Search

Purpose: To determine the role of PEA-15 in breast cancer., Experimental Design: A reverse-phase protein array was used to measure PEA-15 expression levels in 320 human breast cancers; these levels were correlated with clinical and tumor characteristics. PEA-15 was overexpressed by an adenovirus vector or by stably expressing PEA-15 in different breast cancer cell lines. The effects on breast cancer cell survival and on the downstream apoptotic signaling pathway were measured in terms of cell proliferation (trypan blue for cell viability, bromodeoxyuridine incorporation for DNA synthesis), anchorage-independent growth (soft agar colony formation), and apoptosis (fluorescence-activated cell sorter analysis). The preclinical efficacy of Ad.PEA-15 given intratumorally was evaluated in nude mice bearing tumors from s.c. implanted human MDA-MB-468 triple-negative breast cancer cells., Results: In human breast cancers, low levels of PEA-15 expression correlated with high nuclear grade (P < 0.0001) and with negative hormone receptor status (P = 0.0004). Overexpression of PEA-15 in breast cancer cells resulted in growth inhibition, reduction in DNA synthesis, and onset of caspase-8-dependent apoptosis. In athymic nude mice bearing MDA-MB-468 xenografts, tumor volumes were significantly smaller in mice treated intratumorally with Ad.PEA-15 than in control mice (P < 0.0001). Tumors from mice treated with Ad.PEA-15 had increased levels of activated (phosphorylated) extracellular signal-regulated kinase and reduced levels of Ki-67 compared with tumors from nontreated or control-adenovirus-treated mice., Conclusion: PEA-15 has therapeutic potential in breast cancer. Further preclinical and clinical exploration of PEA-15 as a druggable target is warranted.

Two important, related pathways are involved in cancer growth: the insulin/insulin-like growth factor-1 (IGF1) signaling pathway, which is activated when nutrients are available, and the adenosine mono-phosphate-activated protein kinase (AMPK) pathway, activated when cells are starved for carbohydrates. Metformin inhibits transcription of key gluconeogenesis genes in the liver, increases glucose uptake in skeletal muscle, and decreases circulating insulin levels. Metformin reduces levels of circulating glucose, increases insulin sensitivity, and reduces insulin resistance-associated hyperinsulinemia. At the level of cell signaling, metformin activates AMPK. There are extensive preclinical data showing the anticancer effects of metformin in all breast cancer subtypes as well as in cytotoxic therapy-resistant models. These data, and the epidemiological and retrospective data supporting the antineoplastic effects of metformin, provide the rationale to study the role of metformin for breast cancer therapy in a variety of clinical settings.

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 < or = .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.

Purpose: To evaluate HER2 status in residual tumor identified at the time of surgery in patients not achieving a pathologic complete response (pCR) and to determine the effect of alterations in HER2 status on recurrence-free survival (RFS)., Experimental Design: Clinicopathologic data for patients with HER2-overexpressing breast cancer receiving neoadjuvant therapy with a taxane, anthracycline, and concomitant trastuzumab between 2004 and 2007 were reviewed. Surgical specimens for patients achieving less than a pCR were assessed to determine if there was enough residual tissue to evaluate posttreatment HER2 status. RFS was determined using the Kaplan-Meier method and compared by the log-rank statistic., Results: A pCR was achieved in 72 of the 142 (50.7%) patients. Residual tumor was sufficient to assess posttreatment HER2 status in 25 patients. Fluorescence in situ hybridization done on pretreatment specimens confirmed HER2 amplification before beginning therapy. Eight (32.0%) posttreatment tumors were found to be HER2-negative by fluorescence in situ hybridization. At a median follow-up of 37 months (range, 8-56 months), the RFS was significantly better for patients with tumors that retained HER2 amplification (87.5% versus 50%, P = 0.04)., Conclusion: High pCR rates are achieved in patients with HER2-positive breast cancer treated with neoadjuvant trastuzumab in combination with anthracyclines and taxanes. One third of patients with significant residual disease loses HER2 amplification, and this change is associated with poor RFS. Residual tumor identified at the time of surgery should be reassessed for HER2 status, and novel adjuvant therapy strategies need to be studied in this population.

Purpose: To evaluate the risk of recurrence in women diagnosed with T1a and T1b, node-negative, human epidermal growth factor receptor 2 (HER2) -positive breast cancer., Methods: We reviewed 965 T1a,bN0M0 breast cancers diagnosed at our institution between 1990 and 2002. Dedicated breast pathologists confirmed HER2 positivity if 3+ by immunohistochemistry or if it had a ratio of 2.0 or greater by fluorescence in situ hybridization (FISH). Patients who received adjuvant chemotherapy or trastuzumab were excluded. Kaplan-Meier product was used to calculate recurrence-free survival (RFS) and distant recurrence-free survival (DRFS). Cox proportional hazard models were fit to determine associations between HER2 status and survival after adjustment for patient and disease characteristics. Additionally, 350 breast cancers from two other institutions were used for validation., Results: Ten percent of patients had HER2-positive tumors. At a median follow-up of 74 months, there were 72 recurrences. The 5-year RFS rates were 77.1% and 93.7% in patients with HER2-positive and HER2-negative tumors, respectively (P < .001). The 5-year DRFS rates were 86.4% and 97.2% in patients with HER2-positive and HER2-negative tumors, respectively (P < .001). In multivariate analysis, patients with HER2-positive tumors had higher risks of recurrence (hazard ratio [HR], 2.68; 95% CI, 1.44 to 5.0; P = .002) and distant recurrence (HR, 5.3; 95% CI, 2.23 to 12.62; P < .001) than those with HER2-negative tumors. Patients with HER2-positive tumors had 5.09 times (95% CI, 2.56 to 10.14; P < .0001) the rate of recurrences and 7.81 times (95% CI, 3.17 to 19.22; P < .0001) the rate of distant recurrences at 5 years compared with patients who had hormone receptor-positive tumors., Conclusion: Patients with HER2-positive T1abN0M0 tumors have a significant risk of relapse and should be considered for systemic, anti-HER2, adjuvant therapy.

Purpose: Population studies have suggested that metformin use in diabetic patients decreases cancer incidence and mortality. Metformin inhibits the growth of cancer cells in vitro and tumors in vivo. However, there is little clinical data to support this. Our purpose was to determine whether metformin use was associated with a change in pathologic complete response (pCR) rates in diabetic patients with breast cancer receiving neoadjuvant chemotherapy., Patients and Methods: We identified 2,529 patients who received neoadjuvant chemotherapy for early-stage breast cancer between 1990 and 2007. Patients were compared by groups: 68 diabetic patients taking metformin, 87 diabetic patients not taking metformin, and 2,374 nondiabetic patients. pCR rates were compared between the three groups using chi(2) tests of independence and compared pair- wise using a binomial test of proportions. Factors predictive of pCR were assessed using a multivariate logistic regression model., Results: The rate of pCR was 24% in the metformin group, 8.0% in the nonmetformin group, and 16% in the nondiabetic group (P = .02). Pairwise comparisons between the metformin and nonmetformin groups (P = .007) and the nonmetformin and nondiabetic groups (P = .04) were significant. Comparison of the pCR rates between the metformin and nondiabetic groups trended toward but did not meet significance (P = .10). Metformin use was independently predictive of pCR (odds ratio, 2.95; P = .04) after adjustment for diabetes, body mass index, age, stage, grade, receptor status, and neoadjuvant taxane use., Conclusion: Diabetic patients with breast cancer receiving metformin and neoadjuvant chemotherapy have a higher pCR rate than do diabetics not receiving metformin. Additional studies to evaluate the potential of metformin as an antitumor agent are warranted.

Knockdown of the tumor suppressor phosphatase Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) with shRNA in three estrogen receptor (ER)-positive breast cancer cell lines resulted in increased phosphatidylinositol-3 kinase (PI3K) and AKT activities, resistance to tamoxifen and fulvestrant, and hormone-independent growth. PTEN knockdown induced the up-regulation of ER transcriptional activity in MCF-7 cells but decreased ER protein levels and transcriptional activity in T47D and MDA-361 cells. Tamoxifen and fulvestrant treatment inhibited estradiol-induced ER transcriptional activity in all shPTEN cell lines but did not abrogate the increased cell proliferation induced by PTEN knockdown. PTEN knockdown increased basal and ligand-induced activation of the insulin-like growth factor-I (IGF-I) and ErbB3 receptor tyrosine kinases, and prolonged the association of the p85 PI3K subunit with the IGF-I receptor (IGF-IR) effector insulin receptor substrate-1 and with ErbB3, implicating PTEN in the modulation of signaling upstream of PI3K. Consistent with these data, PTEN levels inversely correlated with levels of tyrosine-phosphorylated IGF-IR in tissue lysate arrays of primary breast cancers. Inhibition of IGF-IR and/or ErbB2-mediated activation of ErbB3 with tyrosine kinase inhibitors restored hormone dependence and the growth inhibitory effect of tamoxifen and fulvestrant on shPTEN cells, suggesting that cotargeting both ER and receptor tyrosine kinase pathways holds promise for the treatment of patients with ER+, PTEN-deficient breast cancers.

Breast cancer diagnosed during pregnancy is a challenging situation for the patient and her medical team. As women are delaying childbirth, the incidence is expected to increase. Most of the data surrounding the diagnosis and treatment of cancer during pregnancy is in case reports and small cohort studies. However, the data continues to expand regarding the safety of systemic treatments during the second and third trimesters for both the mother and the fetus. In this article, the use of diagnostic imaging, procedures, surgery and chemotherapy are reviewed as well as prognosis and future pregnancies after the treatment for breast cancer.

Background: Women at a high risk for breast cancer are offered choices for screening or prophylactic surgeries. The aim of this study was to evaluate opinions regarding screening and surgical strategies in high-risk women., Methods: Women at the authors' institution who received BRCA1 of 2 testing before July 2005 were sent a follow-up patient survey. The authors compared responses of women who tested positive for a deleterious mutation with those who tested negative. For those who expressed an opinion (agree vs disagree), a 2-sided Fisher exact test was used to compare responses., Results: A total of 540 surveys were sent, and 312 were returned (58%). Of these, 217 had breast cancer, and 86 women tested positive for a mutation. No BRCA+ women felt mammograms were difficult to get because of discomfort, whereas 5.4% of the BRCA- group did (P = .039). Seventy percent of BRCA+ women agreed that prophylactic mastectomy (PM) is the most effective means for reducing risk, compared with 40% of BRCA- women (P < .001). PM was felt to be the only way to reduce worry in 64.7% of BRCA+ and in 34.4% of BRCA- women (P < .001). PM was felt to be too drastic for 36.1% of BRCA+ and 40.5% of BRCA- women (P = .562). Difficulty in deciding between screening and PM occurred in 23.9% of BRCA+ and 12.5% of BRCA- women (P = .046). After excluding women with bilateral breast cancers, 81.0% of women who agreed that PM was best to reduce risk underwent a PM versus 19.1% of those who disagreed (P < .001). Of women who felt PM was the only way to reduce worry, 84.2% underwent PM. Only 15.8% of women who did not believe that it was the only way to decrease worry underwent PM (P < .001)., Conclusions: BRCA mutation carriers were more likely to believe PM to be the best way to reduce both risk and worry of breast cancer. High-risk women who agreed that PM was more likely to reduce risk and worry of breast cancer were more likely to proceed with this intervention.

Purpose: To examine the androgen receptor (AR) levels in breast cancer and to assess the impact of AR expression on patient outcomes., Experimental Design: Reverse-phase protein arrays were used to measure AR levels and a mass spectroscopy-based approach was used to detect PIK3CA mutations. Means and SDs were generated for AR levels. Linear regression models were used to determine if AR levels differed by tumor subtype and PIK3CA mutation status. Two-sample t tests were used to identify pair-wise differences. Survival probabilities were estimated with the use of the Kaplan-Meier product and log-rank test., Results: The median age was 59 years (23-89 years). Significant differences in AR levels existed among different breast tumor subtypes (highest in estrogen receptor-positive and/or progesterone receptor-positive tumors) as well as by PIK3CA mutation status (P < 0.0001 for both). AR levels were significantly higher in breast tumors with kinase domain PIK3CA mutations versus tumors that are wild type or with PIK3CA helical mutations (P = 0.017 and P < 0.0001, respectively). In 347 patients, dichotomized AR level by the median was a significant prognostic factor of recurrence-free survival (P = 0.0002) and overall survival (P = 0.004). High AR levels were associated with a significantly improved recurrence-free survival in 207 patients with early-stage estrogen/progesterone receptor-positive tumors after adjuvant hormonal therapy. A trend (P = 0.07) was found toward higher AR expression in PIK3CA mutant versus PIK3CA wild-type triple-negative breast tumors., Conclusions: AR levels may represent a prognostic marker in breast cancers and may provide a valuable tool for selecting treatment. There was an association of PIK3CA mutation (kinase domain) with increased AR levels.

Unlabelled: Our objective was to retrospectively evaluate 18F-FDG PET/CT in the initial staging of inflammatory breast cancer (IBC)., Methods: The institutional review board waived informed consent and approved this study, which was compliant with the Health Insurance Portability and Accountability Act. The cases of 41 women with a mean age of 50 y (range, 25-71 y) and newly diagnosed IBC who underwent 18F-FDG PET/CT at diagnosis were retrospectively reviewed. All PET/CT images were analyzed visually and semiquantitatively by 2 physicians. The maximum standardized uptake value in the primary breast, regional nodes (axillary, subpectoral, supraclavicular, internal mammary), and extranodal regions was documented. The accuracy of PET/CT image interpretation was assessed by histopathologic analysis, if available; concurrent or subsequent imaging findings (contrast-enhanced CT, contrast-enhanced MRI, sonography, or PET/CT follow-up); or clinical follow-up., Results: All patients presented with unilateral IBC. PET/CT showed hypermetabolic uptake in the skin in all patients, in the affected breast in 40 (98%), in the ipsilateral axillary nodes in 37 (90%), and in the ipsilateral subpectoral nodes in 18 (44%). Twenty patients (49%) were found to have distant metastases at staging, 7 (17%) of whom were not known to have metastases before undergoing PET/CT. Disease sites included bone, liver, contralateral axilla, lung, chest wall, pelvis, and the subpectoral, supraclavicular, internal mammary, mediastinal, and abdominal nodes., Conclusion: PET/CT should be considered in the initial staging of IBC, as the technique provided valuable information on locoregional and distant disease in this preliminary retrospective study.

Purpose: Overall, breast cancer mortality has been declining in the United States, but survival studies of patients with stage IV disease are limited. The aim of this study was to evaluate trends in and factors affecting survival in a large population-based cohort of patients with newly diagnosed stage IV breast cancer., Patients and Methods: We searched the Surveillance, Epidemiology, and End Results registry to identify female patients with stage IV breast cancer diagnosed between 1988 and 2003. Patients were divided into three groups according to year of diagnosis (1988 to 1993, 1994 to 1998, and 1999 to 2003). Survival outcomes were estimated by the Kaplan-Meier method, and Cox models were fit to determine the characteristics independently associated with survival., Results: We identified 15,438 patients. Median age was 62 years. Median follow-up was 16 months, 18 months, and 11 months in periods 1988 to 1993, 1994 to 1998, and 1999 to 2003, respectively. Median breast cancer-specific survival was 23 months. In the multivariate model, earlier year of diagnosis, grade 3 disease, increasing age, being unmarried, hormone receptor-negative disease, and no surgery were all independently associated with worse overall and breast cancer-specific survival. With each successive year of diagnosis, black patients had an increasingly greater risk of death compared with white patients (hazard ratio, 1.03; 95% CI, 1.00 to 1.06; P = .031)., Conclusion: The survival of patients with newly diagnosed stage IV breast cancer has modestly improved over time, but these data suggest that the disparity in survival between black and white patients has increased.

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 >or= 30 kg/m(2)), overweight (BMI of 25 to < 30 kg/m(2)), or normal/underweight (BMI < 25 kg/m(2)). 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.

The use of neoadjuvant chemotherapy has become more prevalent in the treatment of breast cancer patients. The finding of a pathologic complete response to neoadjuvant chemotherapy (no evidence of residual invasive cancer in the breast and lymph nodes at the time of surgical resection) has been shown to correlate with improved survival. The current version of the American Joint Committee on Cancer (AJCC) staging for breast cancer has a pretreatment clinical stage designation that is determined by clinical and radiographic examination of the patient and a postoperative pathologic stage classification based on the findings in the breast and regional lymph nodes removed at surgery. Pathologic staging has not been validated for patients receiving neoadjuvant chemotherapy; thus, prognosis is determined for these patients based on the pretreatment clinical stage. We hypothesized that clinical and pathologic staging variables could be combined with biological tumor markers to provide a novel means of determining prognosis for patients treated with neoadjuvant chemotherapy. Two scoring systems, based on summing binary indicators for clinical and pathologic substages, negative estrogen receptor status, and grade 3 tumor pathology, were devised to predict 5-year patient outcomes. These scoring systems facilitated separation of the study population into more refined subgroups by outcome than the current AJCC staging system for breast cancer, and provide a novel means for evaluating prognosis after neoadjuvant therapy.

Recent results from large randomized clinical trials have demonstrated that administration of trastuzumab reduces the risk of death by half in patients with early-stage breast cancer; however, controversy still exists as to the timing and duration of treatment with trastuzumab in the adjuvant setting and whether its administration should be continued after recurrence of disease. We present the unusual case of a patient with HER2/neu-positive stage I breast cancer who, after receiving adjuvant trastuzumab, relapsed to develop HER2/neu-negative metastatic disease.

Purpose: To describe the role of Positron Emission Tomography/Computed Tomography (PET/CT), Magnetic Resonance Imaging (MRI), sonography, and mammography in patients with inflammatory breast cancer (IBC)., Materials and Methods: Patients who had been newly diagnosed with IBC and who had undergone mammography, sonography, MRI, PET/CT, or a combination of these were included in this study. The visibility of breast parenchymal lesion (BPLs), skin abnormalities, regional (axillary, supraclavicular, or internal mammary) nodal disease, and distant metastatic disease was documented with the imaging techniques., Results: Eighty patients (median age, 51 years, [range, 25-78 years]) were included in this study: 75 (94%) had undergone mammography, 76 (95%) sonography, 33 (41%) MRI, and 24 (30%) PET/CT. A primary BPL was found in 60 patients (80%) on mammography (mass or calcifications), 72 (95%) on sonography (mass or architectural distortion), 23 (96%) on PET/CT (hypermetabolic BPL), and 33 (100%) on MRI (enhancing BPL). Regional axillary nodal disease was found in 74 patients (93%) by histologic or cytologic examination, in 71 patients (93%) on sonography, in 21 (88%) on PET/CT, in 29 (88%) on MRI, and in 34 (45%) on mammography. Distant metastases in the bone, liver, and contralateral lymph nodes were diagnosed in nine patients (38%) on PET/CT., Conclusion: MRI was the most accurate imaging technique in detecting a primary BPL in IBC patients. Sonography can be useful in diagnosing regional nodal disease. PET/CT provides additional information on distant metastasis, and it should be considered in the initial staging of IBC.

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.

Purpose: The purpose of this retrospective study was to determine the association and prognostic value of body mass index (BMI) at the time of initial diagnosis in patients with locally advanced breast cancer (LABC). The analysis includes the subsets of inflammatory (IBC) and noninflammatory (non-IBC LABC) breast cancer., Experimental Design: We identified 602 patients who had LABC treated on prospective clinical trials. BMI was divided into three groups: (a) < or =24.9 (normal/underweight), (b) 25.0 to 29.9 (overweight), and (c) > or =30 (obese). Kaplan-Meier product limit method was used to estimate survival outcomes. Cox proportional hazards were used to determine associations between survival and BMI and to test for an interaction between BMI and breast cancer type., Results: Eighty-two percent had non-IBC LABC and 18% had IBC. Obese patients tended to have a higher incidence of IBC compared with overweight and normal/underweight groups (P = 0.01). Median follow up was 6 years for all patients. Median overall survival (OS) and recurrence-free survival (RFS) were 8.8 and 5.9 years, respectively. Patients with LABC who were obese or overweight had a significantly worse OS and RFS (P = 0.001) and a higher incidence of visceral recurrence compared with normal/underweight patients. In a multivariable model, BMI remained significantly associated with both OS and RFS for the entire cohort. The interactions between BMI and LABC subsets and between BMI and menopausal status were not statistically significant., Conclusion: Patients with LABC and high BMI have a worse prognosis. Evaluation of the biological factors associated with this observation can provide tools for additional therapeutic interventions.

Purpose: Triple-negative breast cancer (TNBC) is defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) expression. In this study, we compared response to neoadjuvant chemotherapy and survival between patients with TNBC and non-TNBC., Patients and Methods: Analysis of a prospectively collected clinical database was performed. We included 1,118 patients who received neoadjuvant chemotherapy at M.D. Anderson Cancer Center for stage I-III breast cancer from 1985 to 2004 and for whom complete receptor information were available. Clinical and pathologic parameters, pathologic complete response rates (pCR), survival measurements, and organ-specific relapse rates were compared between patients with TNBC and non-TNBC., Results: Two hundred fifty-five patients (23%) had TNBC. Patients with TNBC compared with non-TNBC had significantly higher pCR rates (22% v 11%; P = .034), but decreased 3-year progression-free survival rates (P < .0001) and 3-year overall survival (OS) rates (P < .0001). TNBC was associated with increased risk for visceral metastases (P = .0005), lower risk for bone recurrence (P = .027), and shorter postrecurrence survival (P < .0001). Recurrence and death rates were higher for TNBC only in the first 3 years. If pCR was achieved, patients with TNBC and non-TNBC had similar survival (P = .24). In contrast, patients with residual disease (RD) had worse OS if they had TNBC compared with non-TNBC (P < .0001)., Conclusion: Patients with TNBC have increased pCR rates compared with non-TNBC, and those with pCR have excellent survival. However, patients with RD after neoadjuvant chemotherapy have significantly worse survival if they have TNBC compared with non-TNBC, particularly in the first 3 years.

Purpose: We examined the correlation between HER2 expression and pathologic complete response (pCR) to paclitaxel/FAC (T/FAC) preoperative chemotherapy in breast cancer., Patients and Methods: 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 alpha (TOP2A) and microtubule associated protein tau (MAP-Tau)., Results: 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<0.001). The 5-year relapse-free survival rates were 94% and 70% in HER2+ tumors with and without pCR (P=0.009). HER2 overexpression (odds ratio 2.3, 95%CI: 1.3-3.9, P=0.004), estrogen receptor (ER) status, grade and weekly schedule of paclitaxel were each significantly and independently associated with pCR in multivariate analysis. When patients were stratified by ER status, the pCR rates were 50% for HER2+/ER-, 30% for HER2-/ER-, 19% for HER2+/ER+, and 6% for HER2-/ER+ tumors. HER2 overexpression was associated with lower expression of MAP-tau (P=0.001 and P<0.001) and higher expression of TOP2A mRNAs (P=0.048 and P=0.001) in patients with ER+ disease. ER- cancers had low MAP-tau expression regardless of HER-status., Conclusion: HER2 overexpression is associated with higher rate of pCR to preoperative T/FAC chemotherapy regardless of ER status. HER2 overexpression also correlates with increased TOP2A and decreased MAP-tau expression in ER-positive cancers.

Purpose: Neoadjuvant chemotherapy is being used with increasing frequency for operable breast cancer. We hypothesized that by using clinical and pathologic staging parameters, in conjunction with biologic tumor markers, a novel means of determining prognosis for patients treated with neoadjuvant chemotherapy could be facilitated., Patients and Methods: A prospective database of patients treated with neoadjuvant chemotherapy from 1997 to 2003 was reviewed, and 932 patients meeting inclusion criteria were identified. Clinical and pathologic tumor characteristics, treatment regimens, and patient outcomes were recorded. Cox proportional hazards models were used to create two prognostic scoring systems. American Joint Committee on Cancer (AJCC) clinical and pathologic staging parameters and biologic tumor markers were investigated to devise the scoring systems., Results: Median follow-up time was 5 years (range, 0.4 to 9.4 years). Five-year disease-specific survival rate was 96% for patients who experienced a pathologic complete response (pCR; n = 130) compared with 87% for patients who did not have a pCR (n = 802; P = .001). Two scoring systems, based on summing binary indicators for clinical substages >/= IIB and >/= IIIB, pathologic substages >/= ypIIA and >/= ypIIIC, negative estrogen receptor status, and grade 3 pathology, were devised to predict 5-year patient outcomes. These scoring systems facilitated separation of the study population into more refined subgroups by outcome than the current AJCC staging system., Conclusion: The scoring systems derived in this work provide a novel means for evaluating prognosis after neoadjuvant therapy. Future work will focus on prospective validation of these scoring systems and refinement of the scoring systems through addition of new biologic markers.

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.

Background: 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)., Method: 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., Results: 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)., Conclusion: Second events following DCIS occurs primarily in the opposite breast and have a negative impact on survival.

A 63-year-old Japanese woman was diagnosed with metastatic well-differentiated neuroendocrine carcinoma presenting as a perianal mass without an obvious primary site. Two years later, she presented with a breast mass determined on histologic examination to be the primary neuroendocrine carcinoma. The tumor was weakly positive for estrogen receptor and clearly originated in multifocal ductal carcinoma in situ. At the same time, she was found to have multiple metastases in bone and liver and, later, heart. Most studies report a relatively poor prognosis and limited treatment responsiveness for neuroendocrine breast carcinoma. Better understanding of the cellular origin and molecular pathogenesis of this relatively enigmatic rare disease is required.

Purpose: Despite numerous retrospective and case-control studies, risk factors related to overall survival (OS) and recurrence-free survival (RFS) in bilateral breast cancer are still being defined. The aim of our study was to describe tumor properties, patient characteristics, and method of cancer detection for a large cohort of patients with bilateral breast cancer and to assess the associations of these factors with OS and RFS., Patients and Methods: A retrospective chart review was conducted at the University of Texas M. D. Anderson Cancer Center. Among patients with bilateral breast cancer, we compared primary versus contralateral tumors and synchronous versus metachronous cancers. Patient and second tumor characteristics were evaluated for an association with OS and RFS, as measured from diagnosis of the second tumor., Results: Of 11,234 patients with primary breast cancer seen for an initial visit between July 1, 1997, and December 31, 2004, 771 patients (6.9%) were diagnosed with bilateral breast cancer. The 5-year OS rates based on stage of the second tumor were 87.7%, 87.7%, 69.6%, 45.1%, and 23.8% for stages 0, I, II, III, and IV, respectively (P < .0001). The 5-year OS rates for second tumor detection via mammogram/prophylactic mastectomy, physical examination, and self-examination were 81.6%, 70.9%, and 65.3%, respectively (P = .01). In addition, lymphovascular invasion, nuclear grade, hormonal receptor status, and histology were significantly associated with OS and RFS (P < .05). In a multivariable analysis, clinical stage and lymphovascular invasion remained significantly associated with OS (P < .05)., Conclusion: This study represents the largest single-institution review of bilateral breast cancer. Numerous second tumor characteristics were associated with survival. The results emphasize the importance of earlier detection and improved staging for contralateral breast cancer.

Purpose: With mammographic screening, the frequency of diagnosis of stage T1a,bN0M0 breast cancer has increased. Prognosis after locoregional therapy and benefit from adjuvant systemic therapy are poorly defined. We reviewed T1a,bN0M0 breast cancer cases registered in the Surveillance, Epidemiology, and End Results (SEER) Program to investigate the impact of prognostic factors on breast cancer-specific (BCSM) and non-breast cancer-related mortality., Methods: We identified T1a,bN0M0 breast cancer cases registered in the SEER Program from 1988 to 2001, and used the Kaplan-Meier product limit method to describe overall survival (OS). We estimated the probabilities of death resulting from breast cancer and from other causes, and analyzed associations of patient and tumor characteristics with OS, BCSM, and non-breast cancer-related mortality using the log-rank test, Cox proportional hazards models, and a competing-risk model. We constructed nomograms to assist physicians in adjuvant therapy decision making., Results: We identified 51,246 T1a,bN0M0 cases. Median follow-up was 64 months (range, 1 to 167 months). Median age at diagnosis was 65 years (range, 20 to 101 years). Ten-year probabilities of all-cause mortality and BCSM were 24% and 4%, respectively. Characteristics associated with increased probability of BCSM included age younger than 50 years at diagnosis, high tumor grade, estrogen receptor-negative status, progesterone receptor-negative status, and fewer than six nodes removed at axillary dissection. The constructed nomograms allow a comparison of predicted breast cancer-specific survival and non-breast cancer-specific survival in individual patients., Conclusion: Overall, the prognosis of patients with T1a,bN0M0 breast cancer is excellent. However, subgroups of patients who are at higher risk of BCSM and who should be considered for adjuvant systemic therapy can be identified.

Background: The relation that multifocality at diagnosis had to survival in women < 35 years of age was evaluated., Methods: Three hundred women seen at the M. D. Anderson Cancer Center between 1990 and 2002 were identified. Multifocality was defined as the presence of 2 or more foci of the same tumor clearly separated in the same breast. Patient characteristics and outcomes were tabulated and compared between uni- and multifocality. Survival outcomes were estimated with the Kaplan-Meier product limit method and compared between groups with the log-rank statistic. Cox proportional hazards models were fit to determine the association between multifocality and survival outcomes., Results: The median age was 32 years (range, 17-35). There were 58 patients (19%) with multifocal disease. At a median follow-up of 43.9 months there have been 101 deaths and 138 recurrences. Five-year overall survival (OS) estimates were 69.7% (95% confidence interval [CI], 63.1%, 77.1%) for patients with unifocal disease and 67.3% (95% CI, 54.6%, 83.0%) for patients with multifocal disease (P = .70). Five-year recurrence-free survival (RFS) was 44.4% (95% CI, 37.1%, 53.2%) for patients with unifocal disease and 57.1% (5% CI, 43.3%, 75.4%) for patients with multifocal disease, (P = .36). Nuclear grade was found to be an independent predictor of OS and RFS (hazard ratio [HR], 2.92, 95% CI, 1.24-6.87; HR, 2.09, 95% CI, 1.13-3.83, respectively)., Conclusions: Multifocality does not appear to influence prognosis in patients < 35 years of age. Nuclear grade continues to be an important prognostic factor for breast cancer in this age group.

Background: A previously published prospective randomized phase 3 trial showed that administration of 24 weeks of primary systemic chemotherapy (PST) with paclitaxel and FEC(75) (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/m(2)) weekly for 12 weeks followed by 4 cycles of FEC(75) (500 mg/m(2), 75 mg/m(2), and 500 mg/m(2), 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 FEC(75) chemotherapy. No severe cardiac events were observed with the regimen. The data concur with the results of a previously published trial., ((c) 2007 American Cancer Society.)

Background: The role for completion axillary dissection (CLND) in patients with breast cancer who have tumor-positive sentinel lymph nodes (SLN) has been questioned. The objective of this study was to examine the long-term safety of avoiding CLND in selected patients with positive SLNs., Methods: Patients with invasive breast cancer who underwent SLN biopsy at the authors' institution between 1993 and July 2005 were reviewed. Of 3366 total patients, 750 patients had a positive SLN. There were 196 patients with a positive SLN who did not undergo CLND based on clinician and patient preference. Clinicopathologic variables and treatment patterns were analyzed along with locoregional, distant recurrence, and survival., Results: Most tumors were infiltrating ductal carcinomas (74%), estrogen receptor-positive tumors (82%), progesterone receptor-positive tumors (70%), HER-2/neu-negative tumors (78.6%), and tumors were classified predominantly as either T1 or T2 (95.4%). The median number of SLNs removed was 3, and the median number of positive SLNs was 1. The median size of the tumor deposit in the SLN was 1.0 mm (range, 0.1-12.9 mm). Most SLNs were positive by on hematoxylin and eosin staining (64.3%), whereas 35.7% of SLNs were positive only by immunohistochemistry. Most patients underwent breast conservation (68.9%), radiation (58.2%), and chemotherapy (neoadjuvant in 14.3%, adjuvant in 55.6%). With a median follow-up of 29.5 months, no patients had an axillary recurrence, 1 patient had a supraclavicular lymph node recurrence, and 3 patients developed distant metastases. The median time to recurrence was 32 months., Conclusions: In selected patients who had positive SLNs, the locoregional failure rate was low without CLND. Prospective studies will be valuable to corroborate these results and to refine further the optimal selection criteria for this approach.

The purpose of this study was to evaluate whether the survival of women with inflammatory breast cancer (IBC) treated at our institution has improved over the past 30 years. Three-hundred ninety-eight patients with IBC were treated between 1974 and 2005. Patient characteristics and outcomes were tabulated and compared among decades of diagnosis. Survival outcomes were estimated with the Kaplan-Meier product limit method and compared among groups with the log-rank statistic. Cox proportional hazards models were fit to determine the association between year of diagnosis and survival outcomes after adjustment for patient and disease characteristics and treatments received. The median follow-up was 5.8 years (range, 0.3-23.8 years). There were 238 recurrences and 236 deaths. The median recurrence-free survival (RFS) duration was 2.3 years and the median overall survival (OS) time was 4.2 years. In the models for RFS and OS, after adjustment for patient and disease characteristics, increasing year of diagnosis was not associated with a decrease in the risk for recurrence (hazard ratio, [HR], 1.00; 95% confidence interval [CI], 0.97-1.04) or death (HR, 0.97; 95% CI, 0.94-1.01). Our data show that there has not been an important change in the prognosis of patients with IBC in the last 30 years. Clinical trials focusing on the management of this aggressive disease are warranted. Disclosure of potential conflicts of interest is found at the end of this article.

Purpose: The aim of this study was to investigate the role of postmastectomy radiation therapy in women with breast cancer who achieved a pathologic complete response (pCR) to neoadjuvant chemotherapy., Methods and Materials: We retrospectively identified 226 patients treated at our institution who achieved a pCR at surgery after receiving neoadjuvant chemotherapy. Of these, the 106 patients without inflammatory breast cancer who were treated with mastectomy were analyzed. The patients' clinical stages at diagnosis were I in 2%, II in 31%, IIIA in 30%, IIIB in 25%, and IIIC in 11% (American Joint Committee on Cancer 2003 system). Of the patients, 92% received anthracycline-based chemotherapy, and 38% also received a taxane. A total of 72 patients received postmastectomy radiation therapy, and 34 did not. The actuarial rates of local-regional recurrence (LRR) and survival of the two groups were compared using the log-rank test., Results: The median follow-up of surviving patients was 62 months. Use of radiation therapy did not affect the 10-year rates of LRR for patients with Stage I or II disease (the 10-year LRR rates were 0% for both groups). However, the 10-year LRR rate for patients with Stage III disease was significantly improved with radiation therapy (7.3% +/- 3.5% with vs. 33.3% +/- 15.7% without; p = 0.040). Within this cohort, use of radiation therapy was also associated with improved disease-specific and overall survival., Conclusion: Postmastectomy radiation therapy provides a significant clinical benefit for breast cancer patients who present with clinical Stage III disease and achieve a pCR after neoadjuvant chemotherapy.

Background: The purpose of the study was to describe the clinicopathologic characteristics and clinical outcomes of patients with primary breast angiosarcoma., Methods: The institutional database was searched to identify breast angiosarcoma patients seen between 1965 and 2002. Survival outcomes were estimated by the Kaplan-Meier method. The log-rank test was used to compare groups. Cox proportional hazards models were used for multivariate analysis., Results: In all, 69 patients were identified. Median follow-up was 40 months (range, 0-413 months). Median age was 46. Median tumor size at diagnosis was 5.5 cm. Thirteen (18.8%) patients received prior radiation for invasive breast carcinoma. Most patients underwent total mastectomy with (41%) or without (45%) axillary dissection. Regional metastasis to axillary lymph nodes was rare. There were 38 recurrences and 27 deaths. The 5-year overall (OS) and recurrence-free survival (RFS) rates were 61% (95% confidence interval [CI], 49%-76%) and 44% (95% CI, 33%-58%) with estimated medians of 100 and 37 months, respectively. In Cox proportional hazards models, OS and RFS were significantly associated only with T size and not with patient age, prior radiation, or chemotherapy administration. Of 29 patients treated with chemotherapy at recurrence, there were 4 complete and 10 partial responses (48%) with an anthracycline-ifosfamide or gemcitabine-taxane combination., Conclusions: Breast angiosarcoma is frequently advanced at diagnosis and has a tendency for local-regional recurrence. A significant number of responses to chemotherapy was observed in the metastatic setting. These data suggest that a multidisciplinary therapeutic approach should be employed in high-risk patients with large primary tumors., (Copyright (c) 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.

Introduction: This phase II trial was conducted to assess the efficacy and safety of 10-Ethyl-10-Deaza-Aminopterin (10-EDAM), a folate antagonist, in metastatic breast cancer patients who had received no more than one prior chemotherapy regimen., Methods: Fifty-five patients were treated on an initial weekly dose 80 mg/m(2) of 10-EDAM. Patients who had received a prior chemotherapy regimen in the adjuvant setting (group 1) were considered separately from patients who had received a prior chemotherapy regimen in the metastatic setting (group 2)., Results: The response rate for both groups combined was 18%, and median time to progression was 3 months. Median overall survival was 12 months. Treatment was associated with common chemotherapy-related toxicities, such as 25% grade three or four neutropenia and 20% grade three or four stomatitis., Conclusion: In patients with metastatic breast cancer who had received one prior chemotherapy regimen, 10-EDAM was well tolerated. In general, while definite antitumor activity was documented, time to progression was brief.

Background: The objectives of this study were to determine the locoregional recurrence (LRR) rate and to evaluate the correlation between surgical resection volume (RV) and LRR in patients with breast cancer who underwent segmental mastectomy after achieving a pathologic complete response (pCR) on neoadjuvant chemotherapy., Methods: The authors reviewed the outcomes of all 109 patients who underwent segmental mastectomy after the complete eradication of invasive disease by neoadjuvant chemotherapy at their institution between 1987 and 2002. LRRs were recorded, and RVs after segmental mastectomy were calculated and categorized as small, medium, or large., Results: At a median follow-up of 6.6 years, 3 patients (2.7%) developed LRR. In 2 of those patients, the recurrence was located in the ipsilateral breast; in the other patient, the recurrence was located in the supraclavicular lymph nodes with synchronous distant metastases. The median RV was 73.12 cm3 (range, 2.82-451.51 cm3). Large RVs (>125 cm3) were less common than small RVs (up to 70 cm3) or medium RVs (between 70 cm3 and 125 cm3; P = .009 and P<.0001, respectively). One patient with a small RV had an LRR at 4 years, and 2 patients with medium RVs had LLRs at 2.3 years and 6 years, respectively. The 5-year and 10-year LRR-free survival rates were 98.1% and 96.5%, respectively, and the corresponding overall survival rates were 96% and 92%, respectively., Conclusions: Segmental mastectomy was associated with excellent locoregional control in patients who achieved a pCR after neoadjuvant chemotherapy. Prospective studies are needed to examine whether decreasing the RVs in this patient population leads to an increased LRR rate., ((c) 2006 American Cancer Society.)

Breast cancer is the most common cancer in women in the U.S. and western Europe. Amplification of the her-2/neu gene occurs in approximately 25% of invasive ductal carcinomas of the breast. In experimental models, transfection of the her-2/neu gene results in transformation of mammary epithelial cells. In human breast cancer, amplification of the her-2/neu gene results in protein over expression and poor prognosis. Patients whose tumors have her-2/neu gene amplification have a shorter disease-free survival time than patients whose tumors exhibit a normal her-2/neu gene copy number. her-2/ neu gene amplification identifies a biologically unique subset of aggressive breast tumors that are sensitive to growth inhibition and apoptosis induced by anti-HER-2/neu-targeted therapies. The first HER-2/neu-targeted approach to reach the clinic was trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of the HER-2/neu protein. Trastuzumab therapy prolongs the survival of patients with metastatic HER-2/neu-overexpressing breast cancer when combined with chemotherapy and has recently been demonstrated to lead to dramatic improvements in disease-free survival when used in the adjuvant therapy setting in combination with or following chemotherapy. However, potential cardiotoxicity requires careful patient selection. Here, we review the recently completed clinical trials of adjuvant trastuzumab in the adjuvant setting. HER-2/neu testing, patient selection, cardiotoxicity, duration of therapy, and directions for future research are discussed.

Purpose: To evaluate the cardiac safety of long-term trastuzumab therapy in patients with human epidermal growth receptor 2 (HER2) -overexpressing metastatic breast cancer (MBC) treated at The University of Texas M.D. Anderson Cancer Center (Houston, TX)., Patients and Methods: Among 218 MBC patients treated with trastuzumab-based therapy for at least 1 year, 173 patients were assessable for cardiac toxicity. Cardiac events (CEs) were defined as follows: asymptomatic decrease of left ventricular ejection fraction (LVEF) below 50%; decrease of 20 percentage points in LVEF compared with the baseline; or signs or symptoms of congestive heart failure (CHF)., Results: The median cumulative time for trastuzumab administration was 21.3 months. The median follow-up was 32.6 months (range, 11.8 to 79.0 months). Forty-nine patients (28%) experienced a CE: three patients (1.7%) had an asymptomatic decrease in the LVEF of 20 percentage points, 27 patients (15.6%) experienced grade 2 cardiac toxicity, and 19 patients (10.9%) experienced grade 3 cardiac toxicity. All but three patients had improved LVEF or symptoms of CHF with trastuzumab discontinuation and appropriate therapy. There was one cardiac-related death (0.5%). Baseline LVEF was significantly associated with CE (hazard ratio, 0.94; P = .001). The hazard of a CE among patients taking concomitant taxanes was higher early in the follow-up period but declined during the course of follow-up., Conclusion: The risk of cardiac toxicity of long-term trastuzumab-based therapy is acceptable in this population, and this toxicity is reversible in the majority of the patients. In patients who have experienced a CE, additional treatment with trastuzumab can be considered after recovery of cardiac function.

Purpose: Mammographic screening has led to an increase in the number of small, node-negative breast cancers being diagnosed. Node-negative breast cancers that are < or = 1 cm are stage T1a,bN0M0. Controversy surrounds the prognosis of these patients with locoregional therapy only and the need for adjuvant systemic therapy., Methods: We performed a comprehensive review of the literature describing outcome and prognostic factors in stage T1a,bN0M0 breast cancer. We also reviewed current guidelines for systemic therapy in these patients., Results: Early studies reported 10-year relapse-free survival (RFS) rates higher than 90% without adjuvant systemic therapy, but some more recent data suggest inferior outcomes. High tumor grade is the most consistent factor associated with poor prognosis. Other adverse prognostic factors are younger age, lymphovascular invasion (LVI), high Ki-67, and larger tumors within the T1a,b subgroup. Patients with high-grade tumors and/or LVI may have 10-year RFS rates of less than 75% in the absence of systemic therapy. The prognostic significance of hormone receptor status is unclear. Current guidelines for the systemic management of early-stage breast cancer differ when applied to stage T1a,bN0M0, reflecting the controversial nature of the issue., Conclusion: Adjuvant systemic therapy is advisable for most patients with stage T1a,bN0M0 breast cancer who have grade 3 tumors and/or LVI. Other T1a,bN0M0 cases should be considered for systemic therapy based on clinicopathologic factors with known prognostic significance and assessment of the risk-benefit ratio. More reliable tools are needed to assess the prognosis of patients with stage T1a,bN0M0 breast cancer and their potential to benefit from specific therapeutic agents.

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: To combine clinical variables associated with pathologic complete response (pCR) and distant metastasis-free survival (DMFS) after preoperative chemotherapy (PC) into a prediction nomogram., Patients and Methods: Data from 496 patients treated with anthracycline PC at the Institut Gustave Roussy were used to develop and calibrate a nomogram for pCR based on multivariate logistic regression. This nomogram was tested on two independent cohorts of patients treated at the M.D. Anderson Cancer Center. The first cohort (n = 337) received anthracycline; the second cohort (n = 237) received a combination of paclitaxel and anthracycline PC. A separate nomogram to predict DMFS was developed using Cox proportional hazards regression model., Results: The pCR nomogram based on clinical stage, estrogen receptor status, histologic grade, and number of preoperative chemotherapy cycles had good discrimination and calibration in the training and the anthracycline-treated validation sets (concordance indices, 0.77, 0.79). In the paclitaxel plus anthracycline group, when the predicted pCR rate was less than 14%, the observed rate was 7.5%; for a predicted rate of > or = 38%, the actual rate was 85%. For a predicted rate between 14% to 38%, the observed rates were 50% with weekly and 27% with 3-weekly paclitaxel. This indicates that patients with intermediate chemotherapy sensitivity benefit the most from the optimized schedule of paclitaxel. Patients unlikely to achieve pCR to anthracylines remain at low probability for pCR, even after inclusion of paclitaxel. The nomogram for DMFS had a concordance index of 0.72 in the validation set and outperformed other prediction tools (P = .02)., Conclusion: Our nomograms predict pCR accurately and can serve as a basis to integrate future molecular markers into a clinical prediction model.

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 < or = 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: 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., Methods: Four hundred fifty-two women age < or = 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., Results: 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 (P < 0.0001) 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 (P < 0.0001), or those with > nuclear Grade 3 tumor specimens (P = 0.005)., Conclusions: 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., (Copyright 2005 American Cancer Society.)

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.

In this article, we report on a case of a pregnant patient with synchronous bilateral breast cancer treated with weekly paclitaxel. She presented after right mastectomy and anthracycline-based chemotherapy at an outside facility. Staging studies at our hospital before taxane administration demonstrated a 19-20-week gravid uterus and tumor in the remaining left breast. Weekly paclitaxel was given preoperatively during pregnancy. A normal male infant was delivered. Upon completion of chemotherapy, the patient underwent mastectomy and axillary lymph node dissection followed by comprehensive radiation therapy to the chest wall.

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.

Background: Inflammatory breast carcinoma (IBC) is a rare and aggressive malignancy. Therapy for patients with IBC is multidisciplinary, and response to preoperative chemotherapy is considered an important predictor of outcome. Although only a limited number of molecular markers have been investigated in this setting, none has exhibited prognostic value for patients with IBC., Methods: Immunohistochemical assays for P53, MDM-2, and MUC-1 were performed retrospectively to evaluate potential correlations between these markers and pathologic response, time to progression (TTP), and overall survival (OS) in 19 patients with IBC., Results: After a median follow-up period of 46 months, patients with tumors that overexpressed P53 and did not express MUC-1 had a significantly shorter median TTP and median OS compared with other patients., Conclusions: Expression of P53 and MUC-1 may be predictive of treatment efficacy and outcome for patients with IBC. Furthermore, these two markers may represent novel therapeutic targets in such patients., (Copyright 2004 American Cancer Society.)