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Prognostic Value of Pathologic Complete Response After Primary Chemotherapy in Relation to Hormone Receptor Status and Other Factors

From the Departments of Breast Medical Oncology, Biostatistics and Applied Mathematics, Radiation Oncology, Surgical Oncology, and Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and the Department of Oncology and Hematology, University of Modena e Reggio Emilia, Modena, Italy

Address reprint requests to Ana Maria Gonzalez-Angulo, MD, Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1354, Houston, TX, 77230-1439; e-mail: agonzalez{at}mdanderson.org

	ABSTRACT

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PURPOSE: To evaluate whether hormonal receptor (HR) status can influence the prognostic significance of pathologic complete response (pCR).

PATIENTS AND METHODS: This retrospective analysis included 1,731 patients with stage I to III noninflammatory breast cancer treated between 1988 and 2005 with primary chemotherapy (PC). Ninety-one percent of patients received anthracycline-based PC, and 66% received additional taxane therapy. pCR was defined as no evidence of invasive tumor in the breast and axillary lymph nodes.

RESULTS: Median age was 49 years (range, 19 to 83 years). Sixty-seven percent of patients (n = 1,163) had HR-positive tumors. A pCR was observed in 225 (13%) of 1,731 patients; pCR rates were 24% in HR-negative tumors and 8% in HR-positive tumors (P < .001). A significant survival benefit for patients who achieved pCR compared with no pCR was observed regardless of HR status. In the HR-positive group, 5-year overall survival (OS) rates were 96.4% v 84.5% (P = .04) and 5-year progression-free survival (PFS) rates were 91.1% v 65.3% (P < .0001) for patients with and without pCR, respectively. For the HR-negative group, 5-year OS rates were 83.9% v 67.4% (P = .003) and 5-year PFS rates were 83.4% v 50.0% (P < .0001) for patients with and without pCR, respectively. After adjustment for adjuvant hormonal treatment, HR status, clinical stage, and nuclear grade, patients who achieved a pCR had 0.36 times the risk of death.

CONCLUSION: pCR is associated with better outcome regardless of HR status in breast cancer patients who receive PC.

	INTRODUCTION

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Primary chemotherapy (PC) represents the standard of care for locally advanced and inflammatory breast cancer, and its use is increasing in earlier stage disease. Upfront administration of systemic chemotherapy has proven to increase the rate of breast-conserving surgery (BCS).^1,2 Furthermore, the response to PC and, in particular, the achievement of a pathologic complete response (pCR) are predictors of outcome^3-5 and can be considered as surrogate markers of treatment efficacy. As a consequence, early identification of features that can predict for response may allow a better selection of patients who will benefit from this line of therapy and, more importantly, may spare the patient the toxicity of a potentially ineffective treatment.

Several studies have been conducted with the aim to identify predictive factors of pCR after PC. Despite the lack of a global consensus, the predictive value of hormone receptor (HR) status, tumor grade, and tumor cell proliferation has been established. Poorly differentiated tumors with a high proliferation rate and without expression of HR are more chemosensitive and are associated with a higher percentage of pCR.^6-13 On the contrary, well-differentiated tumors with a low proliferation rate and with expression of HR are less likely to achieve a pCR after PC. However, this relative chemoresistance does not automatically translate into a worse outcome. Ring et al¹³ from the Royal Marsden Hospital have recently reported interesting data showing that, in patients with HR-positive tumors, the achievement of pCR does not correlate with a better outcome compared with not achieving a pCR. Unfortunately, there were few HR-positive patients in the study who achieved a pCR, precluding a definitive conclusion.

To determine whether the association of pCR with overall survival (OS) or progression-free survival (PFS) differed by estrogen receptor (ER) or progesterone receptor (PR) status, we performed a retrospective analysis on patients treated with PC at The University of Texas M.D. Anderson Cancer Center (MDACC; Houston, TX).

	PATIENTS AND METHODS

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Patient Selection
The Department of Breast Medical Oncology database was searched to identify patients with primary invasive noninflammatory breast cancer treated with PC; 1,910 patients were identified. Patients with metastatic disease or inflammatory breast cancer at diagnosis, male patients, and patients not assessable for response in both breast and axilla were excluded, leaving 1,731 patients treated between 1988 and 2005.

The MDACC Institutional Review Board approved the individual clinical trials, and all participants had provided written informed consent before enrollment. Furthermore, for patients treated with PC outside a clinical trial, the Institutional Review Board approved the retrospective review of the medical records for this analysis. Patient characteristics, including clinical stage, menopausal status, ER and PR status, histologic grade, Her2/neu status, type of chemotherapy, type of surgery, and pathologic response in breast and axilla, were recorded.

Pathology
Breast cancer diagnosis was made by needle biopsy of the breast tumor. Dedicated breast pathologists at MDACC reviewed all pathologic specimens. The histologic type of all tumors was defined according to the WHO classification system.¹⁴ The histologic grade was defined according to the modified Black's nuclear grading system.¹⁵ Immunohistochemical analysis to determine ER and PR status was performed using standard procedures on 4-µm sections of paraffin-embedded tissues stained with the following monoclonal antibodies: 6F11 (Novacastra Laboratories Ltd, Burlingame, CA) for ER and 1A6 (Novacastra Laboratories Ltd) for PR. Nuclear staining 10% was considered a positive result. Before 1993, the dextran-coated charcoal ligand-binding method was used to determine ER and PR. HR concentration 10 fmol/mg protein was considered positive. Patients were considered HR positive in case of ER and/or PR positivity.

Her2/neu status was evaluated by immunohistochemistry or by fluorescence in situ hybridization in breast cancer tissue obtained before initiation of PC. Her2/neu-positive tumors were defined as 3+ receptor overexpression on immunohistochemistry staining and/or gene amplification found on fluorescence in situ hybridization testing.

Treatment
In general, 91% of patients received anthracycline-based chemotherapy, and 66% received an additional taxane. Five-hundred seventy-seven patients (33%) received three to six courses of one of the following anthracycline-based chemotherapy regimens: fluorouracil 500 mg/m² intravenously (IV) on days 1 and 4, doxorubicin 50 mg/m² IV continuous infusion over 72 hours, and cyclophosphamide 500 mg/m² IV on day 1, every 3 weeks; doxorubicin 60 mg/m² IV and cyclophosphamide 600 mg/m² IV on day 1, every 3 weeks (AC); or fluorouracil 500 mg/m² IV, epirubicin 100 mg/m² IV, and cyclophosphamide 500 mg/m² IV on day 1, every 3 weeks. One hundred forty-five patients (8%) received single-agent taxane for 3 months (paclitaxel or docetaxel). Nine hundred ninety-eight patients (58%) received taxane-anthracycline combinations for 4 to 6 months. At the completion of the PC, patients underwent definitive surgery. Eligibility for BCS was determined by multidisciplinary evaluation. The approach to BCS after PC has been previously described.¹⁶ Patients who were not candidates for BCS or did not wish to undergo BCS underwent a mastectomy. All patients included in this analysis received axillary node dissection (1,479 patients, 85%) or sentinel node biopsy (239 patients, 14%). Radiation therapy was included in the treatment plan in the following cases: conservating surgery, locally advanced disease, primary tumor measurement before chemotherapy more than 5 cm, and four or more involved axillary nodes after PC.

Adjuvant hormonal therapy was administered according to the standard practice; until 1997, adjuvant tamoxifen was administered only to patients more than 50 years of age, regardless of HR status. Among patients with HR-positive tumors, 723 (62%) received adjuvant tamoxifen, and 184 (16%) received an aromatase inhibitor. Among HR-negative patients, 22 received adjuvant tamoxifen because they were 50 years of age or older at the time of diagnosis or for chemoprevention.

Assessment of Response
pCR was defined as complete disappearance of invasive carcinoma in both breast and axillary lymph nodes. Residual ductal carcinoma-in-situ was included in the pCR category. Twelve patients who did not have surgery because of progression of disease were considered not to have had a pCR.

Statistical Analysis
Patient characteristics were tabulated or described by their median and range overall, by pCR group, and by HR group. A ² test, t test, or Wilcoxon rank sum test was used as appropriate to determine associations between patient characteristics and pCR group or HR group. Median follow-up time was calculated as the median observation time among all patients. OS was measured from the date of response assessment after PC to the date of death or last follow-up. Typically, the date of response assessment was the date of surgery after PC. However, 18 patients had progressive disease, and 12 of these patients did not receive surgery. For these patients, the date of response assessment is the date when progressive disease was determined. PFS was measured from the date of response assessment after PC to the date of first local or distant metastasis or last follow-up. Patients who died before experiencing progression of disease were considered censored for PFS. Survival distributions were estimated with the Kaplan-Meier method, and the log-rank statistic was used to test for differences between groups. Cox proportional hazards models were fit with the intention of testing for an interaction between pCR and HR status. All variables identified a priori as being associated with prognosis as well as all variables found to be related to pCR group or HR group were entered into the model. Significance of each variable was assessed by both the Wald test and the likelihood ratio test. All pair-wise interactions were tested. The proportional hazards assumption and the fit of the model were assessed visually with residual plots.

	RESULTS

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Patients and Response
Table 1 lists patient characteristics overall and by pCR group. Table 2 lists patient characteristics by HR status and, within the HR-positive group, by pCR group. Among all patients, the median age at diagnosis was 49 years. Sixty-six percent of patients received taxane chemotherapy. BCS was performed in 34% of this patient population. Sixty-seven percent of patients were HR positive, 64% had nuclear grade 3 disease, and Her2/neu was positive in 322 (23%) of the 1,379 patients for whom it was determined.

Reflecting the evolving classification of breast cancer, patients were also categorized into the following four groups: HR-positive/Her2/neu-positive (183 patients), HR-positive/Her2/neu-negative (733 patients), HR-negative/Her2/neu-positive (138 patients), and HR-negative/Her2/neu-negative (317 patients); pCR rates for these groups were 15.3%, 6%, 29%, and 22.4%, respectively (P < .0001).

PFS
Table 3 lists estimates of PFS among all patients, by pCR group, and by HR group. This analysis includes 1,730 patients because the response assessment date for one patient was unknown. Median PFS time for the entire patient population was 107 months. PFS was significantly better among patients who achieved a pCR compared with patients who did not achieve a pCR (P < .0001).

Within the HR-negative subgroup, patients who achieved a pCR had significantly better PFS compared with patients who did not achieve a pCR (P < .0001) Similarly, within the subgroup of patients with HR-positive tumors, patients who achieved a pCR had significantly better PFS compared with patients who did not achieve a pCR (P = .002; Fig 1). This difference still existed even when HR-positive patients not treated with adjuvant endocrine therapy were excluded (data not shown).

View larger version (11K): [in this window] [in a new window]   Fig 1. Kaplan-Meier plot of progression-free survival by pathologic complete response (pCR) group (estrogen receptor/progesterone receptor–positive patients).

OS
Table 4 lists the Kaplan-Meier estimates of OS among all patients, by pCR group, and by HR group. Median OS time was 118 months. OS was significantly better among patients who achieved a pCR (P = .002).

Grouping patients by both HR and Her2/neu status, the 5-year OS rates were as follows: HR-positive/Her2/neu-positive, 83.4%; HR- positive/Her2/neu-negative, 85.5%; HR-negative/Her2/neu-positive, 64.8%; and HR-negative/Her2/neu-negative, 64.2% (P < .0001). In HR-negative patients, OS was significantly better for patients who achieved a pCR compared with patients who did not achieve a pCR (P = .003). In HR-positive patients, patients who achieved a pCR had significantly better OS compared with patients who did not achieve a pCR (P = .04; Fig 2). When the analysis was restricted to patients who received adjuvant hormonal therapy, the advantage in OS for patients with pCR compared with patients with no pCR was still present (5-year OS rate, 95.6% v 87.7%, respectively) but not statistically significant (P = .28) probably because of the limited sample size and the lower number of events.

View larger version (11K): [in this window] [in a new window]   Fig 2. Kaplan-Meier plot of overall survival by pathologic complete response (pCR) group (estrogen receptor/progesterone receptor–positive patients).

	DISCUSSION

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However, several aspects deserve further investigation. Recently presented data of National Surgical Adjuvant Breast and Bowel Project B27 showed that, despite an increased pCR rate for the sequential AC-docetaxel (AC-D) arm versus AC alone, there was, as yet, no survival advantage.²⁴ In the same study, a favorable prognosis of patients who achieved a pCR, irrespectively of the regimen used, was confirmed. The relatively small percentage of patients who achieved a pCR (12.8% to 14.3% for AC v 26.1% for AC-D), the concomitant administration of tamoxifen, and the limited number of events might have contributed to obscure the superiority of AC-D.

Another aspect that requires further studies is the apparently paradoxical observation that the tumor features commonly associated with a more favorable prognosis, such as differentiation, low proliferation rate, and expression of HRs, are unfavorable predictors of response to PC. In particular, HR status seems to be predictive of relative chemoresistance; multiple trials have shown that the probability of achieving a pCR is significantly inferior in tumors expressing HR.^6-13 However, because of the limited numbers of HR-positive patients achieving a pCR, the majority of published studies do not report whether the achievement of pCR maintains its prognostic value in these patients too. Moreover, the rescue effect of postoperative hormonal treatment might outweigh the benefit of a pCR achieved with chemotherapy in these endocrine-responsive patients.

The primary aim of our retrospective analysis was to evaluate whether the expression of HR could affect the prognostic value of pCR. The only study that, to our knowledge, has evaluated the prognostic value of pCR according to HR status reported that pCR has no prognostic significance in patients with ER-positive tumors.¹³ In contrast to their findings, in our patient population, both PFS and OS were significantly better for HR-positive patients who achieved a pCR compared with patients with less than a pCR. The criteria to define pCR were the same for both of these analyses, as was the cutoff to define ER positivity. Although PR status was taken into account in our study, it was not in the report from Ring et al.¹³ Other major difference between these two studies is the sample size; we report data from 1,731 patients with 225 pCRs, 91 of which were in HR-positive patients, whereas Ring et al¹³ recorded data from 435 patients with 52 pCRs, 22 of which were in ER-positive patients. In our analysis, we also included patients with inoperable disease, who were excluded by Ring et al.¹³ Furthermore, although patients achieving a pCR in our study and the Ring et al¹³ study experienced similar 5-year PFS and OS (5-year PFS rate: 87% v 75%, respectively; 5-year OS rate: 91% v 91%, respectively), this is less true in the subgroup of pCRs obtained in HR-positive patients (5-year PFS rate: 91% v 73%, respectively; 5-year OS rate: 96% v 79%, respectively). Differences in postoperative treatments and patient characteristics or chance alone might account for this discrepancy. As previously reported, the probability to achieve a pCR is higher in patients with lower clinical stages, high nuclear grade, and HR negativity, and, as expected, both PFS and OS were significantly higher for patients achieving a pCR compared with patients with less than pCR.

In conclusion, in this analysis conducted in more than 1,700 patients, the prognostic value of pCR was confirmed; after adjustment for other prognostic factors, patients who achieved a pCR had 0.41 times the risk of relapse and 0.36 times the risk of death compared with patients who did not achieve a pCR. This analysis confirms that the receptor status is associated with the probability of achieving a pCR with chemotherapy and demonstrates that the achievement of pCR is associated with better outcome irrespective of HR status. Further studies are warranted to determine the prognostic importance of pCR obtained with other treatment modalities such as endocrine agents for HR positivity or trastuzumab for Her2/neu-positive patients.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Valentina Guarneri, Massimo Cristofanilli, Gabriel N. Hortobagyi, Ana M. Gonzalez-Angulo Administrative support: Gabriel N. Hortobagyi Provision of study materials or patients: Shu-Wan Kau, Massimo Cristofanilli, Aman U. Buzdar, Vicente Valero, Funda Meric, Lavinia Middleton, Gabriel N. Hortobagyi Collection and assembly of data: Valentina Guarneri, Shu-Wan Kau Data analysis and interpretation: Kristine Broglio, Thomas Buchholz, Gabriel N. Hortobagyi, Ana M. Gonzalez-Angulo Manuscript writing: Valentina Guarneri, Massimo Cristofanilli, Thomas Buchholz, Gabriel N. Hortobagyi, Ana M. Gonzalez-Angulo Final approval of manuscript: Valentina Guarneri, Kristine Broglio, Shu-Wan Kau, Massimo Cristofanilli, Aman U. Buzdar, Vicente Valero, Thomas Buchholz, Funda Meric, Lavinia Middleton, Gabriel N. Hortobagyi, Ana M. Gonzalez-Angulo

 

	NOTES

 
Supported by the Nellie B. Connally Breast Cancer Research Fund and the Fondazione Komen Italia.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted May 23, 2005; accepted December 14, 2005.

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