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Breast Cancer

Prognostic Value of Initial Clinical Disease Stage After Achieving Pathological Complete Response

Departments of ^aBreast Medical Oncology, ^bQuantitative Sciences, ^cPathology, ^dRadiation Oncology, and ^eSurgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA; ^fDepartment of Medical Oncology, Dubai Hospital, Dubai, United Arab Emirates

Key Words. Breast cancer • Pathological complete response • Prognosis • Clinical stage

Correspondence: Ana M. Gonzalez-Angulo, M.D., Department of Breast Medical Oncology, Unit 1354, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030-4009, USA. Telephone: 713-792-2817; Fax: 713-794-4385; e-mail: agonzalez{at}mdanderson.org

Received June 21, 2007; accepted for publication November 12, 2007.

Disclosure: No potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.

	Learning Objectives

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After completing this course, the reader will be able to:

1. Define survival outcomes in women with early-stage breast cancer who achieve pathological complete response following primary systemic chemotherapy.
   
2. Define the prognostic value of initial clinical stage in women with breast cancer who achieve pathological complete response following primary systemic chemotherapy.
   
3. Define survival outcomes in women with inflammatory breast cancer who achieve pathological complete response following primary systemic chemotherapy.
   

	ABSTRACT

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The aim of this retrospective study was to determine the prognostic impact of initial clinical stage in patients who achieved a pathological complete response (pCR) after receiving primary systemic chemotherapy (PST). Between 1977 and 2006, 489 patients who had achieved a pCR after receiving an anthracycline-based PST regimen were identified. Recurrence-free survival (RFS) and overall survival (OS) were estimated with the Kaplan–Meier product limit method and the differences between groups were compared using the log-rank statistic. Cox proportional hazards models were fit to determine the association of initial clinical stage with survival outcomes after adjusting for patient and tumor characteristics. The median age was 47 years. Twenty (4.1%) patients had stage I disease, 243 (49.7%) had stage II disease, 189 (38.7%) had stage III disease, and 37 (7.5%) had inflammatory breast cancer (IBC). At a median follow-up of 45 months, 59 (12%) patients had experienced disease recurrence. The 5-year RFS and OS rates for the whole cohort were 87.8% and 89.3%, respectively. Lower clinical stage at diagnosis was associated with statistically significant higher RFS and OS rates. In a multivariate model, patients with clinical stage IIIB/C disease and those with IBC had lower RFS rates than patients with clinical stage I/II/IIIA disease. In addition, patients with clinical stage IIIB/C disease and those with IBC had a greater hazard of death than patients with clinical stage I/II/IIIA disease. Overall, patients who achieved a pCR had a low rate of recurrence. However, higher clinical stage and IBC were associated with worse outcomes in breast cancer patients who achieved a pCR after PST.

	INTRODUCTION

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It is estimated that 180,510 new cases of breast cancer will have been diagnosed in the year 2007, with approximately 40,910 women expected to die from this disease [1]. With the introduction of anthracycline-based polychemotherapy regimens, 5-year survival rates have significantly improved for patients with early-stage breast cancer [2]. With the introduction of trastuzumab, a monoclonal antibody targeting the human epidermal growth factor receptor (HER)-2/neu receptor, further improvements in survival have been observed among patients with HER-2/neu–positive disease [3, 4]. Further improvements in survival will depend on methods targeted at individualizing therapy in order to attain maximum therapeutic efficacy.

Primary systemic chemotherapy (PST), a standard approach to treating women with locally advanced and inflammatory breast cancer, is increasingly being used in patients with earlier stage disease. It is associated with a number of advantages, including downstaging of tumors, thereby improving available surgical options and allowing for in vivo assessment of chemosensitivity and thus providing the option to modify chemotherapeutic regimens when necessary. Furthermore, attaining a pathological complete response (pCR) following PST has been shown by a number of investigators [5–9] to be a surrogate marker for superior long-term outcome, thought to result from the eradication of distant mircometastatic invasive residual disease. Taking this phenomenon one step forward, a number of studies have focused on developing regimens to improve the rates of pCR, such as with the addition of taxanes [6] and trastuzumab [10]. In addition, several groups are currently using pCR as a surrogate marker for survival in the design of clinical trials.

Investigators have focused on identifying pathological [11] and clinical [12] factors to predict long-term outcomes in patients with residual disease following PST. In an earlier report based exclusively on patients who achieved a pCR after PST, we showed that premenopausal women with stage IIIB disease who had <10 lymph nodes removed for pathological examination had a higher risk for distant recurrence [13]. The aim of the current retrospective study was to confirm, using an updated and larger cohort, our initial findings, and to primarily determine the prognostic impact of initial clinical stage in patients who achieve a pCR.

	METHODS

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Patient Population
We searched a database maintained at the Breast Medical Oncology Department of The University of Texas M. D. Anderson Cancer Center (MDACC) to retrospectively identify patients with histologically confirmed invasive breast cancer who had received PST and achieved a pCR. Medical charts for all patients were reviewed to confirm the accuracy of clinical variables recorded within the database. All patients had to have received an anthracycline-based chemotherapy regimen either pre- or postoperatively. Exclusion criteria included patients who were male, had stage IV disease, did not receive anthracycline-based chemotherapy, had bilateral disease, or did not undergo definitive surgery. Variables recorded included patient demographics, tumor characteristics, initial clinical stage, administration of taxanes, surgical details, and recurrence information. This retrospective study was approved by the institutional review board of the MDACC.

Staging and Pathology Review
Clinical stage at diagnosis was based on the staging criteria proposed by the American Joint Committee on Cancer (Sixth Edition) in 2003 [14]. Initial biopsy specimens of all patients were used to confirm invasive carcinoma, categorize histological type according to the World Health Organization classification system [15], and define histological grade according to the modified Black's nuclear grading system [16]. pCR was defined as the complete absence of invasive disease in both the breast and axillary lymph nodes. Operative specimens were reviewed to confirm the absence of invasive disease and to record the presence or absence of residual ductal carcinoma in situ (DCIS). Receptor studies were performed on pretreatment needle biopsy samples. Specimens obtained before 1993 were assessed for hormone receptors (HRs) by the dextran-coated charcoal ligand-binding method to determine estrogen receptor (ER) and progesterone receptor (PgR) status. Thereafter, receptor status was determined using immunohistochemistry (IHC) on 4-µm paraffin-embedded tissue sections stained with the following monoclonal antibodies: (a) 6F11 (Novacastra Laboratories Ltd., Burlingame, CA) for ERs and (b) 1A6 (Novacastra Laboratories Ltd.) for PgRs. HER-2/neu status was determined, using initial biopsy specimens, by IHC analysis and/or fluorescence in situ hybridization (FISH). A patient whose tumor stained 3+ by IHC or was gene amplified by FISH was considered to have a HER-2/neu–positive tumor. Patients with HER-2/neu–negative tumors had no demonstrable staining by IHC and/or no gene amplification by FISH.

Statistical Analysis and Outcome Measures
Patient characteristics were tabulated by stage and compared across stage groups with ², Fisher's exact, or Kruskal-Wallis tests as appropriate. Recurrence-free survival (RFS) was calculated from the date of surgery to the date of local or distant disease recurrence or the date of last follow-up. Patients who died before experiencing disease recurrence were considered censored at their date of death for the analysis of RFS. Overall survival (OS) was calculated from the date of surgery to the date of death from any cause or last follow-up. The median follow-up time was calculated as the median observation time among all patients and among patients still alive at their last follow-up. Survival outcomes were estimated with the Kaplan–Meier product limit method and compared between groups with the log-rank statistic. Cox proportional hazard models were fit to determine the association between initial clinical stage and survival outcomes after adjustment for potential confounding patient and tumor characteristics. In the model, clinical stage was considered as three separate groups: (a) stage I/II/IIIA (operable), (b) stage IIIB/C (nonoperable), and (c) inflammatory. Inflammatory breast carcinoma was considered separately because of its known inherently aggressive biology and poor prognostic outcome. Terms of HR status (ER/PgR positive versus negative), nuclear grade, and menopausal status were included in the model regardless of statistical significance because of their clinical significance. Other variables were considered for inclusion in the model if statistical significance was attained by either the Wald test or the likelihood ratio test (LRT). Analyses were performed with SAS 9.1 (SAS Institute, Inc., Cary, NC) and S-Plus 7.0 (Insightful Corp., Seattle, WA). p-values < .05 were considered statistically significant.

	RESULTS

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Patient Characteristics
Between 1977 and 2006, 489 patients in total who fit the eligibility criteria were identified and included in the analysis. One hundred seventy-two (35.2%) patients were diagnosed before 2000, 227 (46.4%) patients were diagnosed between 2000 and 2004, and 90 (18.4%) patients were diagnosed between 2005 and 2006. Patient characteristics crosstabulated by initial clinical stage are summarized in Table 1. All patients received an anthracycline-based chemotherapy regimen, of whom 476 (97.3%) received anthracylines preoperatively and 13 (2.7%) received anthracylines in the postoperative period. Anthracyline-based chemotherapy was administered using one of the following regimens: (a) FEC (500 mg/m² 5-fluorouracil, 100 mg/m² epirubicin, 500 mg/m² cyclophosphamide); (b) FAC (500 mg/m² 5-fluorouracil on days 1 and 4, 50 mg/m² doxorubicin i.v. by continuous infusion over 72 hours on days 1–3, 500 mg/m² cyclophosphamide on day 1); (c) AC (60 mg/m² doxorubicin, 600 mg/m² cyclophosphamide); (d) VACP (500 mg/m² 5-fluorouracil i.v. on day 1, 50 mg/m² doxorubicin i.v. by continuous infusion over 72 hours on days 1–3, 500 mg/m² cyclophosphamide i.v. on day 1, 1 mg/m² vincristine i.v. on day 1, 100 mg/m² prednisone orally on days 1 to 5). Three hundred twenty-seven (67%) patients received taxanes (paclitaxel or docetaxel) in either the pre- or postoperative period. Two hundred ninety-six (60.5%) patients received all chemotherapy preoperatively and 193 (39.5%) patients received part of their chemotherapy regimen in the preoperative period and part in the postoperative period. Sixty (12%) patients had trastuzumab as part of their PST. Twenty (4.1%) patients had stage I disease, 243 (49.7%) had stage II disease, 86 (17.6%) had stage IIIA disease, 60 (12.3%) had stage IIIB disease, 43 (8.8%) had stage IIIC disease, and 37 (7.5%) had inflammatory breast cancer. The median age for the whole cohort was 47 years (range, 21–81 years). The predominant histological subtype was infiltrating ductal carcinoma (96%). Seventy-seven percent and 85% of patients had a negative ER assay and grade III disease, respectively. Information on HER-2/neu status was available for 318 (65%) patients, of whom almost half (44%) had tumors that were HER-2/neu positive, which tended to occur more frequently in patients with higher stage disease. Fifty-four percent of patients underwent a mastectomy, while 46% of patients had breast-conserving surgery. Four hundred one (82%) patients had an axillary lymph node dissection, 84 (17%) patients had a sentinel lymph node biopsy, and four (1%) refused axillary lymph node sampling. The median number of lymph nodes removed was 13 (range, 0–39). Postsurgery, 23% (n = 114) of breast specimens had evidence of residual DCIS.

View larger version (17K): [in this window] [in a new window]   Figure 1. Overall (A) and recurrence-free (B) Survival curves according to initial clinical stage.

	DISCUSSION

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As shown in the recently updated results from the Early Breast Cancer Trialists' Collaborative Group [2], adjuvant anthracycline-based polychemotherapy has substantially decreased the risk for recurrence and death, presumably by eradicating distant micrometastatic disease. The recent addition of trastuzumab to adjuvant regimens for patients with HER-2/neu–positive tumors has substantially decreased the risk for recurrence and subsequently improved OS in this cohort [3, 4]. Despite these major advances, a substantial portion of patients will recur, a fact that impacts survival outcomes. Traditional factors predicting for recurrence have included node-positive disease, higher T stage, high nuclear grade, ER-negative disease, and HER-2/neu–positive disease [17]. Recurrences are presumably attributed to the inability to assess which patients are resistant to treatment when administered in the adjuvant setting. Hypothetically, the ability to achieve a pCR, indicating high tumor chemosensitivity, would also indicate eradication of all distant invasive micrometastatic disease, with resulting low recurrence rates. Our study demonstrates this phenomenon to be true, with low recurrence rates seen in the whole cohort. However, recurrence rates showed a progressively increasing trend from 6% to 13% to 46% in patients with stage I/II disease, stage III disease, and inflammatory breast cancer, respectively, which in turn had an impact on survival outcomes. This highlights the fact that initial clinical stage still plays an important prognostic role in this cohort, and that achieving a pCR does not in all instances predict for eradication of micrometastatic disease. One could hypothesize that with advancing stage of disease, the incidence of micrometastatic clones resistant to conventional chemotherapeutic agents would be higher. It could then be further deduced that using additional cytotoxic agents with noncrossresistant properties would be advantageous in this cohort. Interestingly, HR status and HER-2/neu status, both known to be important prognostic and predictive factors, did not predict for survival outcomes once pCR was achieved. Although these results need to be confirmed in a larger prospective cohort, they are hypothesis generating, indicating that, perhaps, in the setting of patients achieving a pCR, these two variables have more of a predictive role rather than a prognostic one. This theory is supported by the results of the retrospective study by Guarneri and colleagues who showed that patients who attained a pCR had a better overall outcome than patients who had residual disease after PST regardless of their HR status [18]. It should be noted that, in our cohort of patients, 12% received trastuzumab as part of their PST. Because of the small number of patients involved, there was not sufficient power to detect any differences in survival that may have been contributed by trastuzumab. Conversely, because there was an even distribution of trastuzumab administration among patients with stage I, II, and III disease whose tumors over expressed HER-2/neu, no survival differences could be detected.

Inflammatory breast cancer is a rare and aggressive form of locally advanced breast cancer. Before the integration of a multidisciplinary approach into the management schema, inflammatory breast cancer used to be a uniformly fatal disease, with <5% of patients surviving past 5 years [19]. Ueno and colleagues [20] reported on the MDACC experience of inflammatory breast cancer over a 20-year period with a cohort of 178 patients who had received doxorubicin-based PST, of whom 12% had achieved a complete response. In that study, the disease-free survival rate at 15 years was 44% for patients who achieved a complete response to PST, 31% for those who achieved a partial response, and 7% for those who did not respond to PST, thereby highlighting the importance of achieving a complete response even in this very aggressive subset of breast cancer. To our knowledge, we report on the largest cohort of patients with inflammatory breast cancer who have achieved a pCR (n = 37), demonstrating higher 10-year RFS and OS rates of 50.8% (95% CI, 35.7%–72.2%) and 64.7% (95% CI, 48.4%–86.4%), respectively (data not shown). Despite these impressive results in our cohort, 46% of those with inflammatory breast cancer relapsed. With recent studies indicating that the addition of trastuzumab to adjuvant chemotherapy regimens improves disease-free survival and OS [3, 4] in patients whose tumors overexpress HER-2/neu, and the known higher incidence of HER-2/neu [21] in patients with IBC, incorporation of trastuzumab in this setting may translate into better outcomes.

A factor limiting the comparison of pCR rates across different studies is the varied definition of pCR used. In an attempt to standardize the definition, the International Expert Panel on the Use of Neoadjuvant Systemic Treatment has defined pCR as the absence of all evidence of residual disease, including in situ disease, in either the breast or axillary lymph nodes [22]. Interestingly, results from an earlier study conducted at the MDACC [23] retrospectively looking at >2,000 patients who had received PST found that the presence of only residual DCIS did not affect survival outcomes. Our results confirm these findings and indicate that our definition of pCR that incorporates only the absence of invasive disease may be sufficient. However, these results need to be validated in a larger prospective cohort with longer term follow-up. Furthermore, because the definition of pCR also relies on the exclusion of residual cancer, the accuracy and extent of pathologic sampling are critical. Several recent advances in clinical practice are expected to improve the accuracy of this histopathologic definition by directing pathologists to sites of possible residual disease. These include the communication of disease site and treatment history through electronic medical records, placement of metallic indicators in the tumor bed, targeted surgical procedures (segmental mastectomy, sentinel lymph node biopsy), specimen photography and/or radiography, increased pathologist experience with post-treatment specimens, and more detailed histopathologic sampling protocols [24].

In conclusion, although achieving a pCR improves long-term outcomes overall, resulting in a low event rate, initial clinical stage still plays an important prognostic role, with patients with a higher clinical stage at a greater risk for recurrence. Whether or not patients with a higher clinical stage who achieve a pCR would benefit from additional adjuvant systemic therapy is an important research question for future clinical trials.

	ACKNOWLEDGMENTS

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This work was supported in part by the Susan G. Komen Foundation, the Nellie B. Connally Fund for Breast Cancer Research, and the Inflammatory Breast Cancer Research Group. A.M.G.-A. is supported by K23CA121994-01 and ASCO Career Development Award. G.N.H. is supported by DAMD17-02-1-0694 01, 2P30 CA016672 28(PP-4), and P50 CA116199-01.

	FOOTNOTES

 
Conception/design: Shaheenah Dawood, Ana M. Gonzalez-Angulo

Provision of study materials or patients: Shaheenah Dawood, Shu-Wan Kau, Ana M. Gonzalez-Angulo

Collection/assembly of data: Shaheenah Dawood, Shu-Wan Kau, Rabiul Islam, Sean E. McGuire, Ana M. Gonzalez-Angulo

Data analysis and interpretation: Shaheenah Dawood, Kristine Broglio, Ana M. Gonzalez-Angulo

Manuscript writing: Shaheenah Dawood, W. Fraser Symmans, Thomas A. Buchholz, Sean E. McGuire, Funda Meric-Bernstam, Massimo Cristofanilli, Gabriel N. Hortobágyi, Ana M. Gonzalez-Angulo

Final approval of manuscript: Rabiul Islam, W. Fraser Symmans, Thomas A. Buchholz, Sean E. McGuire, Funda Meric-Bernstam, Massimo Cristofanilli, Gabriel N. Hortobágyi, Ana M. Gonzalez-Angulo

	REFERENCES

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