 62.8%. A total of 591 patients were ERBB2+; all of whom received trastuzumab as a component of their neoadjuvant regimen. Most patients (63.8%) had clinical stage II disease (IIA, 30.8%; IIB, 33.0%); 34.0% had clinical stage III disease (IIIA, 14.7%; IIIB, 6.6%; IIIC, 12.7%). A pCR was achieved in 26.0% of patients, with the remaining patients having pathologic stages I (18.4%), IIA (19.3%), IIB (12.7%), IIIA (15.6%), IIIB (1.1%), or IIIC (6.9%) disease. Complete clinicopathologic characteristics and treatment regimens are listed in the eTable 1 in the Supplement.

The median follow-up time was 4.2 years (range, 0.5-11.7 years). The estimated 5-year DSS rate for the entire study population was 89% (95% CI, 87%–90%). Five-year DSS rates by clinical and pathologic stage are shown in Figure 1A and B. Disease-specific survival rates by CPS+EG score using the 2 different cutoffs for ER positivity, 1% (Figure 1C) and 10% (eFigure 1 in the Supplement), were also determined. The AIC values for the 2 models were 3333.06 for a 1% ER positivity or higher cutoff vs 3333.38 for a 10% or higher cutoff, indicating that the model fits were nearly identical though slightly better for the 1% or higher cutoff.

Open in a separate window

Figure 1

Disease-Specific Survival (DSS) in Patients With Breast Cancer Receiving Neoadjuvant Chemotherapy

The DSS was determined based on presenting clinical stage (A), final pathologic stage (B), CPS+EG staging system (clinical-pathologic scoring system incorporating estrogen receptor-negative disease and nuclear grade 3 tumor pathology) (C),^16–18 and Neo-Bioscore, which includes ERBB2 status (D).

The ERBB2 status was added to the CPS+EG model with 1% or higher ER positivity as the cutoff, consistent with current American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP) guidelines.²⁶ Inclusion of ERBB2 status improved the fit of the model, with worse DSS for ERBB2-negative patients. Accordingly, the CPS+EG staging system was further refined to incorporate ERBB2 status by adding 1 additional point for ERBB2-negative status to define a new Neo-Bioscore (Table 1), which includes 8 distinct stages. Neo-Bioscore stratified patients with respect to DSS, with 5-year DSS estimates ranging from 48% to 99% (P < .001) (Figure 1D). Table 2 summarizes 5-year DSS rates for the study cohort stratified according to the clinical and pathologic AJCC stages, the CPS+EG staging system using the 1% cut-off, and the Neo-Bioscore. When the Neo-Bioscore was applied, there was a shift from the CPS+EG score, a more refined stratification in 1786 patients (75%). As detailed in Table 2, this shift reflects the percentage of ERBB2-negative tumors. The DSS rates for each CPS+EG score comparing ERBB2-positive with ERBB2-negative tumors are shown in eFigure 2 in the Supplement. Analyses were repeated excluding 225 ER-positive patients (9.5%) who did not receive endocrine therapy. For these analyses, patients treated prior to 2010 were considered positive if their ER values were 10% or higher, and patients treated from 2010 onward were considered positive if their ER values were 1% or higher. The Neo-Bioscore again stratified patient DSS better than did the presenting clinical stage or the final pathologic stage (Figure 2).

Open in a separate window

Figure 2

Disease-Specific Survival (DSS) in Patients With Breast Cancer Receiving Neoadjuvant Chemotherapy, Limited to Estrogen-Receptor (ER) Negative Patients and ER-Positive Patients Receiving Adjuvant Endocrine Therapy

The DSS was determined based on presenting clinical stage (A), final pathologic stage (B), CPS+EG staging system (clinical-pathologic scoring system incorporating ER-negative disease and nuclear grade 3 tumor pathology) (C),^16–18 and Neo-Bioscore, which includes ERBB2 status (D). For these analyses, patients treated prior to 2010 were considered ER positive at an ER value of 10% or higher Patients treated from 2010 through 2012 were considered ER positive at an ER value of 1% or higher.

Discussion

Our group¹⁶ previously developed the CPS+EG staging system, which incorporates tumor biologic factors including ER status and grade into traditional pretreatment and posttreatment anatomic staging allowing for better DSS stratification of patients with breast cancer receiving neoadjuvant chemotherapy.¹⁶ The staging system was both internally and externally validated.^17,18 A limitation of the CPS+EG staging system is that it cannot be used for patients with ERBB2-positive breast cancer because its development predated the routine use of ERBB2-targeted therapy. In the present study, we validated the CPS+EG staging system with a contemporary cohort and showed that it is applicable regardless of whether a 1% or 10% cutoff is used to define ER positivity–an important finding given the 2010 change in ASCO/CAP guidelines.²⁶ In addition, we showed that ERBB2 status is an important prognostic factor in an era when patients with ERBB2-positive breast cancer are routinely treated with trastuzumab. Incorporation of ERBB2 status into the CPS+EG staging system defines a new staging system, the Neo-Bioscore, which allows for prognostic stratification of patients with breast cancer of all subtypes who receive neoadjuvant chemotherapy.

A recent meta-analysis in which data were pooled from almost 12 000 patients enrolled in 12 neoadjuvant trials showed that a pCR, defined as no residual invasive disease in the breast or axilla (ypT0/is ypN0), was associated with improved eventfree survival and OS.¹¹ It is important to note that, while this survival improvement was demonstrated in the patient-level analysis, when the investigators performed additional analyses to address treatment effects within the individual trials, pCR was not validated as a surrogate end point for improved event-free survival and OS.¹¹ A second meta-analysis that included 29 neoadjuvant therapy trials provided further trial-level data that did not support the use of pCR as a surrogate end point for DFS or OS.²⁷

One strength of the Neo-Bioscore is that it can better stratify DSS for patients who achieve a pCR by accounting for presenting clinical stage and biologic markers. A patient presenting with a stage IIA, grade 2, triple-negative breast cancer who achieves a pCR would have a 98% 5-year expected DSS calculated by CPS+EG (score = 1) and a 97% 5-year expected DSS by Neo-Bioscore (score = 2). In contrast, if a patient presenting with stage IIIC, grade 2, triple-negative breast cancer achieves a pCR, the anticipated 5-year DSS rate would be 87% by CPS+EG (score = 3) and 86% by Neo-Bioscore (score = 4). If a patient presenting with stage IIIC, ERBB2-positive, ER-negative, grade 2 disease achieves pCR, the anticipated 5-year DSS rate would be 87% by CPS+EG (score = 3) and 93% by Neo-Bioscore (score = 3). Taken together, these data emphasize the importance of the extent of disease at presentation and tumor biology in dictating outcomes as well as the value of the Neo-Bioscore over CPS+EG in further stratifying DSS outcomes in patients with ERBB2-positive disease.

The prognosis of patients not achieving pCR is less well defined. Multiple investigators have attempted to determine prognosis in these patients using pathologic measures and/or biologic characteristics. Carey et al¹² have reported that assignment of pathologic stage according to the AJCC staging system can stratify patients with respect to distant DFS and OS. Symmans et al¹⁵ describe the residual cancer burden (RCB), a continuous index that combines pathologic size and cellularity of the primary tumor and the number and size of nodal metastases. The RCB score, which can range from 0 (pCR) to III (extensive residual disease), is a significant predictor of distant relapse-free survival. When applied to posttreatment AJCC stage groups, the RCB can further stratify patients into subgroups with respect to prognosis.

Jones et al¹³ have reported that posttreatment expression of the proliferative marker Ki67 is inversely correlated with recurrence-free and OS for patients not achieving a pCR, and more recently, Sheri et al¹⁴ have reported that adding posttreatment Ki67 to the RCB could improve long-term outcome prediction. These observations regarding the prognostic significance of post-treatment Ki67 are likely due to the fact that patients with a high Ki67 level in the resected tumor have resistant and highly proliferative disease not eradicated with chemotherapy. Interestingly, in the study by Sheri et al, the investigators looked at the additional prognostic information that could be gained from posttreatment ER expression and grade. Consistent with the CPS+EG and Neo-Bioscore, which both showed improved stratification with the inclusion of more biologic factors, they found that the addition of all variables, RCB, Ki67, ER, and grade, provided the most informative prognostic score.¹⁴

Like the CPS+EG staging system, the RCB was defined in a cohort of patients treated prior to the routine use of trastuzumab for ERBB2-positive disease. Of 220 patients in the study by Sheri et al,¹⁴ 53 had ERBB2-positive disease, but fewer than 50% received neoadjuvant trastuzumab. Therefore, the utility of these previously published prognostic scores in patients with ERBB2-positive disease treated with trastuzumab is unknown. The Neo-Bioscore accounts for the favorable effect of trastuzumab on the prognosis of patients with ERBB2-positive disease by assigning an additional point to patients with ERBB2-negative breast cancer. Importantly, this suggests that the CPS+EG staging system can be used as a “backbone” and that it is possible that as new molecular markers are identified, they can be easily incorporated to refine the staging system.

There is a growing body of literature differentiating ERBB2-positive breast cancer by HR expression. In the meta-analysis from Cortazar et al,¹¹ the effect of achieving a pCR on eventfree survival and OS was most pronounced in aggressive breast cancer subtypes including ERBB2-positive, HR-negative disease as well as triple-negative disease. That meta-analysis included 3 trials that reported the administration of trastuzumab for ERBB2-positive patients, the GeparQuattro,²⁵ NOAH,²⁰ and TECHNO²⁴ trials. The pCR rate in the meta-analysis for patients with ERBB2-positive, HR-positive disease was 31% (95% CI, 26%–36%), and the hazard ratio for OS for those achieving a pCR vs those who did not was 0.56 (95% CI, 0.23-1.37). For patients with ERBB2-positive, HR-negative disease, the pCR rate was 50% (95% CI, 45%–56%), and the hazard ratio for OS was 0.08 (95% CI, 0.03-0.22).¹¹ The meta-analysis also included 1157 patients with triple-negative breast cancer, and in these patients, the pCR rate was 34% (95% CI, 31%–36%), and the hazard ratio for OS for those achieving a pCR vs those who did not was 0.16 (95% CI, 0.11-0.25).¹¹ Similarly, in a report of approximately 1100 patients receiving neoadjuvant chemotherapy at MD Anderson between 1985 and 2004, prior to routine evaluation of ERBB2 status and use of trastuzumab, patients with triple-negative breast cancer were found to have significantly higher pCR rates than patients with non-triple-negative breast cancer, 22% vs 11%.²⁸ Interestingly, patients with triple-negative breast cancer who achieved a pCR had a 3-year OS rate of 94%, not significantly different than the 98% in patients with non-triple-negative breast cancer. However, for patients with triple-negative breast cancer who did not achieve a pCR, the 3-year OS rate was 68%. In contrast, for patients with non-triple-negative breast cancer not achieving a pCR, the 3-year OS rate was 88%. Taken together, these data emphasize the importance of achieving a pCR in patients with aggressive subtypes of breast cancer lacking HR expression. This is likely because these patients have already received the majority of their systemic therapy prior to surgery and have residual disease, with the caveat that ERBB2-positive patients currently complete 1 year of trastuzumab therapy. In addition, because they lack HR expression, they are not going to benefit from administration of endocrine therapy. This biologic information is captured by the Neo-Bioscore.

In addition, to meet the growing interest in treating patients with residual disease following neoadjuvant chemotherapy, the Neo-Bioscore could be used to identify high-risk patients for clinical trial participation or to stratify patients in such studies. Two ongoing trials are using the CPS+EG staging system to identify high-risk ER-positive patients with residual disease after neoadjuvant chemotherapy. The PENELOPE-B trial (NCT01864746) trial evaluating the addition of palbociclib to standard endocrine therapy and the OlympiA (NSABP B-55/BIG 6-13; NCT02032823) evaluating olaparib in BRCA-mutated, non-ERBB2-positive breast cancer are both using a CPS+EG score of 3 or higher to define high-risk ER-positive patients. The present study further validates the CPS+EG staging system regardless of the threshold used to define ER positivity and provides the Neo-Bioscore, which could be used in a similar fashion to identify high-risk ERBB2-positive patients to be considered for additional adjuvant therapy trials.

Conclusions

This work represents a continued effort by our group to demonstrate the importance of tumor biology in dictating survival outcomes for patients with breast cancer. In addition to the CPS+EG staging system and the newly defined Neo-Bioscore, which apply to patients receiving neoadjuvant chemotherapy, we have published data for patients undergoing surgery as an initial intervention showing the importance of ER status and grade on prognosis.²⁹ Work is ongoing to update that staging system as well, incorporating ERBB2-positive patients who received trastuzumab. Goals of the AJCC staging system include providing a common language for physicians to communicate regarding a patient’s disease and providing prognostic information. A robust staging system is also critical for identifying and stratifying clinical trials. We therefore suggest that biologic factors and, for patients receiving neoadjuvant chemotherapy, the response to treatment be incorporated into the AJCC staging system, which is currently being revised.

Supplementary Material

Acknowledgments

Footnotes

Contributor Information

Elizabeth A. Mittendorf, Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston.

Jose Vila, Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston.

Susan L. Tucker, Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston.

Mariana Chavez-MacGregor, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston. Department of Health Services Research, The University of Texas MD Anderson Cancer Center, Houston.

Benjamin D. Smith, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston.

W. Fraser Symmans, Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston.

Aysegul A. Sahin, Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston.

Gabriel N. Hortobagyi, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.

Kelly K. Hunt, Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston.

References