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BACKGROUND Current treatments for lymphedema after breast cancer treatment are expensive and require ongoing intervention. Clinical experience and our preliminary published results suggest that acupuncture is safe and potentially useful. This study evaluates the safety and potential efficacy of acupuncture on upper-limb circumference in women with lymphedema. METHODS Women with a clinical diagnosis of breast cancer−related lymphedema (BCRL) for 0.5-5 years and with affected arm circumference ≥2 cm larger than unaffected arm received acupuncture treatment twice weekly for 4 weeks. Affected and unaffected arm circumferences were measured before and after each acupuncture treatment. Response, defined as ≥30% reduction in circumference difference between affected/unaffected arms, was assessed. Monthly follow-up calls for 6 months thereafter were made to document any complications and self-reported lymphedema status. RESULTS Among 37 enrolled patients, 33 were evaluated; 4 discontinued due to time constraints. Mean reduction in arm circumference difference was 0.90 cm (95% CI, 0.72-1.07; P < .0005). Eleven patients (33%) exhibited a reduction of ≥30% after acupuncture treatment. Seventy-six percent of patients received all treatments; 21% missed 1 treatment, and another patient missed 2 treatments. During the treatment period, 14 of the 33 patients reported minor complaints, including mild local bruising or pain/tingling. There were no serious adverse events and no infections or severe exacerbations after 255 treatment sessions and 6 months of follow-up interviews. CONCLUSIONS Acupuncture for BCRL appears safe and may reduce arm circumference. Although these results await confirmation in a randomized trial, acupuncture can be considered for women with no other options for sustained arm circumference reduction. Cancer 2013;119:2455-2461. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Increased pathologic complete response (pCR) rates observed with neoadjuvant chemotherapy (NCT) for some subsets of patients with invasive breast cancer have prompted interest in whether patients who achieved a pCR can be identified preoperatively and potentially spared the morbidity of surgery. The objective of this multicenter, retrospective study was to estimate the accuracy of preoperative magnetic resonance imaging (MRI) in predicting a pCR in the breast.Methods: MRI studies at baseline and after the completion of NCT plus data regarding pathologic response were collected retrospectively from 746 women who received treatment at 8 institutions between 2002 and 2011. Tumors were characterized by immunohistochemical phenotype into 4 categories based on receptor expression: hormone (estrogen and progesterone) receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative (n = 327), HR-positive/HER2-positive, (n = 148), HR-negative/HER2-positive, (n = 101), and triple-negative (HR-negative/HER2 negative; n = 155). In all, 194 of 249 patients (78%) with HER2-positive tumors received trastuzumab. Univariate and multivariate analyses of factors associated with radiographic complete response (rCR) and pCR were performed.Result: For the total group, the rCR and pCR rates were 182 of 746 patients (24%) and 179 of 746 patients (24%), respectively, and the highest pCR rate was observed for the triple-negative subtype (57 of 155 patients; 37%) and the HER2-positive subtype (38 of 101 patients; 38%). The overall accuracy of MRI for predicting pCR was 74%. The variables sensitivity, negative predictive value, positive predictive value, and accuracy differed significantly among tumor subtypes, and the greatest negative predictive value was observed in the triple-negative (60%) and HER2-positive (62%) subtypes.Conclusions: The overall accuracy of MRI for predicting pCR in invasive breast cancer patients who were receiving NCT was 74%. The performance of MRI differed between subtypes, possibly influenced by differences in pCR rates between groups. Future studies will determine whether MRI in combination with directed core biopsy improves the predictive value of MRI for pathologic response. [ABSTRACT FROM AUTHOR]

BACKGROUND: Increased pathologic complete response (pCR) rates observed with neoadjuvant chemotherapy (NCT) for some subsets of patients with invasive breast cancer have prompted interest in whether patients who achieved a pCR can be identified preoperatively and potentially spared the morbidity of surgery. The objective of this multicenter, retrospective study was to estimate the accuracy of preoperative magnetic resonance imaging (MRI) in predicting a pCR in the breast. METHODS: MRI studies at baseline and after the completion of NCT plus data regarding pathologic response were collected retrospectively from 746 women who received treatment at 8 institutions between 2002 and 2011. Tumors were characterized by immunohistochemical phenotype into 4 categories based on receptor expression: hormone (estrogen and progesterone) receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative (n = 327), HR-positive/HER2-positive, (n = 148), HR-negative/HER2-positive, (n = 101), and triple-negative (HR-negative/HER2 negative; n = 155). In all, 194 of 249 patients (78%) with HER2-positive tumors received trastuzumab. Univariate and multivariate analyses of factors associated with radiographic complete response (rCR) and pCR were performed. RESULT: For the total group, the rCR and pCR rates were 182 of 746 patients (24%) and 179 of 746 patients (24%), respectively, and the highest pCR rate was observed for the triple-negative subtype (57 of 155 patients; 37%) and the HER2-positive subtype (38 of 101 patients; 38%). The overall accuracy of MRI for predicting pCR was 74%. The variables sensitivity, negative predictive value, positive predictive value, and accuracy differed significantly among tumor subtypes, and the greatest negative predictive value was observed in the triple-negative (60%) and HER2-positive (62%) subtypes. CONCLUSIONS: The overall accuracy of MRI for predicting pCR in invasive breast cancer patients who were receiving NCT was 74%. The performance of MRI differed between subtypes, possibly influenced by differences in pCR rates between groups. Future studies will determine whether MRI in combination with directed core biopsy improves the predictive value of MRI for pathologic response. Cancer 2013. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND: This study sought to estimate the risk of breast cancer (BC) after a diagnosis of ovarian cancer (OC) associated with mutation of the BRCA1/2 (breast cancer, early onset) genes ( BRCA-OC). METHODS: The Memorial Sloan-Kettering Cancer Center and the University of Pennsylvania, clinical genetics databases were searched to identify women with BRCA-OC who participated in genetic testing and follow-up studies from 1995 to 2009. The primary objective was to determine the risk of developing BC after BRCA-OC. Overall survival (OS) and BC-free survival (BCFS) were determined by the Kaplan-Meier method; patients were censored at the time of last follow-up. RESULTS: A total of 164 patients had BRCA-OC (115 with BRCA1; 49 with BRCA2). Of these 164 patients, 152 developed OC prior to BRCA testing (median time to testing, 2.4 years [0.01-55 years]). Median follow-up from OC for those not developing BC was 5.8 years (0.25-55.6 years). There were 46 deaths, but none were due to BC. The 5- and 10-year OS were 85% (95% confidence interval [CI] = 0.78, 0.90) and 68% (95% CI = 0.59, 0.76), respectively. There were 18 metachronous BC diagnoses. The 5- and 10-year BCFS were 97% (95% CI = 0.92, 0.99) and 91% (95% CI = 0.82, 0.95), respectively. A subset of 64 women were tested either before or within 12 months of BRCA-OC. In this pseudo-incident subset, 5- and 10- year OS was 71% (95% CI = 0.53, 0.83) and 62% (95% CI = 0.44, 0.75), respectively, and 5- and 10-year BCFS were 100% and 87% (95% CI = 0.56, 0.96), respectively. CONCLUSIONS: OS was dominated by OC deaths. Metachronous BC risk was lower than reported for unaffected BRCA mutation carriers. These results support nonsurgical management of BC risk in women with BRCA-OC. Cancer 2013. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background High-quality care must be not only appropriate but also timely. We assessed time to initiation of adjuvant chemotherapy for breast cancer as well as factors associated with delay to help identify targets for future efforts to reduce unnecessary delays. Methods Using data from the National Comprehensive Cancer Network (NCCN) Outcomes Database, we assessed the time from pathological diagnosis to initiation of chemotherapy (TTC) among 6622 women with stage I to stage III breast cancer diagnosed from 2003 through 2009 and treated with adjuvant chemotherapy in nine NCCN centers. Multivariable models were constructed to examine factors associated with TTC. All statistical tests were two-sided. Results Mean TTC was 12.0 weeks overall and increased over the study period. A number of factors were associated with a longer TTC. The largest effects were associated with therapeutic factors, including immediate postmastectomy reconstruction (2.7 weeks; P < .001), re-excision (2.1 weeks; P < .001), and use of the 21-gene reverse-transcription polymerase chain reaction assay (2.2 weeks; P < .001). In comparison with white women, a longer TTC was observed among black (1.5 weeks; P < .001) and Hispanic (0.8 weeks; P < .001) women. For black women, the observed disparity was greater among women who transferred their care to the NCCN center after diagnosis (Pinteraction = .008) and among women with Medicare vs commercial insurance (Pinteraction < .001). Conclusions Most observed variation in TTC was related to use of appropriate therapeutic interventions. This suggests the importance of targeted efforts to minimize potentially preventable causes of delay, including inefficient transfers in care or prolonged appointment wait times. [ABSTRACT FROM PUBLISHER]

BACKGROUND: In this retrospective, single-institution study, the authors examine the maximum standardized uptake value (SUVmax) on positron emission tomography/computed tomography (PET/CT) images as a prognostic variable in patients with newly diagnosed metastatic breast cancer (MBC). METHODS: Patients with ≥1 metastatic lesion on PET/CT images that were obtained within 60 days of their MBC diagnosis between January 1, 2001 and December 31, 2008 were included. Patients were excluded if they had received chemotherapy ≤30 days before the PET/CT images were obtained. Electronic medical reports were reviewed to determine the SUVmax and overall survival. Because of intraindividual variation in the SUV by body site, separate analyses were conducted by metastatic site. Relationships between site-specific PET/CT variable tertiles and overall survival were assessed using Cox regression; hazard ratios for the highest tertile versus the lowest tertile were reported. RESULTS: In total, 253 patients were identified, and their median age was 57 years (range, 27-90 years). Of these, 152 patients (60%) died, and the median follow-up was 40 months. On univariate analysis, SUVmax tertile was strongly associated with overall survival in patients who had bone metastases (N = 141; hazard ratio, 3.13; 95% confidence interval, 1.79-5.48; P < .001). This effect was maintained on multivariate analysis (HR = 3.19; 95% confidence interval, 1.64-6.20, P = .002) after correcting for known prognostic variables. A greater risk of death was associated with SUVmax tertile in patients who had metastases to the liver (N = 46; hazard ratio, 2.07; 95% confidence interval, 0.90-4.76), lymph nodes (N = 149; hazard ratio, 1.1; 95% confidence interval, 0.69-1.88), and lung (N = 62; hazard ratio, 2.2; 95% confidence interval, 0.97-4.95), although these results were not significant ( P = .18, P = .31, and P = .095, respectively). CONCLUSIONS: The current results indicate that PET/CT has value as a prognostic tool in patients with newly diagnosed MBC to bone. Cancer 2012. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND: The authors evaluated the clinical characteristics, natural history, and outcomes of patients who had ≤1 cm, lymph node-negative, triple-negative breast cancer (TNBC). METHODS: After excluding patients who had received neoadjuvant therapy, 1022 patients with TNBC who underwent definitive breast surgery during 1999 to 2006 were identified from an institutional database. In total, 194 who had lymph node-negative tumors that measured ≤1 cm comprised the study population. Clinical data were abstracted, and survival outcomes were analyzed. RESULTS: The median follow-up was 73 months (range, 5-143 months). The median age at diagnosis was 55.5 years (range, 27-84 years). Tumor (T) classification was microscopic (T1mic) in 16 patients (8.2%), T1a in 49 patients (25.3%), and T1b in 129 patients (66.5%). Most tumors were poorly differentiated (n = 142; 73%), lacked lymphovascular invasion (n = 170; 87.6%), and were detected by screening (n = 134; 69%). In total, 129 patients (66.5%) underwent breast-conserving surgery, and 65 patients (33.5%) underwent mastectomy. One hundred thirteen patients (58%) received adjuvant chemotherapy, and 123 patients (63%) received whole-breast radiation. The patients who received chemotherapy had more adverse clinical and disease features (younger age, T1b tumor, poor tumor grade; all P < .05). Results from testing for the breast cancer ( BRCA) susceptibility gene were available for 49 women: 19 women had BRCA1 mutations, 7 women had BRCA2 mutations, and 23 women had no mutations. For the entire group, the 5-year local recurrence-free survival rate was 95%, and the 5-year distant metastasis-free survival rate was 95%. There was no difference between patients with T1mic/T1a tumors and patients with T1b tumors in the distant recurrence rate (94.5% vs 95.5%, respectively; P = .81) or in the receipt of chemotherapy (95.9% vs 94.5%, respectively; P = .63). CONCLUSIONS: Excellent 5-year locoregional and distant control rates were achievable in patients with TNBC who had tumors ≤1.0 cm, 58% of whom received chemotherapy. These results identified a group of patients with TNBC who had favorable outcomes after early detection and multimodality treatment. Cancer 2012. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]

Patients with breast cancer, which lacks ER, PR, and HER2; 'triple negative' (TNBC), are at increased risk of brain metastases (BMs). However, the impact of modern therapy on the risk of BMs and outcomes remains largely unknown. In this retrospective, single-institution study we assessed the incidence of BMs, the therapeutic options, and overall survival, in a recent cohort of patients with TNBC. Women diagnosed with early stage TNBC from January 1, 1998 to December 31, 2007 were identified through institutional databases. Electronic medical records were reviewed to assess patterns of recurrence, treatment, and survival. In total, 1,323 patients, median age 53 years (range 20-91), were identified. There were 298 patients (23%) who developed metastatic disease, of whom, 99 (33%) developed BMs, representing 7.5% of the entire cohort. Following BM diagnosis, treatment consisted of: radiotherapy 87 (88%) patients, resection 26 (26%) patients, and systemic chemotherapy 70 (71%) patients, with a median of 1.0 (range 0-8) chemotherapy regimens. The actuarial median survival from diagnosis of BMs is 5 months (95% CI 4-7 months). This single-institution, retrospective study confirms that the prognosis for patients with BMs from TNBC remains poor. This group of patients urgently needs improved therapies. [ABSTRACT FROM AUTHOR]

BACKGROUND: Pregnancy-associated breast cancer (PABC) may be defined as breast cancer diagnosed during pregnancy or within 1 year of giving birth. Conflicting data exist regarding the impact of pregnancy on clinical features and prognosis of breast cancer. METHODS: A single-institution retrospective chart review was performed of 99 patients identified with PABC between 1992 and 2007. Non-PABC controls were matched 2:1 to PABC cases by year of diagnosis and age. The differences in clinical features were compared between cases and controls using chi-square tests. Univariate and multivariate analyses were performed to assess the effect of PABC on survival. RESULTS: Of the 99 PABC cases, breast cancer was diagnosed during pregnancy in 36 patients, and after delivery in 63. PABC cases were more likely than controls to be negative for estrogen receptor (59% vs 31%, P < .0001) and negative for progesterone receptor (72% vs 40%, P < .0001). Cases were also more likely to have advanced T class ( P = .0271) and N class ( P = .0104) and higher grade tumors ( P = .0115). With a median follow-up of 6.3 years for cases and 4.7 years for controls, overall survival did not differ between cases and controls ( P = .0787). On multivariate analysis, the independent prognostic factors for overall survival were estrogen receptor status ( P = .0031) and N class ( P = .0003). The diagnosis of PABC was not an independent prognostic factor ( P = .1317). CONCLUSIONS: PABC is associated with more adverse tumor features than non-PABC matched for age and year of diagnosis. After correcting for pathologic features, the diagnosis of PABC is not in itself an adverse prognostic factor for survival. Cancer 2011. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND: Breast reconstruction with tissue expander (TE)/permanent implant (PI) followed by postmastectomy radiation (PMRT) is an increasingly popular treatment for breast cancer patients. The long-term rates of permanent implant removal or replacement (PIRR) and clinical outcomes in patients treated with a uniform reconstructive surgery and radiation regimen were evaluated. METHODS: Between 1996 and 2006, 1639 patients with stage II-III breast cancer received modified radical mastectomy (MRM) at Memorial Sloan-Kettering Cancer Center. A total of 751 received TE placement at the time of mastectomy. Of these, 151 patients went on to receive chemotherapy and exchange of the TE for a permanent implant, followed by PMRT. Clinical outcomes and PIRR-free rates were estimated by Kaplan-Meier methods. Cox regression model was used to examine patient, disease, and treatment characteristics associated with PIRR. RESULTS: Median follow-up was 86 months (range, 11-161 months). The 7-year PIRR-free rate was 71% (38 PIRRs in 35 patients). The 7-year rate of PI replacement was 17.1% (21), and removal was 13.3% (17). Reasons for PIRR included infection (15); implant extrusion, shift, leak, or rupture (4); patient request (1), or multifactorial (17). On univariate analysis, no factor was significantly associated with PIRR. Two patients experienced local recurrence in the chest wall, both after 7 years. The 7-year distant metastasis-free survival rate was 81% and overall survival 93%. CONCLUSIONS: Favorable 7-year PIRR rates and clinical outcomes were achieved in a sizable cohort of patients treated with homogeneous sequencing, radiation, and reconstructive surgery and lengthy follow-up. Factors predictive for high risk of PIRR were not identifiable in this population. Cancer 2012. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND: Randomized data suggest that axillary clearance is not necessary in select, clinically lymph node-negative women with positive sentinel lymph node (SLN) biopsies (SLNBs) who undergo breast-conserving surgery or receive whole-breast radiotherapy and systemic therapy. The additional value of axillary radiotherapy in these patients is unknown. METHODS: The authors identified 326 patients with positive SLNBs who underwent breast-conserving surgery without axillary lymph node dissection from 1997 to 2009. SLN tumor deposits measured ≤0.2 mm in 58% of patients, 0.3 to 2.0 mm in 35% of patients, and >2 mm in 7% Patients. Ninety-three percent of patients received adjuvant radiotherapy. Radiation fields were categorized as standard tangents, high tangents, comprehensive (tangents plus supraclavicular), or partial breast to reflect coverage of the axilla. Standard tangents included both prone and supine positions. Regional failure was defined as recurrence in the ipsilateral supraclavicular, axillary, or internal mammary lymph nodes. RESULTS: The median follow-up was 55 months (range, 1-158 months). The 4-year rates of regional control, local control, disease-free survival, and overall survival were 99%, 98%, 95%, and 91%, respectively. Three patients had regional recurrences. Two of those patients received adjuvant radiotherapy with standard supine tangents, and 1 patient did not receive radiotherapy. No regional recurrences occurred among 66 patients who received radiotherapy in the prone position. CONCLUSIONS: Regional control was high (99% at 4 years) in patients who had low-volume SLN disease who did not undergo axillary dissection, regardless of whether the axilla was irradiated. Whole-breast radiation alone, including in the prone position, is sufficient treatment after breast-conserving surgery for select patients with tumor-containing SLNs who omit axillary dissection. Cancer 2012;. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND: Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer have a higher risk of locoregional recurrence (LRR), even in the setting of early stage, lymph node-negative disease. In this sequential, retrospective study, the authors evaluated whether adjuvant trastuzumab was associated with reduced LRR in women with lymph node-negative, HER2-positive disease who received breast-conservation therapy (BCT). METHODS: By using an institutional database, 197 women were identified who had lymph node-negative, HER2-positive breast cancer measuring ≤5 cm diagnosed between 2002 and 2008 and who received BCT, including whole-breast irradiation. Two cohorts were compared: 70 women who did not receive trastuzumab (the no-trastuzumab cohort) and 102 women who did receive trastuzumab (the trastuzumab cohort). Kaplan-Meier methods were used to estimate LRR-free survival. RESULTS: The 2 cohorts were similar in age, tumor size, histology, and hormone receptor status. Chemotherapy was received by 73% of the no-trastuzumab cohort and by 100% of the trastuzumab cohort. In both groups, 99% of patients completed radiotherapy with a median dose of 60 Gray. The median recurrence-free follow-up was 86 months for the no-trastuzumab cohort and 47 months for the trastuzumab cohort. The 3-year LRR-free survival rate was 90% (95% confidence interval, 83%-97%) for the no-trastuzumab cohort and 99% (95% confidence interval, 97%-100%) for the trastuzumab cohort. In the no-trastuzumab cohort, LRR occurred in 7 patients (median time to LRR, 14 months). In the trastuzumab cohort, there was 1 LRR at 14 months. CONCLUSIONS: Even among women with lower risk breast cancer, the relatively high locoregional failure rates associated with positive HER2 status could be reduced markedly with adjuvant trastuzumab chemotherapy. Within 3 years, a 10% LRR rate without trastuzumab and a 1% LRR rate with trastuzumab were observed in women with lymph node-negative disease who received BCT. Cancer 2012. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND: Previous research has found an 80% return-to-work rate in mid-income white breast cancer survivors, but little is known about the employment trajectory of low-income minorities or whites. We set out to compare the trajectories of low-income Latina and non-Latina white survivors and to identify correlates of employment status. METHODS: Participants were low-income women who had localized breast cancer, spoke English or Spanish, and were employed at the time of diagnosis. Interviews were conducted 6, 18, and 36 months after diagnosis. Multivariate logistic regression was used to identify independent correlates of employment status at 18 months. RESULTS: Of 290 participants, 62% were Latina. Latinas were less likely than non-Latina whites to be working 6 months (27% vs 49%; P = .0002) and 18 months (45% vs 59%; P = .02) after diagnosis, but at 36 months there was no significant difference (53% vs 59%; P = .29). Latinas were more likely to be manual laborers than were non-Latina whites ( P < .0001). Baseline job type and receipt of axillary node dissection were associated with employment status among Latinas but not non-Latina whites. CONCLUSIONS: Neither low-income Latinas nor non-Latina whites approached the 80% rate of return to work seen in wealthier white populations. Latinas followed a protracted return-to-work trajectory compared to non-Latina whites, and differences in job type appear to have played an important role. Manual laborers may be disproportionately impacted by surgical procedures that limit physical activity. This can inform the development of rehabilitative interventions and may have important implications for the surgical and postsurgical management of patients. Cancer 2011;. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

BACKGROUND: Several large, randomized trials established the benefits of adjuvant trastuzumab with chemotherapy. However, the benefit for women with small, node-negative HER2-positive (HER2+) disease is unknown, as these patients were largely excluded from these trials. Therefore, a retrospective, single-institution, sequential cohort study of women with small, node-negative, HER2+ breast cancer who did or did not receive adjuvant trastuzumab was conducted. METHODS: Women with ≤2 cm, node-negative, HER2+ (immunohistochemistry 3+ or fluorescence in situ hybridization ≥2) breast cancer were identified through an institutional database. A 'no-trastuzumab' cohort of 106 trastuzumab-untreated women diagnosed between January 1, 2002 and May 14, 2004 and a 'trastuzumab' cohort of 155 trastuzumab-treated women diagnosed between May 16, 2005 and December 31, 2008 were described. Survival and recurrence outcomes were estimated by Kaplan-Meier methods. RESULTS: The cohorts were similar in age, median tumor size, histology, hormone receptor status, hormone therapy, and locoregional therapy. Chemotherapy was administered in 66% and 100% of the 'no trastuzumab' and 'trastuzumab' cohorts, respectively. The median recurrence-free and survival follow-up was: 6.5 years (0.7-8.5) and 6.8 years (0.7-8.5), respectively, for the 'no trastuzumab' cohort and 3.0 years (0.5-5.2) and 3.0 years (0.6-5.2), respectively, for the 'trastuzumab' cohort. The 3-year locoregional invasive recurrence-free, distant recurrence-free, invasive disease-free, and overall survival were 92% versus 98% ( P = .0137), 95% versus 100% ( P = .0072), 82% versus 97% ( P < .0001), and 97% versus 99% ( P = .18) for the 'no trastuzumab' and 'trastuzumab' cohorts, respectively. CONCLUSIONS: Women with small, node-negative, HER2+ primary breast cancers likely derive significant benefit from adjuvant trastuzumab with chemotherapy. Cancer 2011;. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

PURPOSE In breast cancer, preclinical models suggest that antiangiogenic therapy in combination with antiestrogens may prevent or overcome resistance to endocrine therapy. This review aims to discuss feasibility and phase II studies that have led to ongoing randomized trials of combination treatment with antiangiogenic agents and endocrine therapy. METHODS A systematic search of PubMed and conference databases was performed to identify reports of phase I-III clinical trials investigating combination endocrine therapy with antiangiogenic agents in breast cancer. In addition, results of our feasibility trial of letrozole plus bevacizumab were updated. RESULTS We identified 11 trials that reported data for or are currently evaluating the combination of antiangiogenic agents with endocrine therapy: seven trials evaluated endocrine therapy plus bevacizumab, and four trials evaluated endocrine therapy plus tyrosine kinase inhibitors (TKIs) of vascular endothelial growth factor receptor (VEGFR). Side effects that have emerged from this combination include hypertension (HTN), proteinuria, and ''off-target'' TKI side effects including skin rash and diarrhea. Early efficacy data suggests activity for this combination. CONCLUSION Clinical trials have demonstrated the feasibility of endocrine therapy in combination with antiangiogenic agents. Phase III proof-of-efficacy trials of endocrine plus anti-VEGF therapy are ongoing (CALGB 40503, GEICAM 2006-11/GBG 51). [ABSTRACT FROM AUTHOR]

BACKGROUND: Capecitabine has antitumor activity in metastatic breast cancer (MBC); however, its optimal dose and schedule remain unclear. Mathematical modeling predicts that a capecitabine schedule 7 days of treatment followed by 7 days of rest (7-7) will improve efficacy and minimize toxicity. Bevacizumab has demonstrated the ability to improve outcomes when it is added to chemotherapy, including capecitabine, in the first-line and second-line settings. METHODS: Patients with measurable MBC received oral capecitabine (2000 mg twice daily; 7-7), and intravenous bevacizumab (10 mg/kg every 2 weeks). The primary endpoint was the response rate. Secondary endpoints included toxicity, the clinical benefit rate, and progression-free survival (PFS). RESULTS: Forty-one patients were treated. After a median of 7 cycles (range, 1-32 cycles), partial responses were observed in 20% of patients, and stable disease for ≥6 months was noted in 35% patients. The median PFS was 8 months. The most common treatment-related toxicities were hand-foot syndrome (49% grade 2, 20% grade 3/4) hypertension (12% grade 2, 10% grade 3/4), and fatigue (12% grade 2, 2% grade 3/4). Diarrhea (5% grade 2, 0% grade 3/4), nausea (0% grade 2-4), and vomiting (0% grade 2-4) were rare. CONCLUSIONS: Capecitabine administered for 7 days followed by a 7-day rest in combination with bevacizumab had modest efficacy and an acceptable toxicity profile in patients with MBC. Gastrointestinal toxicity with this schedule was minimal. Cancer 2011;. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

Clinical benefits from trastuzumab and other anti-HER2 therapies in patients with HER2 amplified breast cancer remain limited by primary or acquired resistance. To identify potential mechanisms of resistance, we established trastuzumab-resistant HER2 amplified breast cancer cells by chronic exposure to trastuzumab treatment. Genomewide copy-number variation analyses of the resistant cells compared with parental cells revealed a focal amplification of genomic DNA containing the cyclin E gene. In a cohort of 34 HER2+ patients treated with trastuzumab-based therapy, we found that cyclin E amplification/overexpression was associated with a worse clinical benefit (33.3% compared with 87.5%, P < 0.02) and a lower progression-free survival (6 mo vs. 14 mo, P < 0.002) compared with nonoverexpressing cyclin E tumors. To dissect the potential role of cyclin E in trastuzumab resistance, we studied the effects of cyclin E overexpression and cyclin E suppression. Cyclin E overexpression resulted in resistance to trastuzumab both in vitro and in vivo. Inhibition of cyclin E activity in cyclin E-amplified trastuzumab resistant clones, either by knockdown of cyclin E expression or treatment with cyclin-dependent kinase 2 (CDK2) inhibitors, led to a dramatic decrease in proliferation and enhanced apoptosis. In vivo, CDK2 inhibition significantly reduced tumor growth of trastuzumab-resistant xenografts. Our findings point to a causative role for cyclin E overexpression and the consequent increase in CDK2 activity in trastuzumab resistance and suggest that treatment with CDK2 inhibitors may be a valid strategy in patients with breast tumors with HER2 and cyclin E coamplification/overexpression. [ABSTRACT FROM AUTHOR]

The article focuses on a study which examined the influence of race/ethnicity and tumor subtype on pathologic complete response (pCR) after receiving neoadjuvant chemotherapy. The study included 2.074 patients diagnosed with breast cancer between 1994 and 2008, and were treated with neoadjuvant anthracycline- and taxane-based chemotherapy. It found that lack of pCR, breast cancer subtytpe, grade 3 tumors and lymphovascular invasion were associated with recurrence-free survival (RFS) and overall survival (OS).

Background: To hasten and improve anticancer drug development, we created a novel approach to generating and analyzing preclinical dose-scheduling data so as to optimize benefit-to-toxicity ratios. Methods: We applied mathematical methods based upon Norton-Simon growth kinetic modeling to tumor-volume data from breast cancer xenografts treated with capecitabine (Xeloda®, Roche) at the conventional schedule of 14 days of treatment followed by a 7-day rest (14-7). Results: The model predicted that 7 days of treatment followed by a 7-day rest (7-7) would be superior. Subsequent preclinical studies demonstrated that this biweekly capecitabine schedule allowed for safe delivery of higher daily doses, improved tumor response, and prolonged animal survival. Conclusions: We demonstrated that the application of Norton-Simon modeling to the design and analysis of preclinical data predicts an improved capecitabine dosing schedule in xenograft models. This method warrants further investigation and application in clinical drug development. [ABSTRACT FROM AUTHOR]

Abstract: Background/purpose: To evaluate radiation plans of patients undergoing mastectomy with immediate expander-implant reconstruction followed by postmastectomy radiation therapy (PMRT). Materials/methods: We identified 41 patients from June 2004 to May 2007 who underwent mastectomy, immediate expander-implant reconstruction, and PMRT with intensity-modulated radiation therapy. We assessed chest wall (CW) coverage and volume of heart and lung irradiated. Results: In 73% of patients, all CW borders were adequately covered, and in 22%, all but 1 border were adequately covered. The total lung V 20 was<20% in 39/41 patients. The mean lung V 20 was 13% (range, 3–23%), and the mean heart D mean was 2.81Gy (range, 0.53–9.60Gy). In patients with left-sided lesions without internal mammary nodes (IMNs) treatment (n =22), the mean lung V 20 was 12.6% and the mean heart D mean was 3.90Gy, and in the patient with IMN treatment, the lung V 20 was 18% and heart D mean was 8.04Gy. For right-sided lesions without IMN treatment (n =12), the mean lung V 20 was 12.4% and the mean heart D mean was 0.90Gy, and in patients with IMN treatment (n =6), these numbers were 17.8% and 1.76Gy. At a median follow-up of 29months, the 30-month actuarial local control was 97%. Conclusions: In women undergoing immediate expander-implant reconstruction, PMRT can achieve excellent local control with acceptable heart and lung doses. These results can be achieved even when the IMN are being treated, although doses to the heart and lungs will be higher. [Copyright &y& Elsevier]

Summary: Background: The 21-gene recurrence score assay is prognostic for women with node-negative, oestrogen-receptor-positive breast cancer treated with tamoxifen. A low recurrence score predicts little benefit of chemotherapy. For node-positive breast cancer, we investigated whether the recurrence score was prognostic in women treated with tamoxifen alone and whether it identified those who might not benefit from anthracycline-based chemotherapy, despite higher risks of recurrence. Methods: The phase 3 trial SWOG-8814 for postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer showed that chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF) before tamoxifen (CAF-T) added survival benefit to treatment with tamoxifen alone. Optional tumour banking yielded specimens for determination of recurrence score by RT-PCR. In this retrospective analysis, we assessed the effect of recurrence score on disease-free survival by treatment group (tamoxifen vs CAF-T) using Cox regression, adjusting for number of positive nodes. Findings: There were 367 specimens (40% of the 927 patients in the tamoxifen and CAF-T groups) with sufficient RNA for analysis (tamoxifen, n=148; CAF-T, n=219). The recurrence score was prognostic in the tamoxifen-alone group (p=0·006; hazard ratio [HR] 2·64, 95% CI 1·33–5·27, for a 50-point difference in recurrence score). There was no benefit of CAF in patients with a low recurrence score (score <18; log-rank p=0·97; HR 1·02, 0·54–1·93), but an improvement in disease-free survival for those with a high recurrence score (score ≥31; log-rank p=0·033; HR 0·59, 0·35–1·01), after adjustment for number of positive nodes. The recurrence score by treatment interaction was significant in the first 5 years (p=0·029), with no additional prediction beyond 5 years (p=0·58), although the cumulative benefit remained at 10 years. Results were similar for overall survival and breast-cancer-specific survival. Interpretation: The recurrence score is prognostic for tamoxifen-treated patients with positive nodes and predicts significant benefit of CAF in tumours with a high recurrence score. A low recurrence score identifies women who might not benefit from anthracycline-based chemotherapy, despite positive nodes. Funding: National Cancer Institute and Genomic Health. [Copyright &y& Elsevier]

Breast tumor volume measured on MRI has been used to assess response to neoadjuvant chemotherapy. However, accurate and reproducible delineation of breast lesions can be challenging, since the lesions may have complicated topological structures and heterogeneous intensity distributions. In this article, the authors present an advanced computerized method to semiautomatically segment tumor volumes on T1-weighted, contrast-enhanced breast MRI. The method starts with manual selection of a region of interest (ROI) that contains the lesion to be segmented in a single image, followed by automated separation of the lesion volume from its surrounding breast parenchyma by using a unique combination of the image processing techniques including Gaussian mixture modeling and a marker-controlled watershed transform. Explicitly, the Gaussian mixture modeling is applied to an intensity histogram of the pixels inside the ROI to distinguish the tumor class from other tissues. Based on the ROI and the intensity distribution of the tumor, internal and external markers are determined and the tumor contour is delineated using the marker-controlled watershed transform. To obtain the tumor volume, the segmented tumor in one slice is propagated to the adjacent slice to form an ROI in that slice. The marker-controlled watershed segmentation is then used again to obtain a tumor contour in the propagated slice. This procedure is terminated when there is no lesion in an adjacent slice. To reduce measurement variations possibly caused by the manual selection of the ROI, the segmentation result is refined based on an automatically determined ROI based on the segmented volume. The algorithm was applied to 13 patients with breast cancer, prospectively accrued prior to beginning neoadjuvant chemotherapy. Each patient had two MRI scans, a baseline MRI examination prior to commencing neoadjuvant chemotherapy and a 1 week follow-up after receiving the first dose of neoadjuvant chemotherapy. Blinded to the computer segmentation results, two experienced radiologists manually delineated all tumors independently. The computer results were then compared with the manually generated results using the volume overlap ratio, defined as the intersection of the computer- and radiologist-generated tumor volumes divided by the union of the two. The algorithm reached overall overlap ratios of 62.6%±9.1% and 61.0%±11.3% in comparison to the two manual segmentation results, respectively. The overall overlap ratio between the two radiologists’ manual segmentations was 64.3%±10.4%. Preliminary results suggest that the proposed algorithm is a promising method for assisting in tumor volume measurement in contrast-enhanced breast MRI. [ABSTRACT FROM AUTHOR]

Summary: Metastasis may arise years after removal of a primary tumor. The mechanisms allowing latent disseminated cancer cells to survive are unknown. We report that a gene expression signature of Src activation is associated with late-onset bone metastasis in breast cancer. This link is independent of hormone receptor status or breast cancer subtype. In breast cancer cells, Src is dispensable for homing to the bones or lungs but is critical for the survival and outgrowth of these cells in the bone marrow. Src mediates AKT regulation and cancer cell survival responses to CXCL12 and TNF-related apoptosis-inducing ligand (TRAIL), factors that are distinctively expressed in the bone metastasis microenvironment. Breast cancer cells that lodge in the bone marrow succumb in this environment when deprived of Src activity. [Copyright &y& Elsevier]

Abstract: Mutation screening of the breast and ovarian cancer predisposition genes BRCA1 and BRCA2 is becoming an increasingly important part of clinical practice. Classification of rare non-truncating sequence variants in the BRCA1 and BRCA2 genes is problematic because it is not known whether these subtle changes alter function sufficiently to predispose cells to cancer development. Several studies have reported the biochemical analysis of BRCA2 variants, which disrupted the 5′ and 3′splicing consensus elements (the GU-AG rule). However, little has been done to look into the consequences of variants located outside the 5′ and 3′ consensus splice sites. cDNA analysis demonstrates that the BRCA2*IVS4-12del5 splice site variant results in the deletion of exon 5, and the gene putatively produces a truncated BRCA2 protein of 164 amino acids instead of 3418 with the incorporation of 22 out of frame amino acids. The pattern of breast, melanoma, and pancreatic cancers in the paternal kindred is consistent with autosomal dominant inheritance of a deleterious BRCA2 mutation. Analysis of a tumor specimen indicates loss of heterozygosity (LOH). Sequence alignment indicates the deleted region is well conserved across different species. These results support the conclusion that BRCA2 IVS4-12del5 is a deleterious mutation. This study will shed light on the reclassification of intronic variants that do not disrupt the 5′ and 3′ splice sites (the GU-AG rule). [Copyright &y& Elsevier]

Purpose: To determine intervals between surgery and adjuvant chemotherapy and radiation in patients treated with mastectomy with immediate expander-implant reconstruction, and to evaluate locoregional and distant control and overall survival in these patients. Methods and Materials: Between May 1996 and March 2004, 104 patients with Stage II–III breast cancer were routinely treated at our institution under the following algorithm: (1) definitive mastectomy with axillary lymph node dissection and immediate tissue expander placement, (2) tissue expansion during chemotherapy, (3) exchange of tissue expander for permanent implant, (4) radiation. Patient, disease, and treatment characteristics and clinical outcomes were retrospectively evaluated. Results: Median age was 45 years. Twenty-six percent of patients were Stage II and 74% Stage III. All received adjuvant chemotherapy. Estrogen receptor staining was positive in 77%, and 78% received hormone therapy. Radiation was delivered to the chest wall with daily 0.5-cm bolus and to the supraclavicular fossa. Median dose was 5040 cGy. Median interval from surgery to chemotherapy was 5 weeks, from completion of chemotherapy to exchange 4 weeks, and from exchange to radiation 4 weeks. Median interval from completion of chemotherapy to start of radiation was 8 weeks. Median follow-up was 64 months from date of mastectomy. The 5-year rate for locoregional disease control was 100%, for distant metastasis-free survival 90%, and for overall survival 96%. Conclusions: Mastectomy with immediate expander-implant reconstruction, adjuvant chemotherapy, and radiation results in a median interval of 8 weeks from completion of chemotherapy to initiation of radiation and seems to be associated with acceptable 5-year locoregional control, distant metastasis-free survival, and overall survival. [Copyright &y& Elsevier]

Introduction. Sexual dysfunction, including problems with vaginal dryness, dyspareunia, decreased libido, and difficulty with orgasm, is a common complaint among female breast cancer survivors. Despite the prevalence of female sexual dysfunction, there is a lack of Food and Drug Administration (FDA)-approved treatment options for hypoactive sexual desire disorder (HSDD) in women. Testosterone therapy may be one option. Aim. This is a case series describing the experience of breast cancer patients who used testosterone to treat sexual dysfunction. Methods. We report on three patients with a history of breast cancer who chose to continue testosterone therapy for improved sexual function despite conflicting reports of efficacy and lack of safety data on testosterone use in breast cancer patients. The patients described here expressed understanding of the risks and adamantly wished to continue testosterone therapy. Main Outcome Measures. All patients received a comprehensive sexual medicine evaluation including complete gynecological and psychosexual evaluations. Results. The improved sexual functioning is a quality-of-life parameter for these patients, and the unknown testosterone safety profile is an individually accepted level of risk. As studies emerge reporting beneficial effects of testosterone on libido and sexual function, the use of testosterone-containing therapies can be expected to increase among postmenopausal women. Conclusions. Further studies are needed to investigate the long-term effects of testosterone use in patients with breast cancer or at increased risk for developing breast cancer to definitively address the safety issues. Krychman ML, Stelling CJ, Carter J, and Hudis CA. A case series of androgen use in breast cancer survivors with sexual dysfunction. J Sex Med 2007;4:1769–1774. [ABSTRACT FROM AUTHOR]

Background: The status of human epidermal growth factor receptor type 2 (HER2) in breast-cancer cells predicts clinical outcomes in women who receive adjuvant anthracycline-based chemotherapy. We hypothesized that HER2 positivity predicts a benefit from adjuvant doxorubicin doses above standard levels, from the addition of paclitaxel after adjuvant chemotherapy with doxorubicin plus cyclophosphamide, or from both. Methods: We randomly selected 1500 women from 3121 women with node-positive breast cancer who had been randomly assigned to receive doxorubicin (60, 75, or 90 mg per square meter of body-surface area) plus cyclophosphamide (600 mg per square meter) for four cycles, followed by four cycles of paclitaxel (175 mg per square meter) or observation. Tissue blocks from 1322 of these 1500 women were available. Immunohistochemical analyses of these tissue specimens for HER2 with the CB11 monoclonal antibody against HER2 or with a polyclonal-antibody assay kit and fluorescence in situ hybridization for HER2 amplification were performed. Results: No interaction was observed between HER2 positivity and doxorubicin doses above 60 mg per square meter. HER2 positivity was, however, associated with a significant benefit from paclitaxel. The interaction between HER2 positivity and the addition of paclitaxel to the treatment was associated with a hazard ratio for recurrence of 0.59 (P=0.01). Patients with a HER2-positive breast cancer benefited from paclitaxel, regardless of estrogen-receptor status, but paclitaxel did not benefit patients with HER2-negative, estrogen-receptor–positive cancers. Conclusions: The expression or amplification, or both, of HER2 by a breast cancer is associated with a benefit from the addition of paclitaxel after adjuvant treatment with doxorubicin (<60 mg per square meter) plus cyclophosphamide in node-positive breast cancer, regardless of estrogen-receptor status. Patients with HER2-negative, estrogen-receptor–positive, node-positive breast cancer may gain little benefit from the administration of paclitaxel after adjuvant chemotherapy with doxorubicin plus cyclophosphamide. N Engl J Med 2007;357:1496-506. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Previous studies demonstrate differing treatment patterns between older and younger patients with breast cancer. To explore the reasons for these disparities we conducted a survey of 28 oncologists specializing in breast cancer. Design and methods: Twenty-eight medical oncologists from Memorial Sloan-Kettering Cancer Center and the University of California Los Angeles who specialize in the treatment of breast cancer were asked to provide adjuvant treatment recommendations in hypothetical scenarios featuring older patients with high-risk breast cancer. For each of these hypothetical patients, the patient''s age was varied over four possible values (70, 75, 80, or 85 years of age) and health and functional status varied across three possible states (perfect health, average health, or major health problems). Survey data were compiled and analyzed to determine the impact of theoretical patient age, baseline health, and functional status on their treatment recommendations. Results: The proportion of oncologists who recommended adjuvant chemotherapy decreased as the patient''s age increased or as the patient''s functional status and health status decreased. For 96% of physicians (95% CI, 82–100%), patient age influenced chemotherapy recommendations, controlling for health/functional status; the same proportion of respondents were influenced by health/functional status, controlling for patient age. There was increased variability in treatment recommendations as the patient''s age increased or functional status and health status decreased. Conclusion: Among these medical oncologists who primarily treat breast cancer adjuvant treatment recommendations vary based on patient age, health, and functional status. Future studies are needed to correlate age, health, and functional status with the risks and benefits of adjuvant therapy so that consensus guidelines can be formed. A more comprehensive baseline assessment of the older patient, such as can be derived from a comprehensive geriatric assessment may be useful in this regard. [Copyright &y& Elsevier]

Background: Preclinical and observational studies suggest a relationship between dietary fat intake and breast cancer, but the association remains controversial. We carried out a randomized, prospective, multicenter clinical trial to test the effect of a dietary intervention designed to reduce fat intake in women with resected, early-stage breast cancer receiving conventional cancer management. Methods: A total of 2437 women were randomly assigned between February 1994 and January 2001 in a ratio of 40 : 60 to dietary intervention (n = 975) or control (n = 1462) groups. An interim analysis was performed after a median follow-up of 60 months when funding for the intervention ceased. Mean differences between dietary intervention and control groups in nutrient intakes and anthropometric variables were compared with (tests. Relapse-free survival was examined using Kaplan-Meier analysis, stratified log-rank tests, and Cox proportional hazards models. Statistical tests were two-sided. Results: Dietary fat intake was lower in the intervention than in the control group (fat grams/day at 12 months, 33.3 [95% confidence interval {CI} = 32.2 to 34.5] versus 51.3 [95% CI = 50.0 to 52.7], respectively; P<.001), corresponding to a statistically significant (P = .005), 6-pound lower mean body weight in the intervention group. A total of 277 relapse events (local, regional, distant, or ipsilateral breast cancer recurrence or new contralateral breast cancer) have been reported in 96 of 975 (9.8%) women in the dietary group and 181 of 1462 (12.4%) women in the control group. The hazard ratio of relapse events in the intervention group compared with the control group was 0.76 (95% CI = 0.60 to 0.98, p = .077 for stratified log rank and P = .034 for adjusted Cox model analysis). Exploratory analyses suggested a differential effect of the dietary intervention based on hormonal receptor status. Conclusions: A lifestyle intervention reducing dietary fat intake, with modest influence on body weight, may improve relapse-free survival of breast cancer patients receiving conventional cancer management. Longer, ongoing nonintervention follow-up will address original protocol design plans, which called for 3 years of follow-up after completion of recruitment. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To examine the toxicity experienced by a cohort of older women receiving adjuvant chemotherapy for breast cancer and the longitudinal effect on their functional status and quality of life (QOL). DESIGN: A geriatric assessment measuring functional status, comorbidity, mood, nutritional status, and QOL was performed before chemotherapy, at the end of chemotherapy, and 6 months later. SETTING: This prospective longitudinal study was conducted at Memorial Sloan-Kettering Cancer Center, New York, New York. PARTICIPANTS: Fifty patients aged 65 and older with Stage I to III breast cancer receiving any adjuvant chemotherapy; 49 were evaluable. MEASUREMENTS: The chemotherapy regimen and the toxicity to chemotherapy were recorded. A geriatric assessment was performed before the start of chemotherapy, on completion of chemotherapy, and 6 months after completion of chemotherapy. QOL testing was performed at the same times. RESULTS: Patients (mean age 68, range 65-84) received an anthracycline-based chemotherapy regimen (n=15) or cyclophosphamide 600 mg/m² intravenously (IV), methotrexate 40 mg/m² IV, 5-fluorouracil 600 mg/m² IV every 3 weeks for eight cycles (n=34). Grade 3 or 4 toxicity occurred in 53% (n=26), hematological toxicity in 27% (n=13), and nonhematological toxicity in 31% (n=15). Despite toxicity, there was no significant longitudinal change in functional status or QOL. CONCLUSION: Despite toxicity from adjuvant chemotherapy, this cohort of relatively young older patients maintained their functional status and QOL from before chemotherapy to 6 months postchemotherapy. Subtle changes in higher-order functioning would require assessment using different geriatric assessment tools. [ABSTRACT FROM AUTHOR]

The article presents a medical report concerning estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. The article suggests the much progress has been made in the treatment of early stage breast cancer, and that in patients with hormone-sensitive tumors, tamoxifen reduces the risk of recurrence and death by more than 30%. Additionally, treatment with aromatase inhibitors further reduces the risk of recurrence in post-menopausal women with estrogen-receptor positive tumors.

Purpose. To determine the association of phosphorylated/activated HER2 (P-HER2) and response to taxane chemotherapy in patients with metastatic breast cancer (MBC). Materials and Methods. Archived tumor specimens of patients with MBC treated on clinical trials with taxane monotherapy were analyzed by immunohistochemistry (IHC) for the presence of phosphorylated HER2 using the PN2A monoclonal antibody. Chi-squared analysis was performed to evaluate the association of P-HER2 status and efficacy of single agent taxane therapy. Results. One hundred twenty-six cases were identified as evaluable for both IHC and clinical outcome. Twelve cases (10 percent) were positive for P-HER2, of which 5 had evidence of clinical progression and 7 had evidence of clinical benefit with taxane therapy. Of the 114 cases that were negative for P-HER2, 20 demonstrated progression and 94 had clinical benefit. Chi-squared analysis revealed a significant correlation between the presence of P-HER2 and resistance to taxane therapy, chi2 = 3.9724 and p = 0.046. Conclusions. Phosphorylated/activated HER2 is associated with clinical resistance to single agent taxane therapy for MBC. The likelihood of direct progression of disease on taxane was greater in cases of PN2A-positive tumors (42 percent) as opposed to PN2A-negative ones (18 percent, p = 0.046). Functional assessment of HER2 status may provide unique predictive information not seen with conventional assessments. [ABSTRACT FROM AUTHOR]

Objective: A number of age-related physiological changes contribute to an increased risk of toxicity of cancer chemotherapy in the elderly. One of the most important of these changes is the progressive decline in renal function with aging. We sought to determine the association between calculated creatinine clearance (CLCR) and grade 3 or 4 toxicities during adjuvant chemotherapy in women ≥65 years of age with breast cancer. Design and methods: We identified 1405 patients ≥65 years of age who had been treated for primary invasive breast cancer at Memorial Sloan-Kettering Cancer Center between January 1998 and December 2000. Patients were included in this analysis if they had stage I-III breast cancer and had received adjuvant chemotherapy. Patients were excluded if they had a prior history of breast cancer or chemotherapy, or had no baseline creatinine value available for review. Results: The 126 patients who met our criteria had received either cyclophosphamide, methotrexate and fluorouracil (CMF) [n = 65, mean age 71, range 65-78] or an anthracycline-based regimen (n = 61, mean age 69, range 65-79). The majority of patients (97%) had a normal creatinine. CLCR, as calculated by the Cockcroft-Gault and Jeliffe formulas, decreased with increasing age (increased age associated with decreased Cockcroft-Gault [p = 0.02]; increased age associated with decreased Jeliffe [p < 0.01]). In multivariate analysis, after controlling for age and co-morbidity, a CLCR <50 mL/min by the Cockcroft-Gault formula was associated with an increased risk of fever and neutropenia (odds ratio [OR] 3.60; 95% CI 1.00, 12.94; p = 0.05) and a CLCR <50 mL/min by the Jeliffe formula was associated with a trend towards an increased risk of fever and neutropenia (OR 3.30; 95% CI 0.91, 12.33; p = 0.07), grade 3 or 4 haematological toxicity (OR 2.43; 95% CI 0.90, 6.55; p = 0.08), and need for erythropoietin (OR 4.15; 95% CI 0.81, 2.99; p = 0.09). An increase in creatinine (as a continuous variable) was associated with a trend towards an increased risk of grade 3 or 4 haematological toxicity (OR 5.81; 95% CI 0.96, 35.33; p = 0.06). Conclusions: In this cohort of older breast cancer patients, a decreased CLCR and increased creatinine was associated with an increased risk of fever and neutropenia or haematological toxicity. CLCR should be considered when determining chemotherapy dosage in the elderly. [ABSTRACT FROM AUTHOR]

Purpose: To determine the association between changes in complete blood counts and grade 3 or 4 toxicities from cycle 1 to cycle 2 during adjuvant chemotherapy in women ≥65 years of age with breast cancer. Design and methods: A retrospective review was performed on 1405 patients ≥65 years of age who were treated for primary invasive breast cancer at Memorial Sloan-Kettering Cancer Center between January 1998 and December 2000. From this cohort, we identified patients with stage I–III breast cancer who received adjuvant chemotherapy: cyclophosphamide, methotrexate and fluorouracil (CMF) or the anthracycline-based regimens doxorubicin and cyclophosphamide (AC) or AC followed by paclitaxel (AC-T). Patients were excluded from the analysis if they had a prior history of breast cancer or chemotherapy, or if they had no baseline blood counts available for review. Toxicities, dose modification and causality were recorded. Results: The 104 patients who met our criteria had received either CMF (n = 58; mean age 70.6 years, range 65–78) or an anthracycline-based regimen (n = 46; mean age 68.9 years, range 65–77). Of these patients, 50% experienced treatment delay or treatment-related grade 3 or 4 toxicity. A decrease in white blood cell count and absolute neutrophil count from cycle 1 to cycle 2 was associated with grade 3 or 4 haematological toxicity, febrile neutropenia, hospitalisation and initiation of filgrastim for secondary prophylaxis. A decrease in haemoglobin was associated with febrile neutropenia and hospitalisation. Advanced age was not associated with a significant change in complete blood counts, other than a decline in absolute neutrophil count in patients receiving CMF. Conclusions: In this cohort of older patients who received chemotherapy for breast cancer, changes in blood counts from cycle 1 to cycle 2 were associated with increased risk of treatment-related grade 3 or 4 toxicity. [ABSTRACT FROM AUTHOR]

Context Adjuvant chemotherapy improves survival for patients with local-regional breast cancer, but healthy older patients at high risk of recurrence are frequently not offered adjuvant chemotherapy, and the benefit of adjuvant chemotherapy in older patients is uncertain. Objective To compare the benefits and toxic effects of adjuvant chemotherapy among breast cancer patients in age groups of 50 years or younger, 51 to 64 years, and 65 years or older. Design and Setting Retrospective review of data from 4 randomized trials that accrued patients from academic and community medical centers between 1975 and 1999. Median follow-up for all patients was 9.6 years. All trials randomized patients to different regimens, doses, schedules, and durations of chemotherapy and all had a treatment arm with doses or schedules that were regarded to be "high" and potentially more toxic. Patients A total of 6487 women with lymph node--positive breast cancer; 542 (8%) patients were 65 years or older and 159 (2%) were 70 years or older. Main Outcome Measure Comparison of disease-free survival, overall survival, and treatment-related mortality among different age groups. Results Multivariate analysis showed that smaller tumor size, fewer positive lymph nodes, more chemotherapy, and tamoxifen use were all significantly (P<.001) related to longer disease-free and overall survival. There was no association between age and disease-free survival. Overall survival was significantly (P<.001) worse for patients aged 65 or older because of death from causes other than breast cancer. Thirty-three deaths (0.5% of all patients) were attributed to treatment, and older women had higher treatment-related mortality. Older women and younger women derived similar reductions in breast cancer mortality and recurrence from regimens containing more chemotherapy. Conclusion Age alone should not be a contraindication to the use of optimal chemotherapy regimens in older women who are in good general health. [ABSTRACT FROM AUTHOR]

Purposes: To retrospectively determine the factors influencing treatment decisions in older breast cancer patients at a single center. Experimental design: 216 patients age &ges;75 seen in post-treatment follow-up between January, 1997 and June, 2000 were identified in the Memorial Sloan–Kettering breast cancer database. Eligible patients were &ges;75 years old at diagnosis, had a diagnosis of stage I, II, or III breast cancer, and received their follow-up care at Memorial Sloan Kettering Cancer Center. A retrospective chart review was performed. Patients were stratified by: (1) prognostic factors (age (75–79 or &ges;80), Charlson comorbidity score, tumor size, nodal status, stage, ER, PR, creatinine, albumin, hemoglobin, and liver function tests), (2) local treatment (lumpectomy, axillary lymph node dissection (AxLND), radiation (XRT), modified radical mastectomy (MRM)) and (3) systemic treatment (tamoxifen, chemotherapy). Combined local treatment was defined as (a) lumpectomy, AxLND, XRT or (b) MRM, AxLND, XRT (if tumor &ges;5 cm or &ges;4+ lymph nodes). Results: 96 patients were eligible for this study: 46 patients (75–79 years); 50 patients (&ges;80 years). The majority of patients (74%) were treated with lumpectomy but those &ges;80 were less likely to receive XRT (94% age 75–80; 45% age >80; P<0.01). Patients &ges;80 were also less likely to receive AxLND (94% age 75–79; 62% age &ges;80; P<0.01). A logistic regression model identified two independent prognostic variables for not receiving combined local treatment: increased age (P<0.01) and increased comorbidity score (P=0.01). Increased age did not correlate with increased comorbidity (P=0.48). 5.2% of patients received adjuvant chemotherapy (all age <80). 83% of ER positive patients received tamoxifen (89% age 75–79; 79% age >80). Conclusion: We hypothesize that both comorbidity and age play a significant role in influencing treatment decisions in the older breast cancer patient but these two variables are not necessarily correlated. Prospective studies are needed to determine the relative impact of these variables. [Copyright &y& Elsevier]

Determines the toxicity and immunogenicity of synthetic globo H-keyhole limpet hemocyanin conjugates, a carbohydrate antigen commonly found on breast cancer cells and its a potential target for vaccine therapy. Administration of the globo-H vaccine to metastatic breast cancer patients; Tabulation of observed toxicitiy of the vaccine.

A single-arm pilot study explored the feasibility of adapting in Interpersonal Psychotherapy (IPT) by telephone to reduce psychological distress and to enhance coping during cancer treatment. Therapy focuses on role transitions, interpersonal conflicts, and grief precipitated by cancer. Breast cancer patients receiving high-dose chemotherapy received weekly sessions with a psychologist throughout chemotherapy and for 1 month afterwards. Patients could invite one ‘partner’ to receive individual telephone IPT. Psychosocial functioning was assessed using standardized measures at study entry, after chemotherapy, and following telephone IPT. Accrual and participation supplied evidence of feasibility: 14 patients and 10 partners were recruited, 82.5% of those eligible. Patients had a mean of 16 sessions; partners had a mean of 11. Participants rated their satisfaction with the program between ‘good’ and ‘excellent’. A test of the efficacy of telephone IPT requires a larger, randomized trial. In order to standardize the intervention, a treatment manual was developed. This study indicated the importance of outreach to family members as well as to cancer patients, intensive patient education about oncology treatment and the medical care setting, and psychosocial services that continue after cancer treatment has been completed. Copyright © 2000 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

While ductal carcinoma in situ (DCIS) is known as a precursor lesion to most invasive breast carcinomas, the mechanisms underlying this transition remain enigmatic. DCIS is typically diagnosed by the mammographic detection of microcalcifications (MC). MCs consisting of non-stoichiometric hydroxyapatite (HA) mineral are frequently associated with malignant disease, yet it is unclear whether HA can actively promote malignancy. To investigate this outstanding question, we compared phenotypic outcomes of breast cancer cells cultured in control or HA-containing poly(lactide- co- glycolide) (PLG) scaffolds. Exposure to HA mineral in scaffolds increased the expression of pro-tumorigenic interleukin-8 (IL-8) among transformed but not benign cells. Notably, MCF10DCIS.com cells cultured in HA scaffolds adopted morphological changes associated with increased invasiveness and exhibited increased motility that were dependent on IL-8 signaling. Moreover, MCF10DCIS.com xenografts in HA scaffolds displayed evidence of enhanced malignant progression relative to xenografts in control scaffolds. These experimental findings were supported by a pathological analysis of clinical DCIS specimens, which correlated the presence of MCs with increased IL-8 staining and ductal proliferation. Collectively, our work suggests that HA mineral may stimulate malignancy in preinvasive DCIS cells and validate PLG scaffolds as useful tools to study cell-mineral interactions. [ABSTRACT FROM AUTHOR]

Background: A 21-gene expression assay (Oncotype DX recurrence score [RS]) that uses reverse transcriptase-polymerase chain reaction is used clinically in patients with early-stage, estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast carcinoma (ER+/HER2- BC) to determine both prognosis with tamoxifen therapy and the usefulness of adding adjuvant chemotherapy. Use of the assay is associated with reductions in overall chemotherapy use. The current study examined the treatments and outcomes in patients with low RS.Methods: The authors reviewed the institutional database to identify patients with lymph node-negative, ER+/HER2- BC who were treated at the study institution between September 2008 and August 2013 and their 21-gene RS results.Results: A total of 1406 consecutive patients with lymph node-negative ER+/HER2- BC and a low RS were identified (510 patients had an RS of 0-10 and 896 patients had an RS of 11-17). The median age at the time of diagnosis of BC was 56 years; 63 patients (4%) were aged <40 years. Overall, 1361 patients (97%) received endocrine therapy and 170 patients (12%) received chemotherapy. The median follow-up was 46 months. Six patients (0.4%) developed distant metastases (1 patient with an RS of 5 and 5 patients with an RS of 11-17). In the cohorts of patients with an RS of 11 to 17, the absolute rate of distant metastasis among patients aged <40 years was 7.1% (3 of 42 patients) versus 0.2% among patients aged ≥40 years (2 of 854 patients).Conclusions: The data from the current study document a 0.4% rate of distant metastasis within 5 years of BC diagnosis among patients with lymph node-negative ER+/HER2- BC with an RS <18. Patients aged <40 years at the time of BC diagnosis were observed to have a higher rate of distant metastases. Analysis of data from other studies is necessary to validate this observation further. Cancer 2017;131-137. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Purpose: We evaluated associations among comorbidity, toxicity, time to relapse (TTR), and overall survival (OS) in older women with early-stage breast cancer receiving adjuvant chemotherapy. Methods: Cancer and Leukemia Group B 49907 (Alliance) randomly assigned women 65 years old with stages I-III breast cancer to standard adjuvant chemotherapy or capecitabine. We reviewed data from 329 women who participated in the quality of life companion study CALGB 70103 and completed the Physical Health Subscale of the Older American Resources and Services Questionnaire. This questionnaire captures data on 14 comorbid conditions and the degree to which each interferes with daily activities. A comorbidity burden score was computed by multiplying the total number of conditions by each condition's level of interference with function. Outcomes were grade 3 to 5 toxicity, TTR, and OS. Logistic regression was used to evaluate associations between comorbidity and toxicity, and Cox proportional hazards models for TTR and survival. Results: Number of comorbidities ranged from 0 to 10 (median 2); the comorbidity burden score ranged from 0 to 25 (median 3). The most common conditions were arthritis (58%) and hypertension (55%). Comorbidity was associated with shorter OS, but not with toxicity or TTR. The hazard of death increased by 18% for each comorbidity (hazard ratio [HR]=1.18, 95% CI=1.06 to 1.33) after adjusting for age, tumor size, treatment, node and receptor status. Comorbidity burden score was similarly associated with OS (HR=1.08; 95% CI, 1.03 to 1.14). Conclusions: Among older women enrolled onto a clinical trial, comorbidity was associated with shorter OS, but not toxicity or relapse. [ABSTRACT FROM AUTHOR]

Background: Sorafenib is an oral multikinase inhibitor with antiangiogenic/antiproliferative activity. A randomized phase 2b screening trial in human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer demonstrated a significant improvement in progression-free survival (PFS) when sorafenib was added to capecitabine versus placebo (median 6.4 versus 4.1 months; hazard ratio = 0.58; P = 0.001). Most drug-related adverse events were Grade 1/2 in severity with the exception of Grade 3 hand-foot skin reaction/syndrome (44% versus 14%, respectively). These results suggest a role for the combination of sorafenib and capecitabine in breast cancer and supported a phase 3 confirmatory trial. Here we describe RESILIENCE - a multinational, double-blind, randomized, placebo-controlled, phase 3 trial - assessing the addition of sorafenib to first- or second-line capecitabine in advanced HER2-negative breast cancer.Methods/design: Eligibility criteria include ≥18 years of age, ≤1 prior chemotherapy regimen for metastatic disease, and resistant to/failed taxane and anthracycline or no indication for further anthracycline. Prior treatment with a vascular endothelial growth factor inhibitor is not allowed. Patients with significant cardiovascular disease or active brain metastases are not eligible. Patients are stratified by hormone-receptor status, geographic region, and prior metastatic chemotherapy status and randomized (1:1) to capecitabine (1000 mg/m2 orally twice daily (BID), days 1 to 14 of 21) in combination with sorafenib (orally BID, days 1 to 21, total dose 600 mg/day) or matching placebo. Capecitabine and sorafenib/placebo doses can be escalated to 1250 mg/m2 BID and 400 mg BID, respectively, as tolerated, or reduced to manage toxicity. Dose re-escalation after a reduction is allowed for sorafenib/placebo but not for capecitabine. This dosing algorithm was designed to mitigate dermatologic and other toxicity, in addition to detailed guidelines for prophylactic and symptomatic treatment. Radiographic assessment is every 6 weeks for 36 weeks, and every 9 weeks thereafter. The primary endpoint is PFS by blinded independent central review (Response Evaluation Criteria in Solid Tumors 1.1 criteria). Secondary endpoints include overall survival, time to progression, overall response rate, duration of response, and safety. Enrollment began in November 2010 with a target of approximately 519 patients.Discussion: RESILIENCE will provide definitive PFS data for the combination of sorafenib and capecitabine in advanced HER2-negative breast cancer and better characterize the benefit-to-risk profile.Trial Registration: Clinicaltrials.gov, NCT01234337. [ABSTRACT FROM AUTHOR]

Summary: The neoadjuvant setting provides a unique opportunity to study the effect of systemic treatments on breast cancer biology and to identify clinically useful prognostic and predictive biomarkers. Discrepancies and inconsistencies in the use of definitions and endpoint assessments in this setting confound the analysis and interpretation of results across clinical trials and hinder research progress. This Review represents a joint effort of the Breast International Group and the National Cancer Institute-sponsored North American Breast Cancer Group to provide clinicians and researchers with a series of standardised definitions and endpoints that could be implemented in future neoadjuvant clinical trials. Definitions of the setting of interest and of survival endpoints are recommended, together with proposals for standard assessment of the response to treatment, use of functional and molecular imaging endpoints, and characterisation and selection of the population to treat. We expect that implementation of these recommendations will improve the conduct, reporting, and effectiveness of clinical trials and fully exploit the clinical and scientific potential of the neoadjuvant setting in breast cancer. [ABSTRACT FROM AUTHOR]

Post-transcriptional regulators have emerged as robust effectors of metastasis and display deregulated expression through unknown mechanisms. Here, we reveal that the human microRNA-335 locus undergoes genetic deletion and epigenetic promoter hypermethylation in every metastatic derivative obtained from independent patients' malignant cell populations. Genetic deletion of miR-335 is a common event in human breast cancer, is enriched for in breast cancer metastases, and also correlates with ovarian cancer recurrence. We furthermore identify miR-335 as a robust inhibitor of tumor reinitiation. We thus implicate the miR-335 locus on 7q32.2 as the first selective metastasis suppressor and tumor initiation suppressor locus in human breast cancer. [ABSTRACT FROM AUTHOR]

Background: In women 70 years of age or older who have early breast cancer, it is unclear whether lumpectomy plus tamoxifen is as effective as lumpectomy followed by tamoxifen plus radiation therapy. Methods: Between July 1994 and February 1999, we randomly assigned 636 women who were 70 years of age or older and who had clinical stage I (T1N0M0 according to the tumor–node–metastasis classification), estrogen-receptor–positive breast carcinoma treated by lumpectomy to receive tamoxifen plus radiation therapy (317 women) or tamoxifen alone (319 women). Primary end points were the time to local or regional recurrence, the frequency of mastectomy for recurrence, breast-cancer–specific survival, the time to distant metastasis, and overall survival. Results: The only significant difference between the two groups was in the rate of local or regional recurrence at five years (1 percent in the group given tamoxifen plus irradiation and 4 percent in the group given tamoxifen alone, P<0.001). There were no significant differences between the two groups with regard to the rates of mastectomy for local recurrence, distant metastases, or five-year rates of overall survival (87 percent in the group given tamoxifen plus irradiation and 86 percent in the tamoxifen group, P=0.94). Assessment by physicians and patients of cosmetic results and adverse events uniformly rated tamoxifen plus irradiation inferior to tamoxifen alone. Conclusions: Lumpectomy plus adjuvant therapy with tamoxifen alone is a realistic choice for the treatment of women 70 years of age or older who have early, estrogen-receptor–positive breast cancer. N Engl J Med 2004;351:971-7. [ABSTRACT FROM AUTHOR]

Background: Risk-reducing salpingo-oophorectomy is often considered by carriers of BRCA mutations who have completed childbearing. However, there are limited data supporting the efficacy of this approach. We prospectively compared the effect of risk-reducing salpingo-oophorectomy with that of surveillance for ovarian cancer on the incidence of subsequent breast cancer and BRCA-related gynecologic cancers in women with BRCA mutations. Methods: All women with BRCA1 or BRCA2 mutations identified during a six-year period were offered enrollment in a prospective follow-up study. A total of 170 women 35 years of age or older who had not undergone bilateral oophorectomy chose to undergo either surveillance for ovarian cancer or risk-reducing salpingo-oophorectomy. Follow-up involved an annual questionnaire, telephone contact, and reviews of medical records. The time to cancer in the two groups was compared by Kaplan–Meier analysis and a Cox proportional-hazards model. Results: During a mean follow-up of 24.2 months, breast cancer was diagnosed in 3 of the 98 women who chose risk-reducing salpingo-oophorectomy and peritoneal cancer was diagnosed in 1 woman in this group. Among the 72 women who chose surveillance, breast cancer was diagnosed in 8, ovarian cancer in 4, and peritoneal cancer in 1. The time to breast cancer or BRCA-related gynecologic cancer was longer in the salpingo-oophorectomy group, with a hazard ratio for subsequent breast cancer or BRCA-related gynecologic cancer of 0.25 (95 percent confidence interval, 0.08 to 0.74). Conclusions: Salpingo-oophorectomy in carriers of BRCA mutations can decrease the risk of breast cancer and BRCA-related gynecologic cancer. (N Engl J Med 2002;346:1609-15.) [ABSTRACT FROM AUTHOR]