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Glutathione-S-transferase-pi (GST-pi) is a detoxification enzyme expressed in breast cancer; however its involvement in chemotherapy sensitivity and prognosis is not well understood. We evaluated the expression of GSTpi and its predictive role of chemotherapy response. Breast tumor samples from 166 patients at stage I/II of the disease were immunostained for GST-pi, and the expression was 96 %. There was a trend toward improved disease-free survival with high GST-pi expression (p =.09). There was a statistically non-significant association between high GST-pi expression and improved outcome with adjuvant chemotherapy (p =.055). Further studies should evaluate the role of GST-pi expression in relation to response to different chemotherapies.

There is limited prognostic information to identify breast cancer patients who are at risk for late recurrences after adjuvant or neoadjuvant systemic therapy (AST). We evaluated the residual risk of recurrence and prognostic factors of 2838 patients with stage I–III breast cancer who were treated with AST between January 1, 1985, and November 1, 2001, and remained disease free for 5 years. Residual recurrence-free survival was estimated from the landmark of 5 years after AST to date of first recurrence or last follow-up using the Kaplan–Meier method. The log-rank test (two-sided) was used to compare groups. Residual recurrence-free survival rates at 5 and 10 years were 89% and 80%, respectively, and 216 patients developed a recurrence event. The 5-year residual risks of recurrence for patients with stage I, II, and III cancers were 7% (95% confidence interval [CI] = 3% to 15%), 11% (95% CI = 9% to 13%), and 13% (95% CI = 10% to 17%), respectively (P = .02). In multivariable analysis, stage, grade, hormone receptor status, and endocrine therapy were associated with late recurrences. Breast cancer patients have a substantial residual risk of recurrence, and selected tumor characteristics are associated with late recurrences.

Learning Objectives After completing this course, the reader will be able to: Define survival outcomes in women with early-stage breast cancer who achieve pathological complete response following primary systemic chemotherapy.Define the prognostic value of initial clinical stage in women with breast cancer who achieve pathological complete response following primary systemic chemotherapy.Define survival outcomes in women with inflammatory breast cancer who achieve pathological complete response following primary systemic chemotherapy. CME Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at CME.TheOncologist.com 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.

We examined the correlation between HER2 expression and pathologic complete response (pCR) to paclitaxel/FAC (T/FAC) preoperative chemotherapy in breast cancer. Retrospective analysis of data including 534 patients treated with preoperative T/FAC was performed. Gene expression results were available from two datasets of 132 and 286 patients, and were used to examine the co-expression of HER2 and topoisomerase II α (TOP2A) and microtubule associated protein tau (MAP-Tau). Of the 534 patients, 105 (20%) had HER2-overexpressing breast cancer. The pCR rates were 33% and 15% for patients with HER2+ and HER2- tumors (P

The detection of circulating tumor cells (CTCs) predicts overall survival in patients with metastatic breast cancer (MBC). However, it is unknown whether CTCs have superior value compared with other standard prognostic factors. We compared the prognostic significance of CTCs with clinical and laboratory measures of tumor burden and phenotypic subtype of disease.One hundred fifty-one patients with MBC evaluated between 2000 and 2006 were included in this retrospective analysis. Circulating tumor cells were isolated and enumerated in whole blood using an immunomagnetic bead system (CellSearch System). Overall survival was evaluated according to the level of CTCs (negative:5 CTCs per 7.5 mL of blood; positive:or=5 CTCs per 7.5 mL of blood), Swenerton score, cancer antigen 27-29 level, age (50 years vs.or=50 years), hormone-receptor status and HER2 status, metastatic site, and type and line of therapy.The median age of patients was 53 years (range, 24-88 years), and 44% of the patients had5 CTCs. The median overall survival for negative versus positive CTCs were 29.3 months and 13.5 months, respectively (P0.0001). In the multivariable Cox model, the detection ofor=5 CTCs demonstrated the highest hazard ratio with 2.2 times the risk of death (P=0.003). The prognostic value was independent of measure of tumor burden and type and line of therapy, and phenotypic subtype of the disease.Circulating tumor cells have superior and independent prognostic value of tumor burden and disease phenotype and might represent an important marker of tumor biology in MBC. Detection of CTCs should be considered for new staging stratification of patients with MBC.

BACKGROUND. A previously published prospective randomized phase 3 trial showed that administration of 24 weeks of primary systemic chemotherapy (PST) with paclitaxel and FEC75 (fluorouracil, epirubicin, cyclophosphamide) concurrently with trastuzumab in patients with HER2-positive primary breast cancer resulted in a 60% pathologic complete response rate (PCR) with no associated severe cardiac toxicity. The purpose of this study was to review the efficacy and safety of a similar regimen outside the setting of a clinical trial. METHODS. Patients with HER2-positive breast cancer (defined as either immunohistochemical 3+ or fluorescence in situ hybridization-positive) that had received 24 weeks of neoadjuvant trastuzumab concurrently with taxane and anthracycline-based chemotherapy between 2004 and 2006 were included in the analysis. PST chemotherapy consisted of paclitaxel (80 mg/m2) weekly for 12 weeks followed by 4 cycles of FEC75 (500 mg/m2, 75 mg/m2, and 500 mg/m2, respectively). RESULTS. Forty patients were identified. The median age was 48 years (range, 29–81). In all, 60% of patients had stage III disease and 4 had inflammatory breast cancer. The PCR rate was 55% (95% confidence interval [CI], 38.5%–70.7%). At a median follow-up of 19 months. 5 patients had a recurrence, of which 4 did not achieve a PCR. No severe cardiac events were observed. CONCLUSIONS. Stage II and III HER2-positive breast cancer patients achieved a high rate of PCR with trastuzumab given concurrently with paclitaxel and FEC75 chemotherapy. No severe cardiac events were observed with the regimen. The data concur with the results of a previously published trial. Cancer 2007. © 2007 American Cancer Society.

To determine the influence of race on breast cancer treatment and on recurrence and breast cancer specific death.The study population consisted of 6,054 African-American or white women who were diagnosed with breast cancer and received at least one of the treatments including mastectomy or breast conservative surgery, radiation, adjuvant chemotherapy, neo-adjuvant chemotherapy, and adjuvant endocrine therapy at M.D. Anderson Cancer Center between June 1997 and February 2005. The clinical outcomes were disease-free survival and breast-cancer-specific survival. Logistic regression analysis was performed to investigate if race was associated with the selection of each primary treatment while adjusting for tumor characteristics at diagnosis. Cox proportional hazards model was used to determine the effect of race on recurrence-free survival and breast-cancer-specific survival controlling for tumor characteristics, presence of co-morbidity conditions and use of these treatments.The use of any primary treatment for breast cancer was not significantly different by race after adjusting for tumor characteristics and co-morbidity conditions. Although tumor characteristics at diagnosis explained the major differences in clinical outcomes, race remained an independent prognostic factor for breast-cancer-specific survival (P=0.002), and a marginally significant factor for disease-free survival (P=0.063) in multivariate analyses.Equal treatment may not lead to equal clinical outcomes given similar tumor characteristics at diagnosis. To reduce racial differences in breast cancer recurrence and survival, it is important to have a better understanding of differences in tumor biology by race and to promote the use of early detection programs among African-American women.

Purpose To identify clinicopathological factors predictive of distant metastasis in patients who had a pathologic complete response (pCR) after neoadjuvant chemotherapy (NC). Methods Retrospective review of 226 patients at our institution identified as having a pCR was performed. Clinical stage at diagnosis was I (2%), II (36%), IIIA (27%), IIIB (23%), and IIIC (12%). Eleven percent of all patients were inflammatory breast cancers (IBC). Ninety-five percent received anthracycline-based chemotherapy; 42% also received taxane-based therapy. The relationship of distant metastasis with clinicopathologic factors was evaluated, and Cox regression analysis was performed to identify independent predictors of development of distant metastasis. Results Median follow-up was 63 months. There were 31 distant metastases. Ten-year distant metastasis-free rate was 82%. Multivariate Cox regression analysis using combined stage revealed that clinical stages IIIB, IIIC, and IBC (hazard ratio [HR], 4.24; 95% CI, 1.96 to 9.18; P < .0001), identification of ≤ 10 lymph nodes (HR, 2.94; 95% CI, 1.40 to 6.15; P = .004), and premenopausal status (HR, 3.08; 95% CI, 1.25 to 7.59; P = .015) predicted for distant metastasis. Freedom from distant metastasis at 10 years was 97% for no factors, 88% for one factor, 77% for two factors, and 31% for three factors (P < .0001). Conclusion A small percentage of breast cancer patients with pCR experience recurrence. We identified factors that independently predicted for distant metastasis development. Our data suggest that premenopausal patients with advanced local disease and suboptimal axillary node evaluation may be candidates for clinical trials to determine whether more aggressive or investigational adjuvant therapy will be of benefit.

BACKGROUND In three prospective, single-arm studies, the authors previously showed an improved outcome for anthracycline-naive patients with isolated sites of recurrent breast carcinoma (BC) who were treated with doxorubicin-based chemotherapy after local therapy (surgery and/or radiotherapy). In the current report, the initial results are presented from a Phase II trial of docetaxel (100 mg/m2 every 21 days for 6 cycles) given after local therapy for recurrent BC (Stage IV BC with no evidence of clinically measurable disease) in patients who received prior adjuvant anthracycline-based chemotherapy, and the authors provide an update of the 3 previous studies. An analysis of prognostic factors for these patients also is presented. METHODS Eligibility criteria for all studies included histologic proof of recurrent BC that had been resected and/or irradiated with curative intent. Survival was calculated using the Kaplan–Meier method. Univariate survival analyses were performed to test for associations between patient characteristics and outcome (log-rank test). Cox proportional hazards models were used to determine the multivariable correlations between patient characteristics and outcome. RESULTS The median follow-up for the docetaxel-based trial (n = 26 patients) was 45 months. Early outcomes for this study are promising. The median disease-free survival (DFS) was 44 months, and the 3-year DFS and overall survival (OS) rates were 58% and 87%, respectively. In the 3 doxorubicin-based studies, the median follow-up was 121.5 months for all living patients, and the estimated 20-year DFS and OS rates were both 26%. On multivariable analysis of patients from all 4 studies, the only significant prognostic factor for DFS and OS (P = 0.0006) was the number of involved axillary lymph nodes at initial diagnosis. CONCLUSIONS A proportion of patients with isolated BC recurrences achieved prolonged DFS with combined-modality treatment. Patients who receive anthracycline-based chemotherapy at primary diagnosis may benefit from local treatment followed by docetaxel-based chemotherapy for isolated recurrences. The only significant independent prognostic factor was the number of involved axillary lymph nodes at initial diagnosis. Cancer 2005. © 2005 American Cancer Society.

The purpose of the current study was to describe a population of young patients with breast carcinoma, their characteristics at the time of diagnosis, and the association of these characteristics with disease recurrence and survival.Four hundred fifty-two women ageor = 35 years with breast carcinoma were registered at The University of Texas M. D. Anderson Cancer Center (Houston, TX) between 1990 and 2002. The relation between clinicopathologic factors and disease recurrence-free survival (RFS) and overall survival (OS) was assessed. Cox regression analysis was used to identify independent survival predictors.The median age of the patients was 32 years. Most of the patients were white, and 20% were obese. Approximately 50% reported oral contraceptive use, 34% reported a family history of breast carcinoma, and 5% reported a family history of ovarian carcinoma. Sixty-nine percent of tumors were nuclear Grade 3 (using the modified Black's nuclear grading system), 52% had positive estrogen receptors, and 48% had positive progesterone receptors. HER-2/neu status was available in 60% of tumor specimens and 34% were HER-2/neu positive. The median follow-up was 36 months. There were 185 disease recurrences and 84 deaths. RFS was significantly shorter in patients who reported a family history of ovarian carcinoma (P0.0001) and in those who had hormone receptor-negative tumor specimens (P = 0.001). OS was significantly shorter in patients who reported a family history of ovarian carcinoma (P = 0.001), those who had hormone receptor-negative tumor specimens (P0.0001), or those withnuclear Grade 3 tumor specimens (P = 0.005).This young population with breast carcinoma was found to have more aggressive biologic features. Hormone receptor negativity and a family history of ovarian carcinoma were associated with shorter RFS and OS.

Background Taxane-based chemotherapy has been associated with an increased risk of radiation pneumonitis in patients with breast cancer. To obtain additional information about this association, we investigated the association between paclitaxel chemotherapy and radiation pneumonitis in patients participating in a phase III randomized study. Methods Five hundred and twenty-four breast cancer patients were prospectively and randomly assigned to receive either four cycles of paclitaxel followed by four cycles of 5-fluorouracil, doxorubicin, cyclophosphamide (FAC) or eight cycles of FAC. One hundred and eighty-nine of these patients (100 in the paclitaxel-FAC group and 89 in the FAC group) subsequently underwent radiation therapy in our institution and had medical records available to review for pulmonary symptoms. In addition, a radiologist who was unaware of the type of treatment scored chest x-ray changes after radiation treatment. Crude rates of radiation pneumonitis were compared with chi-square or Fisher's exact test, and actuarial rates were assessed with Kaplan-Meier and log-rank tests. All statistical tests were two-sided. Results No difference in the rate of clinically relevant radiation pneumonitis was observed between the two groups (5.0% in the paclitaxel-FAC group versus 4.5% in the FAC group; difference = 0.5%, 95% CI = -6.6% to 5.5%; P = 1.00). Oral steroids for pneumonitis were taken by two patients in the paclitaxel-FAC group but by none in the FAC group, and no patient was hospitalized for or died of radiation pneumonitis. The paclitaxel-FAC group (39.3%) had a higher rate of radiographic changes after irradiation than the FAC group (23.7%; difference = 15.6%, 95% CI = -0.11% to 28.8%; P = .034). Conclusion Patients with breast cancer treated with sequential paclitaxel, FAC, and radiation therapy appeared to have a very low rate of clinically relevant radiation pneumonitis that was no different from that of patients treated with FAC alone.

BACKGROUND The current study was performed to determine the incidence of central nervous system (CNS) metastases and to examine associated disease characteristics in a group of patients with locally advanced breast carcinoma (LABC) or inflammatory breast carcinoma (IBC) treated at The University of Texas M. D. Anderson Cancer Center (Houston, TX). METHODS Seven hundred sixty-eight patients treated with multimodality therapy between 1982 and 2000 in any of 6 neoadjuvant trials were eligible for the current study. Five hundred ninety-two patients (77%) had LABC, and 176 (23%) had IBC. CNS disease was defined as the presence of brain metastases or leptomeningeal disease. Time to detection of CNS disease and overall survival were estimated using the Kaplan–Meier product-limit method, and differences were evaluated using log-rank tests. RESULTS The median patient age was 48 years. Most tumors were classified as T4 lesions (58%) and exhibited lymph node involvement (78%). Fifty-one percent of all tumors had positive hormone receptor status. At a median follow-up duration of 9.5 years, 61 patients (8%) had developed CNS metastases, with the CNS representing the first site of recurrence for 38 of these 61 (63%). Characteristics associated with the development of CNS metastases over time included negative hormone receptor status (P = 0.03), Grade 3 disease (P = 0.01), and larger tumor size (P = 0.02). The median time to detection of CNS metastases was 2.3 years. Ten patients (16%) remained alive after treatment for CNS metastases. The median survival from the time of diagnosis of CNS metastases was 8 months. CONCLUSIONS CNS metastases from breast carcinoma were relatively uncommon and were strongly associated with more aggressive clinical presentation. Survival from the time of diagnosis of such metastases generally was short. Cancer 2004. © 2004 American Cancer Society.

The treatment of inflammatory breast cancer includes preoperative anthracycline-based chemotherapy, surgery, and radiation therapy. In the past few years, taxanes, mainly paclitaxel, have been frequently used for preoperative chemotherapy, usually in sequence with anthracyclines. The purpose of this retrospective analysis was to determine how adding paclitaxel to anthracycline-based regimens affects prognosis. A total of 240 patients treated in 6 consecutive trials between 1973 and 2000 were included in the analysis. Group 1 (N = 178) consisted of patients treated in the first 4 trials (1973-1993) with FAC (5-fluorouracil/doxorubicin/cyclophosphamide) based regimens. Group 2 (N = 62) consisted of patients treated in the last 2 trials (1994-2000) with FAC followed by paclitaxel given every 3 weeks or given in a high-dose weekly schedule. The 2 groups differed with respect to median follow-up durations, which were 148 months (range, 85-283 months) in group 1 and 45 months (range, 21-99 months) in group 2. Estrogen receptor (ER) status was negative in 58 cases (33%) in group 1 and 40 cases (65%) in group 2. There was no difference in median age between the groups. The objective response rates (complete and partial) were similar (group 1, 74%; group 2, 82%). The median overall survival (OS) and progression-free survival (PFS) were better in the patients treated with paclitaxel, and these differences reached statistical significance in the patients with ER-negative disease (median OS: group 1, 32 months; group 2, 54 months; P = 0.03; median PFS: group 1, 18 months; group 2, 27 months; P = 0.04). It may be concluded that the addition of paclitaxel to anthracycline-based therapy resulted in a statistically significant improvement in outcome in patients with ER-negative inflammatory breast cancer.

It has been suggested that expression of anti-apoptotic proteins such as Bcl-2 or BAG-1 may confer cellular resistance to chemotherapy. A corollary of this hypothesis is that expression of these proteins may predict clinical response to treatment and that Bcl-2- or BAG-1-positive cells may selectively be enriched in postchemotherapy tissue specimens. The goal of this exploratory pilot study was to assess these two predictions by using immunohistochemistry in 29 paired pre- and postchemotherapy breast tissue specimens obtained from patients who underwent preoperative doxorubicin-based chemotherapy. All breast cancers expressed BAG-1 protein, and, in individual tumors, 40-100% of neoplastic cells stained positive for this protein. Homogenous cytoplasmic staining was typically observed, though neoplastic cells also showed nuclear staining in many specimens. We found no correlation between prechemotherapy expression of BAG-1 and subsequent pathological response to cytotoxic therapy. Paired pre- and posttreatment specimens showed similar levels of BAG-1 expression when residual tumor could be assessed. Bcl-2 was expressed in 55% of cancers and was localized to the cytoplasm. Absence of Bcl-2 expression in prechemotherapy specimens was associated with more frequent complete pathological response (58% vs. 20%; p = 0.04). However, similar to BAG-1, no difference between pre- and posttherapy expression of Bcl-2 was observed in neoplastic cells in paired tissue specimens. These observations suggest that BAG-1 contributes an important cellular function to breast epithelial cells, which is reflected by its ubiquitous expression in these tissues. However, it does not appear to determine response to doxorubicin-based chemotherapy. In contrast, lack of Bcl-2 expression was associated with a higher probability of complete pathological response to doxorubicin-based chemotherapy.

BACKGROUND The objective of this study was to determine whether HER-2 overexpression is associated with improved response to neoadjuvant chemotherapy with 5-fluorouracil, doxorubicin, cyclophosphamide (FAC) in patients with breast carcinoma. METHODS Ninety-seven patients with Stage I–III breast carcinoma were included. HER-2 expression was determined by routine clinical laboratory assessment, and tumors with 3 + immunohistochemistry staining intensity or gene amplification by fluorescent in situ hybridization were considered HER-2 positive. Response was assessed by physical examination, imaging assessment, and pathologic assessment at the time of surgery. RESULTS The median patient age was 45 years. At baseline, 68% of patients had lymph node positive disease, 87% had ≥ T2 tumors, and 28% of patients had HER-2 positive tumors. Eighty-four percent of patients received four courses of FAC, 8% of patients received 3 courses of FAC, and the remaining 8% of patients received 5–6 courses of FAC. The clinical response rate (complete response [CR] and partial response [PR]) was 78%, the imaging response rate (CR and PR) was 64%, and 15% of patients had a good pathologic response, defined as a CR or minimal residual disease (tumor measuring < 1 cm in greatest dimension and negative lymph nodes). Concordance between the three methods of response assessment (clinical, pathologic, and imaging) was modest and was best between clinical assessment and imaging assessment (64% concordance). HER-2 status did not correlate with pathologic or clinical response (assessed by physical examination or imaging), although a nonsignificant trend was noted toward better response in patients with breast tumors that overexpressed HER-2. CONCLUSIONS The authors found no significant correlation between HER-2 expression and clinical or pathologic response to neoadjuvant chemotherapy in patients with breast carcinoma. Cancer 2003;97:1758–65. © 2003 American Cancer Society. DOI 10.1002/cncr.11245

BACKGROUND Despite advances in therapies for breast cancer, improvement in survival for patients with recurrent or metastatic breast cancer has been difficult to establish. The objective of the current study was to determine whether the survival of women with recurrent breast cancer has improved from 1974 to 2000. METHODS The authors analyzed the survival experience of 834 women who developed recurrent breast cancer between November 1974 and December 2000. All patients had been treated previously with adjuvant anthracycline-based protocols. Patients were divided into five consecutive groups based on year of breast cancer recurrence, and survival was compared across the five groups. Because some prognostic variables were divided unevenly divided among the cohorts, a multivariate model was created to determine the association of year of recurrence and survival after accounting for other prognostic factors. RESULTS In the unadjusted analysis, there was a statistically significant improvement in survival across the five groups, and the more recent cohorts had longer survival (P < 0.001). Other variables that predicted longer survival after breast cancer recurrence included smaller initial tumor size, lower stage of disease, fewer lymph nodes involved, longer disease-free interval, estrogen receptor–positive tumors, and nonvisceral dominant site of disease recurrence. In the multivariate analysis, which adjusted for these prognostic factors, year of recurrence was associated with a trend toward improved survival, with a 1% reduction in risk for each increasing year. CONCLUSIONS For these cohorts of patients, the authors present data suggesting that the prognosis for patients with recurrent breast cancer improved between 1974 and 2000. Cancer 2004;100:44–52. © 2003 American Cancer Society.

BACKGROUND The objective of this study was to analyze the outcome of treatment in young women with breast carcinoma who were treated at a single institution and to develop a clearer understanding of the natural history of the disease in these women. METHODS One hundred eighty-five women age ≤ 30 years in whom a diagnosis of invasive breast carcinoma was made between October 1985 and September 1995 were identified in the Tumor Registry data base. Patient data were obtained by chart review. All female patients with breast carcinoma who were age > 30 years and who were identified in the same data base and received treatment during the same period served as the control population. The stage-stratified overall survival (OS) rate for the study patients was compared with the OS rate for both the control population and patients in the National Cancer Data Base (NCDB). RESULTS Of 185 patients, 11% presented with Stage I disease, 45% presented with Stage II disease, 38% presented with Stage III disease, and 6% presented with Stage IV disease. Twenty-nine percent of patients with Stage I disease received adjuvant therapy, and 84% of patients with Stage II disease and 96% of patients with Stage III disease received either adjuvant or neoadjuvant chemotherapy. Among patients with Stage I disease, 8 patients underwent mastectomy and 13 patients underwent breast-conserving surgery (BCS). Among patients with Stage II disease, 66 patients underwent mastectomy and 17 patients underwent BCS. Among patients with Stage III disease, 65 patients underwent mastectomy and 5 patients underwent BCS. The 5-year OS rate was 87% for patients with Stage I disease, 60% for patients with Stage II disease, 42% for patients with Stage III disease, and 16% for patients with Stage IV disease. Compared with the control patients and those in the NCDB, there was a trend toward worse OS rates in women age ≤ 30 years. CONCLUSIONS Women who are diagnosed with breast carcinoma at an age ≤ 30 years appear to have a poorer prognosis compared with that for their older counterparts. Cancer 2001;92:2523–8. © 2001 American Cancer Society.

Background. A delay in administration of radiation therapy has been suggested to increase the risk of local recurrence after breast-conserving surgery. Methods. The data were retrospectively reviewed from 552 patients in whom treatment consisted of total mastectomy (n = 467) or segmental mastectomy (n=85), irradiation, and combination chemotherapy. Of these, 463 patients received radiation therapy first, and 89 received chemotherapy first. The pattern of failures was compared between the subgroups according to the order of administration chemotherapy and irradiation and its effect on the local control of disease. Results. The median follow-up time of the local mastectomy subgroup was 133 months; of the segmental mastectomy subgroup, it was 39 months

BACKGROUND: This study was performed to evaluate the outcomes of patients with locally advanced breast cancer (LABC) who were treated with a multidisciplinary approach including primary systemic chemotherapy and noncross-resistant adjuvant chemotherapy. METHODS: Patients with LABC received 4 or 6 cycles of doxorubicin and docetaxel (DT) as primary systemic chemotherapy (PST) every 21 days. Patients with adequate response underwent surgery followed by adjuvant chemotherapy according to pathologic response: complete (pCR), 2 more cycles of DT; partial (pPR), 2 more cycles of DT followed by 6 cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (5-FU) (CMF); and minor (pMR), 6 cycles of CMF. Patients then received radiation and tamoxifen (hormone receptor-positive patients only). RESULTS: Eighty-eight patients were evaluable. Seventy-four patients had an adequate response to DT and were considered operable, and 72 underwent surgery. Ten patients (13.9%) achieved a pCR, 22 (30.5%) achieved a pPR, and 40 achieved a pMR (55.5%). Fourteen patients were considered nonoperable after DT and underwent salvage CMF therapy. Five of these patients underwent surgery and 1 had achieved a pCR. The estimated 5-year recurrence-free survival (RFS) rates for patients with pCR, pPR, and pMR were 80%, 77%, and 59%, respectively, and the estimated 5-year overall survival (OS) rates were 90%, 91%, and 74%, respectively. The 5-year OS rates were 82% for initially operable and 21% for initially inoperable patients (P ≤ .001) CONCLUSIONS: Multidisciplinary therapy that includes PST with DT and adjuvant therapy with CMF administered according to the clinical and pathologic response is associated with high long-term RFS and OS rates in patients with LABC. Clinical or pathologic PR or CR to DT predicts improved RFS and OS. Cancer 2010. Published 2010 by the American Cancer Society.

Purpose The goal of this study was to describe the effect of race on pathologic complete response (pCR) rates and survival outcomes in women with triple receptor–negative (TN) breast cancers. Patients and Methods Four hundred seventy-one patients with TN breast cancer diagnosed between 1996 and 2005 and treated with primary systemic chemotherapy were included. pCR was defined as no residual invasive cancer in the breast and axillary lymph nodes. Overall survival (OS) and recurrence-free survival (RFS) were estimated using the Kaplan-Meier product-limit method and compared between groups using the log-rank test. Cox proportional hazards models were fitted for each survival outcome to determine the relationship of patient and tumor variables with outcome. Results Median follow-up time was 24.5 months. One hundred patients (21.2%) were black, and 371 patients (78.8%) were white/other race. Seventeen percent of black patients (n = 17) and 25.1% of white/other patients (n = 93) achieved a pCR (P = .091). Three-year RFS rates were 68% (95% CI, 56% to 76%) and 62% (95% CI, 57% to 67%) for black and white/other patients, respectively, with no significant difference observed between the two groups (P = .302). Three-year OS was similar for the two racial groups. After controlling for patient and tumor characteristics, race was not significantly associated with RFS (hazard ratio [HR] = 1.08; 95% CI, 0.69 to 1.68; P = .747) or OS (HR = 1.08; 95% CI, 0.69 to 1.68; P = .735) when white/other patients were compared with black patients. Conclusion Race does not significantly affect pCR rates or survival outcomes in women with TN breast cancer treated in a single institution under the same treatment conditions.

Purpose To understand the mechanism through which obesity in breast cancer patients is associated with poorer outcome, we evaluated body mass index (BMI) and response to neoadjuvant chemotherapy (NC) in women with operable breast cancer. Patients and Methods From May 1990 to July 2004, 1,169 patients were diagnosed with invasive breast cancer at M. D. Anderson Cancer Center and received NC before surgery. Patients were categorized as obese (BMI ≥ 30 kg/m2), overweight (BMI of 25 to < 30 kg/m2), or normal/underweight (BMI < 25 kg/m2). Logistic regression was used to examine associations between BMI and pathologic complete response (pCR). Breast cancer–specific, progression-free, and overall survival times were examined using the Kaplan-Meier method and Cox proportional hazards regression analysis. All statistical tests were two-sided. Results Median age was 50 years; 30% of patients were obese, 32% were overweight, and 38% were normal or underweight. In multivariate analysis, there was no significant difference in pCR for obese compared with normal weight patients (odds ratio [OR] = 0.78; 95% CI, 0.49 to 1.26). Overweight and the combination of overweight and obese patients were significantly less likely to have a pCR (OR = 0.59; 95% CI, 0.37 to 0.95; and OR = 0.67; 95% CI, 0.45 to 0.99, respectively). Obese patients were more likely to have hormone-negative tumors (P < .01), stage III tumors (P < .01), and worse overall survival (P = .006) at a median follow-up time of 4.1 years. Conclusion Higher BMI was associated with worse pCR to NC. In addition, its association with worse overall survival suggests that greater attention should be focused on this risk factor to optimize the care of breast cancer patients.

Purpose: To assess the effect of tumor detection method (screening versus symptom-based diagnosis) in predicting breast cancer survival and investigate how biological features of breast cancer are related to the tumor detection method. Patients and Methods: The study population consisted of 5,481 women diagnosed with primary invasive breast cancer between 1997 and 2005 and received their treatment at The University of Texas M. D. Anderson Cancer Center. Results: Patients with symptom-detected tumors had an increased risk of recurrence or death [relative risk (RR), 1.34; P = 0.006] and breast cancer–specific death (RR, 1.31; P = 0.117) than patients with screen-detected tumors after adjusting for tumor characteristics and treatments received. This relationship was especially evident among estrogen receptor (ER)–negative tumors (RR, 1.60 for breast cancer recurrence for ER-negative tumors; RR, 1.18 for ER-positive tumors). ER status and Ki-67 expression were statistically significantly associated with symptom detection rate after adjusting for patients' age, tumor stage, tumor size, and nuclear grade [odds ratio (OR) of ER negative versus ER positive, 1.35; P < 0.001; OR of Ki-67 10-30% versus 30% versus Conclusion: The method of detection was a statistically significant independent predictor of breast cancer recurrence. Information on the method of tumor detection should be collected to improve the prediction of prognosis of breast cancer patients. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1096–103)

BACKGROUND Inflammatory breast cancer (IBC) is a rare, aggressive form of breast cancer with poorly understood prognostic variables. The purpose of this study was to define the prognostic impact of HER-2 status on survival outcomes of patients with IBC. METHODS In all, 179 patients with IBC, diagnosed between 1989 and 2005, with known HER-2 status, and treated with an anthracycline-based chemotherapy regimen without trastuzumab, were included in the analysis. Patients with HER-2-positive disease who received trastuzumab at the time of disease recurrence were included. Survival outcomes were estimated by the Kaplan-Meier product limit method and compared across groups using the log-rank statistic. A Cox proportional hazards model was fitted to determine the association of survival outcomes with HER-2 status after adjusting for patient and tumor characteristics. RESULTS A total of 111 patients (62%) had HER-2-negative disease and 68 (38%) had HER-2-positive disease. The median follow-up among all patients was 35 months. At the time of the analysis, 62 patients (55.9%) with HER-2-negative disease and 42 patients (61.8%) with HER-2-positive disease had a recurrence. Thirty-one patients (73.8%) with HER-2-positive disease who had a disease recurrence went on to receive trastuzumab. On univariate analysis, no statistically significant difference was observed for either recurrence-free survival (P = .75) or overall survival (P = .24) between patients who had HER-2-positive disease and those who had HER-2-negative disease. In a multivariate model, HER-2 status did not appear to significantly affect recurrence-free survival (hazards ratio [HR] of 0.75; 95% confidence interval [95% CI], 0.46–1.22 [P = .241]). In the multivariate model, patients with HER-2-positive disease had a decreased hazard of death (HR of 0.56; 95% CI, 0.34–0.93 [P = .024]) compared with patients with HER-2-negative disease. CONCLUSIONS HER-2 status, in the absence of trastuzumab, did not appear to significantly affect recurrence-free survival. After adjusting for other characteristics, the addition of trastuzumab in the metastatic setting significantly improved survival in the HER-2-positive group above and beyond that of the HER-2-negative group. This gives us further insight into the biology of this aggressive disease and underlines the major effect of targeted intervention. Cancer 2008. © 2008 American Cancer Society.

Breast cancer is the second most common cause of central nervous system (CNS) metastases. Several risk factors for CNS metastases have been reported. The objective of the current study was to describe clinicopathologic characteristics and prognostic factors in breast cancer patients with CNS metastases.The authors retrospectively evaluated clinical data from 420 patients who had been diagnosed with breast cancer and CNS metastasis between 1994 and 2004 at the University of Texas M. D. Anderson Cancer Center.The median age of the patients at the time of diagnosis of breast cancer was 45 years (range, 25-77 years). Premenopausal and postmenopausal patients were distributed equally. Most patients had invasive ductal histology (91.2%), grade 3 tumors (81.4%) (using the modified Black nuclear grading system), T2 tumor classification (40.1%), and N1 lymph node status (59.7%) diagnosis. Forty percent of patients had estrogen receptor (ER)-positive disease, and 34% had progesterone receptor-positive disease. HER-2/neu status was recorded for only 248 patients, and 39% of the patients in that group had HER-2/neu-positive disease. The most common sites of first metastasis were liver, bone, and lung. CNS metastasis was the site of first recurrence in 53 patients (12%). In total, 329 patients had received either neoadjuvant treatment (113 patients) or adjuvant chemotherapy (216 patients). The majority of those patients (74.4%) had received anthracycline-based regimens. Metastasis was solitary in 111 patients (26.4%), and 29 patients had only leptomeningeal metastases. The median time from breast cancer diagnosis to CNS metastasis was 30.9 months (range, from -5 months to 216.7 months). The median follow-up after a diagnosis of CNS metastasis was 6 months (range, 7-95.9 months). In all, 359 patients died, and the overall median survival was 6.8 months. Only age at diagnosis and ER status were associated significantly with overall survival in the multivariate analysis.The current results indicated that the prognosis remains patients with breast cancer metastatic to the CNS. More effective treatment approaches are needed for patients with CNS metastases, even for those with favorable prognostic factors, such as ER-positive tumors or younger age.

BACKGROUND. Inflammatory breast cancer (IBC) is the most aggressive manifestation of primary breast cancer. The authors compared the prognostic features of IBC and non-IBC locally advanced breast cancer (LABC) to gain insight into the biology of this disease entity. METHODS. This retrospective analysis consisted of 1071 patients, comprising 240 patients with IBC and 831 patients with non-IBC LABC who were enrolled in 10 consecutive clinical trials (5 from each disease group). All patients received similar multidisciplinary treatment. The authors measured time to disease recurrence for each individual site from the start of treatment to the date of disease recurrence or last follow-up (recurrence-free survival) and overall survival rates to the date of last follow-up or death. RESULTS. The median follow-up period was 69 months (range, 1–367 months). Pathologically complete response rates were 13.9% and 11.7% in the IBC and non-IBC LABC groups, respectively (P 5 .42). The 5-year estimates of cumulative incidence of recurrence were 64.8 % and 43.4% (P < .0001), respectively, for IBC and non-IBC LABC. IBC had significantly higher cumulative incidence of locoregional recurrence and distant soft-tissue and bone disease. The 5-year overall survival (OS) rate was 40.5% for the IBC group (95% CI, 34.5%–47.4%) and 63.2% for the non-IBC LABC group (95% CI, 60.0%–66.6%; P < .0001). CONCLUSIONS. IBC was associated with a worse prognosis and a distinctive pattern of early recurrence compared with LABC. These data suggested that investigating factors affecting ‘‘homing’’ of cancer cells may provide novel treatment strategies for IBC. Cancer 2007;110:1436–44. � 2007 American Cancer Society.

Purpose To determine whether residual ductal carcinoma in situ (DCIS) after completion of preoperative chemotherapy affects the outcome of patients with histologically defined complete eradication of invasive cancer. Patients and Methods Retrospective analysis of a database including 2,302 breast cancer patients treated with neoadjuvant chemotherapy at The University of Texas M.D. Anderson Cancer Center between 1980 and 2004 was performed. The overall survival (OS), disease-free survival (DFS), and local recurrence-free survival were compared for patients with no residual invasive or in situ cancer (pathologic complete response [pCR]) and patients with no residual invasive cancer but persistent in situ disease (pCR+DCIS). Results The mean follow-up time was 250 months. Of the 2,302 treated patients, 78 (3.4%) had pCR, 199 (8.6%) had pCR+DCIS, and 2,025 (88%) had residual invasive cancer. For patients with pCR and pCR+DCIS, the 5-year DFS rates (87.1% in both groups) and 10-year DFS rates (81.3% v 81.7%, respectively) were similar; the 5-year OS rates (91.9% v 92.5%, respectively) and 10-year OS rates (91.8% v 92.5%, respectively) were also similar and significantly better than the rate of patients with residual invasive cancer (74.4%; P < .001). The 5-year locoregional recurrence-free survival rates were also not different between patients with pCR (92.8%; 95% CI, 86.1% to 96.4%) and patients with pCR+DCIS (90.9%; 95% CI, 77.3% to 96.5%; P = .63). Conclusion Residual DCIS in patients who experience complete eradication of the invasive cancer in the breast and lymph nodes does not adversely affect survival or local recurrence rate. Inclusion of patients with residual DCIS in the definition of pCR is justified when this outcome is used as an early surrogate for long-term survival.

The purpose of this study was to describe clinical characteristics and outcome of mammographically and clinically detected new cancers in patients with previously diagnosed ductal carcinoma in situ (DCIS). Our database was searched to identify patients with a primary diagnosis of DCIS. Those with prior evidence of invasive carcinoma were excluded from the analysis. Cumulative incidence of new cancers was estimated according to the method of Gray. Survival times were estimated using the Kaplan Meier product limit method. A total of 799 patients diagnosed and treated for DCIS were included in the analysis. Median age at diagnosis was 54 years (range 22–88 years) and median tumor size was 1.4 cm (range 0.2–15 cm). After a median follow-up of 2.9 years, 45 patients (5.6%) had a second event: 14 (31%) with in-situ and 31 (69%) with invasive disease. Median disease-free interval was 3.5 years (range 0.5–20.8 years). The majority of second events (63%) occurred in the opposite breast (P = 0.048) and the cumulative incidence at 5 years was 6.6%. Overall survival at 5 years was 97.4%; that for the second event was 76.1%. For mammography and self-palpation, respectively, the 5-year survival by method of detection of the second event was 63.2% and 100% (P = 0.08 with a 33% power to detect a difference). Second events following DCIS occurs primarily in the opposite breast and have a negative impact on survival.

Purpose The objective of this study was to compare the differential expression of established histopathologic and biologic markers of proliferation, apoptosis, and angiogenesis in invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC) in a group of axillary node-negative breast cancers. Patients and Methods Two hundred twenty patients with axillary node-negative ILC and IDC who underwent surgery at the University of Texas M. D. Anderson Cancer Center between 1978 and 1995 had tissue available for analysis. Of these, 206 (94%) had IDC and 14 (6%) had ILC. Estrogen receptors, progesterone receptors, tumor and stromal expression of vascular endothelial growth factor receptor 2, CD44, laminin-5, E-cadherin, and topoisomerase-2 were evaluated by immunohistochemical analysis. HER2/ neu and α 6 β 4 integrin were evaluated by in situ hybridization. The Fisher exact test was used to calculate significant differences between ILC and IDC. Median age was 59 years. Results Invasive lobular carcinoma was more likely to occur in patients aged > 50 years. Invasive lobular carcinoma tended to be > 2 cm (50% vs. 39%), have a nuclear grade of 1/2 (100% vs. 72%), be estrogen receptor positive (93% vs. 70%), HER2/ neu negative (92% vs. 68%), have high CD44 expression (31% vs. 16%), low stromal vascular endothelial growth factor receptor 2 expression (36% vs. 47%), no E-cadherin expression (0 vs. 90%), and low laminin-5 expression (15% vs. 25%), compared with IDC. Conclusion Invasive lobular carcinoma and IDC might be distinct histologic types of breast cancer with different expression of biologic markers. These differences, not all being statistically significant in this small study, might generate hypotheses to develop tailored options for future systemic therapy.

BACKGROUND Breast carcinoma axillary lymph node (ALN) pathologic complete response (pCR) after primary chemotherapy is associated with significantly higher recurrence-free survival (RFS) and overall survival (OS) rates. The purpose of the current study was to determine long-term outcome in patients achieving a pCR of cytologically proven inflammatory breast carcinoma ALN metastases after primary chemotherapy. METHODS Patients with cytologically documented ALN metastases from inflammatory breast carcinoma were treated in three prospective primary chemotherapy trials. After surgery, patients were subdivided into those patients with and those patients without residual ALN carcinoma. Survival was calculated using the Kaplan–Meier method. RESULTS Of 175 patients treated, 61 had cytologically confirmed ALN metastases. Fourteen patients (23%) achieved a pCR of the ALNs after primary chemotherapy. The 5-year OS and RFS rates were found to be improved in those patients achieving a pCR of the ALNs (82.5% [95% confidence interval (95% CI), 62.8–100%] and 78.6% [95%CI, 59.8–100%], respectively, vs. 37.1% [95%CI, 25.4–54.2%] and 25.4% [95%CI, 15.5–41.5%], respectively) (P = 0.01 [for OS] and P = 0.001 [for RFS]). Combination anthracycline and taxane-based primary chemotherapy resulted in significantly more patients achieving an ALN pCR (45% vs. 16%; P = 0.01). CONCLUSIONS pCR of ALN metastases is associated with an excellent prognosis in patients with inflammatory breast carcinoma. The rates of ALN pCR are nearly 50% in patients with inflammatory breast carcinoma who are treated with anthracyclines and weekly paclitaxel before surgery. However, those patients with residual ALN disease at the time of surgery greatly require the introduction of novel therapeutic strategies. Cancer 2006. © 2006 American Cancer Society.

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.

Purpose Pathologic complete remission (pCR) of primary breast tumors after primary chemotherapy (PCT) is associated with higher relapse-free survival (RFS) and overall survival (OS) rates. The purpose of this study was to determine long-term outcome in patients achieving pCR of cytologically proven axillary lymph node (ALN) metastases. Methods Patients with cytologically documented ALN metastases were treated in five prospective PCT trials. After surgery, patients were subdivided into those with and without residual ALN carcinoma. Survival was calculated by the Kaplan-Meier method. Results Of 925 patients treated, 403 patients had cytologically confirmed ALN metastases. Eighty-nine patients (22%) achieved ALN pCR after PCT. Compared with the group without ALN pCR, 5-year OS and RFS were improved in patients achieving ALN pCR (93% [95% CI, 87.5 to 98.5] and 87% [95% CI, 79.7 to 94.3] v 72% [95% CI, 66.5 to 77.5] and 60% [95% CI, 54.1 to 65.9], respectively; P < .0001). Residual primary tumor did not affect outcome of those with ALN pCR. Combination anthracycline/taxane-based PCT resulted in significantly more ALN pCRs, although outcome after ALN pCR was not improved by taxanes. We constructed a nomogram demonstrating that patients who do not benefit from neoadjuvant anthracyclines are unlikely to benefit from subsequent taxanes. Conclusion ALN pCR is associated with an excellent prognosis, even with a residual primary tumor, pointing to biologic differences between primary and metastatic cells. ALN pCR represents an early surrogate marker of long-term outcome. Response to initial PCT has important potential as a guide to subsequent therapy.

BACKGROUND The majority of patients with breast carcinoma with ≥ 10 metastatic axillary lymph nodes (ALNs) develop recurrent disease within 5 years from diagnosis. The purpose of the current study, performed retrospectively, was to characterize the natural history of this subset of patients, both before and after the advent of adjuvant anthracycline-based chemotherapy and tamoxifen. METHODS Retrospectively, patients with primary breast carcinoma (N = 882) with ≥ 10 metastatic ALNs, treated between 1954 and 1998, were selected from 3 institutions: The University of Texas M. D. Anderson Cancer Center (Houston, TX); the Institut Gustave Roussy (Villejuif, France); and Hospital Clinico Universitario (Valencia, Spain). All patient data had been registered prospectively in clinical databases. One group consisted of 314 patients treated with locoregional therapy alone (no adjuvant therapy) from 1954 to 1983. The second group included 568 patients who received adjuvant anthracycline-based chemotherapy between 1974 and 1998 with or without adjuvant tamoxifen. RESULTS The median follow-up time was 140 months. Disease-free survival rates at 15 and 20 years for the no adjuvant therapy and adjuvant therapy groups were 17% and 16% versus 26% and 24%, respectively. The overall survival rates at 20 years for the no adjuvant therapy and the adjuvant therapy groups were 9% and 21%, respectively. By multivariate analysis, the independent factors associated with survival in the adjuvant therapy group were tumor size and the number of metastatic lymph nodes. CONCLUSIONS The retrospective analysis suggested that adjuvant anthracycline-based chemotherapy and hormonal therapy have altered the natural history in this high-risk group of patients. However, despite such improvements, survival rates remained low, and innovative therapeutic approaches are, therefore, needed to improve clinical outcomes. Cancer 2005. © 2005 American Cancer Society.

BACKGROUND To investigate the role of primary hypothyroidism (HYPT) on breast carcinogenesis, the authors evaluated 1) the association between HYPT and a diagnosis of invasive breast carcinoma and 2) the clinicopathologic characteristics of breast carcinoma in patients with HYPT. METHODS For this retrospective chart review study, 1136 women with primary breast carcinoma (PBC) were identified from the authors' departmental data base. These women (cases) were frequency-matched for age (± 5 years) and ethnicity with 1088 healthy participants (controls) who attended a breast carcinona screening clinic. Women with HYPT who were receiving thyroid-replacement therapy before they were diagnosed with breast carcinoma or before the screening visit were identified. RESULTS The mean ages of cases and controls (51.6 years vs. 51.0 years, respectively; P = 0.30) and their menopausal status (65.4% premenopausal vs. 62% postmenopausal; P = 0.10) were comparable. Two hundred forty-two women in the case group (10.9%) with HYPT were identified. The prevalence of this condition was significantly greater the control group compared with the case group (14.9% vs. 7.0%, respectively; P < 0.001). PBC patients were 57% less likely to have HYPT compared with their healthy counterparts (odds ratio, 0.43l 95% confidence interval, 0.33–0.57). Seventy-eight white patients with PBC had HYPT and, compared with women who were euthyroid, they were older at the time of diagnosis (58.8 years vs. 51.1 years; P < 0.001), were more likely to have localized disease (95.0% vs. 85.9% clinical T1 or T2 disease, respectively; P = 0.025), and were more likely to have no pathologic lymph node involvement (62.8% vs. 54.4%; P = 0.15). CONCLUSIONS Primary HYPT was associated with a reduced risk for PBC and a more indolent invasive disease. These data suggest a possible biologic role for thyroid hormone in the etiology of breast carcinoma and indicate areas of research for the prevention and treatment of breast carcinoma. Cancer 2005. © 2005 American Cancer Society.

Purpose To investigate the impact of histologic type invasive lobular carcinoma (ILC) versus invasive ductal carcinoma (IDC) on response to primary chemotherapy (PC) and long-term outcome. Patients and Methods The study included 1,034 patients with stage II and III breast cancer who participated in six clinical trials of PC at our institution between 1985 and 2002. One hundred twenty-two patients (12%) had ILC and 912 (88%) had IDC. All patients received anthracycline-based PC, and 346 patients (33.5%) also received a taxane as part of PC. Pathologic complete response (pCR) was defined as no evidence of invasive disease in the breast and axillary lymph nodes. Results The median patient age was 48 years (range, 18 to 79 years). Patients with ILC tended to be older (median age, 53 years v 47 years for patients with IDC) and have more hormone-receptor–positive tumors (92% v 62%; P < .001), lower nuclear grade (nuclear grade 3, 16% v 56%; P < .001), and higher stage at diagnosis (10% v 0% with stage IIIB or IIIC disease; P < .001). Patients with ILC were less likely to have a pCR (3% v 15%; P < .001) and had a larger number of involved axillary lymph nodes (41% v 26% had > 3 involved nodes; P = .001). At a median follow-up time of 70 months, ILC patients tended to have longer recurrence-free survival (P = .004) and overall survival (P = .001). Conclusion ILC is characterized by lower rates of pathologic response to PC but better long-term outcomes compared to IDC. pCR might not be a prognostic indicator for this group of patients.

Purpose: Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer. Nuclear expression of p53 protein in breast cancer correlates with more aggressive tumors. We retrospectively analyze the expression of p53 as a prognostic marker to predict pathological complete response and survival in patients with IBC. Experimental Design: Fifty-nine patients with IBC were treated from January 1994 to April 2000. Forty-eight patients were included. Diagnostic core biopsies were taken before treatment was started. Expression of hormone receptors and p53 was determined by immunohistochemistry. All patients received an anthracycline-based regimen preoperatively; 22 patients (46%) also received paclitaxel. Forty-four patients (92%) achieved an objective clinical response and underwent mastectomies. Results: Median age at diagnosis was 48 years. Thirty patients (63%) had hormone receptor-negative tumors. Twenty-eight patients (58%) had p53-positive tumors, and 20 patients (42%) had p53-negative tumors. Nine patients (19%) achieved a pathological complete response. At a median follow-up of 77 months, 28 recurrences (58%) and 26 deaths (54%) had occurred. Patients with p53-positive tumors were younger (P = 0.02) and tended to have lower 5-year progression-free survival rates (35% versus 55%; P = 0.3) and overall survival rates (44% versus 54%; P = 0.4). Conclusions: This retrospective analysis demonstrates that nuclear p53 protein expression may represent an adverse prognostic marker in IBC and may provide a valuable tool for selecting treatment for this aggressive disease.

Paclitaxel has significant antitumor activity in patients with metastaticbreast cancer who have been previously treated with or exposed to anthracycline-containing chemotherapy. In this prospective randomized trial, the role of paclitaxel was evaluated in an adjuvant setting to determine its impact on reducing the risk of recurrence in patients with operable breast cancer.Five hundred twenty-four patients were randomized to be treated either with 4 cycles of paclitaxel followed by 4 cycles of combination therapy with 5-fluorouracil, Adriamycin, and cyclophosphamide (Pac/FAC) or with 8 cycles of FAC alone. Patients with intact primary breast cancer received the initial 4 cycles of paclitaxel or 4 cycles of FAC in a neoadjuvant setting. Planned duration of therapy was the same in all patients. After completion of 8 cycles of chemotherapy, those patients who wereor =50 years and whose tumors were positive for estrogen receptors received tamoxifen for 5 years.Ninety-two patients have had a recurrence after a median follow-up of 60 months with a range of 5-89 months. Estimated disease-free survival at 48 months was 0.83 for FAC and 0.86 for Pac/FAC group. The difference between the two groups was not statistically significant (P = 0.09). The overall estimated hazard ratio for Pac/FAC compared with FAC derived by fitting the Cox regression model and incorporating terms for prognostic factors was 0.66.Preliminary results suggest that the addition of paclitaxel to a FAC regimen of adjuvant or neoadjuvant therapy may further reduce the risk of disease recurrence; however, differences were not statistically significant. At the time of this analysis, there have been 47 deaths. The survival data are too preliminary to permit meaningful evaluation of the impact of paclitaxel on mortality.

We conducted a single-institution study to determine whether local therapy plus six cycles of chemotherapy with 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) followed by 5 years of tamoxifen is superior to local treatment alone in terms of disease-free survival (DFS) and overall survival (OS) in patients with stage IV breast cancer with no evidence of disease (stage IV-NED breast cancer). Patients with breast cancer were eligible if they had histologic proof of a locoregional or distant recurrence that had been curatively resected, irradiated, or both and had no other evidence of disease. Patients who had received prior anthracycline therapy were not eligible. All patients received six cycles of intravenous FAC, with cycles repeated every 3 weeks. After completion of chemotherapy, patients whose tumors had not previously demonstrated resistance to tamoxifen and had positive or unknown estrogen receptor status received tamoxifen 20 mg by mouth daily for 5 years. Patients in this study were compared with a historical control population (patients with stage IV-NED breast cancer who never received systemic therapy) as well as with the patients in two previously reported trials of chemotherapy for stage IV-NED disease. Forty-seven patients were registered, but only 45 were evaluable. There was a highly statistically significant difference ( p < 0.001) in OS and DFS among the four groups, with patients in our most recent study having the best OS and DFS at 3 years compared with the control group (84% vs. 55% and 66% vs. 11%, respectively). When patients in all four groups were analyzed together in search of prognostic factors, we found that patients whose primary tumors had negative axillary lymph nodes had a statistically significant improvement in OS and DFS ( p < 0.01) compared with patients with positive axillary lymph nodes. No survival differences were found between patients with positive and those with negative hormone receptor status. This study demonstrates a benefit in terms of OS and DFS for patients with stage IV-NED breast cancer who receive doxorubicin-based adjuvant chemotherapy. The benefit was greater on patients with node-negative primary tumors. In patients with stage IV-NED disease, doxorubicin-based chemotherapy should be considered standard treatment after adequate local control is achieved.

PURPOSE: To compare prospectively the antitumor activity of single-agent paclitaxel to the three-drug combination of fluorouracil, doxorubicin, and cyclophosphamide (FAC) as neoadjuvant therapy in patients with operable breast cancer. PATIENTS AND METHODS: Patients with T1-3N0-1M0 disease were randomized to receive either paclitaxel (250 mg/m2) as 24-hour infusion or FAC in standard doses at every-3-week intervals. Each patient was treated with four cycles of preoperative chemotherapy. Clinical response and extent of residual disease in the breast and lymph nodes was assessed after four cycles of induction chemotherapy. RESULTS: A total of 174 patients were registered, and 87 were randomized to each arm of the study. Clinical response, ie, complete and partial responses, was similar in both arms of the study. Three patients in the FAC arm and one patient in the paclitaxel subgroup had progressive disease. The extent of residual disease by intent-to-treat analysis at the time of surgery was similar between the two arms of the study. CONCLUSION: The results of this prospective study demonstrated that single-agent paclitaxel as neoadjuvant therapy has significant antitumor activity, and this was clinically comparable to FAC. Similar fractions of patients had clinical complete and partial responses, and very few patients had no response to either therapy. The value of alternate non–cross-resistant therapies as used in this protocol on the clinical course of this disease would require longer follow-up.