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Purpose: Women with HER2-positive breast cancer treated prior to effective anti-HER2 therapy have higher rates of local–regional recurrence (LRR) than those with HER2-negative disease. Effective systemic therapy, however, has been shown to decrease LRR. This study examines LRR in women with HER2-positive breast cancer treated on a single-arm prospective multicenter trial of adjuvant trastuzumab (H) and paclitaxel (T). Methods: Patients with HER2-positive tumors ≤ 3.0 cm with negative axillary nodes or micrometastatic disease were eligible. Systemic therapy included weekly T and H for 12 weeks followed by continuation of H to complete 1 year. Radiation therapy (RT) was required following breast-conserving surgery (BCS), but dose and fields were not specified. Disease-free survival (DFS) and LRR-free survival were calculated using the Kaplan–Meier method. Results: Of the 410 patients enrolled from September 2007 to September 2010, 406 initiated protocol therapy and formed the basis of this analysis. A total of 272 (67%) had hormone receptor-positive tumors. Of 162 patients undergoing mastectomy, local therapy records were unavailable for two. None of the 160 for whom records were available received RT. Among 244 BCS patients, detailed RT records were available for 217 (89%). With a median follow-up of 6.5 years, 7-year DFS was 93.3% (95% CI 90.4–96.2), and LRR-free survival was 98.6% (95% CI 97.4–99.8). Conclusion: LRR in this select group of early-stage patients with HER2-positive disease receiving effective anti-HER2 therapy is extremely low. If confirmed in additional studies, future investigational efforts should focus on de-escalating local therapy. [ABSTRACT FROM AUTHOR]

Background: In hormone receptor-positive advanced breast cancer, a progression-free survival benefit was reported with addition of bevacizumab to first-line letrozole. However, increased toxicity was observed. We hypothesized that functional age measures could be used to identify patients at risk for toxicity while receiving letrozole plus bevacizumab for hormone receptor-positive advanced breast cancer.Methods: CALGB 40503 was a phase III trial that enrolled patients with hormone receptor-positive advanced breast cancer randomized to letrozole with or without bevacizumab. Patients randomized to bevacizumab were approached to complete a validated assessment tool evaluating physical function, comorbidity, cognition, psychological state, social support, and nutritional status. The relationship between pretreatment assessment measures and the incidence of grade ≥ 3 (National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0) adverse events was determined.Results: One hundred thirteen (58%) of 195 patients treated with letrozole plus bevacizumab completed the pretreatment assessment questionnaire. One patient was excluded due to missing adverse event data. The median age of patients was 56. Frequently reported grade ≥ 3 adverse events were hypertension (26%), pain (20%), and proteinuria (7%). Two hemorrhagic events (one grade 5) and 1 thrombosis event occurred. Age ≥ 65 years (p < 0.01), decreased vision (p = 0.04), and poorer pretreatment physical function measures (p < 0.05) were found on univariate analysis to be significantly associated with increased incidence of grade ≥ 3 adverse events. Upon multivariate analysis, age ≥ 65 years (p = 0.01) and decreased vision (p = 0.04) remained significant. Univariable and multivariable logistic regression models demonstrated associations between age, vision, the ability to walk up flights of stairs, and grade ≥ 3 adverse events.Conclusions: Age (≥ 65 years), decreased vision, and impairments in physical function correlated with increased incidence of toxicity in patients receiving first-line letrozole plus bevacizumab. When evaluating therapy likely to increase toxicity, functional assessment measures can identify patients at increased risk for side effects who may benefit from closer monitoring. [ABSTRACT FROM AUTHOR]

Purpose: HER2 copy number by fluorescence in situ hybridization (FISH) is typically reported relative to the centromere enumeration probe 17 (CEP17). HER2/CEP17 ratio could be impacted by alterations in the number of chromosome 17 copies. Monosomy of chromosome 17 (m17) is found in ~ 1900 cases of early-stage HER2-positive breast cancer annually in the United States; however, the efficacy of HER2-directed trastuzumab therapy in these patients is not well characterized. Here, we retrospectively identified HER2-amplified, stage I–III breast cancers with m17 and characterized the impact of trastuzumab treatment.Methods: From January 1, 2000 to June 1, 2011, we identified 99 women with HER2-amplified m17 breast cancers, as defined by a CEP17 signal of < 1.5 per nucleus and a HER2/CEP17 ratio of ≥ 2.0.Results: Most HER2-amplified m17 patients were treated with trastuzumab plus chemotherapy (51%, n = 50), whereas 31% (n = 31) received chemotherapy alone and 18% (n = 18) received no chemotherapy. The 4-year overall survival (OS) was superior with trastuzumab compared to chemotherapy alone or no chemotherapy (100 vs. 93 vs. 81%, respectively; p = 0.005). OS was not influenced by estrogen/progesterone-receptor (ER/PR) status, tumor stage, or degree of FISH positivity. A proportion of patients who would be considered HER2-negative by standard immunohistochemistry staging criteria (0–1+) were HER2 amplified by FISH.Conclusions: In the largest series reported to date, patients with HER2-amplified m17 cancers treated with trastuzumab have outcomes comparable to patients from the large phase III adjuvant trastuzumab trials who were HER2-positive, supporting the critical role of HER2-directed therapy in this patient population. [ABSTRACT FROM AUTHOR]

Purpose: Musculoskeletal events (MEs) resulting from breast cancer treatment can significantly interfere with the quality of life (QOL) of older adults. We evaluated the incidence of MEs in women 65 years and older who had surgery and adjuvant chemotherapy for breast cancer, and the impact of treatment on MEs and arm function. Patients and methods: Patient-reported data in Alliance/CALGB 49907 were collected using the EORTC QLQ-BR23 and physician-reported adverse events to characterize self-reported MEs and incidence of lymphedema. EORTC QLQ-BR23 items related to musculoskeletal events were analyzed in this study and data collected at study entry (post-operative) and 12 and 24 months post-entry. Results: Lymphedema, arm function, and ME data were available for 321 patients. One or more MEs were reported by 87% (median number = 3) and 64% (median number = 1) of patients post-operatively and at 24 months. At 24 months 2% had persistence of six MEs. Seventy-four percent experienced at least ≥3/6 types of MEs over the 24-month period. Detection of lymphedema at any time during the study was noted in 7.5% of the patients and appeared to be associated with the type of chemotherapy given: CMF 16.4%, capecitabine 5.8%, and AC 4%. Mastectomy and axillary node dissection were associated with the most MEs. LROM correlated with poorer arm function at all time periods. Conclusion: Potentially debilitating MEs occur in three-fourths of elderly women undergoing standard therapy for breast cancer. Emphasis should be placed on prevention, identification, and treatment of these MEs to improve QOL. [ABSTRACT FROM AUTHOR]

Purpose: Trastuzumab improves overall survival for women with HER2-positive breast cancer but is associated with cardiotoxicity, especially when administered after anthracyclines. Use of non-anthracycline trastuzumab-based regimens is rising, particularly for patients with low-risk disease or with multiple cardiovascular risk factors. We performed a single-center retrospective cohort study to assess the cardiac safety of trastuzumab without anthracyclines outside of a clinical trial setting. Methods: A retrospective chart review was conducted of patients with HER2-positive early-stage breast cancer receiving non-anthracycline trastuzumab-based therapy between January 2010 and June 2014. Cardiovascular risk factors, left ventricular ejection fraction (LVEF), and treatment interruption data were collected. The primary outcome was a cardiac event (CE), defined by New York Heart Association class III or IV heart failure or cardiac death. The secondary outcome was a significant asymptomatic decline of LVEF ( >10% to <55% or >16% from baseline). Results: A total of 165 patients were identified with a median age of 59 years (range 32-85 years). Seventy (42%) had hypertension, 52 (32%) had hyperlipidemia, 29 (18%) had diabetes, and 5 (3%) had coronary artery disease. All patients had a LVEF >50% (median 67%; range 50-80%) at baseline. Two (1.2%) patients with multiple cardiovascular risk factors developed a CE. After discontinuation of trastuzumab, both patients had recovery of LVEF to >50% and resolution of heart failure symptoms. Ten (6.1%) patients developed significant asymptomatic LVEF decline during trastuzumab therapy. Conclusions: The overall incidence of symptomatic heart failure and asymptomatic LVEF decline among patients receiving trastuzumab without anthracyclines remains low. These findings suggest that less intensive cardiac monitoring may be appropriate during trastuzumab therapy without anthracyclines. [ABSTRACT FROM AUTHOR]

Background/purpose: The 21-gene recurrence score (RS) assay evaluates the likelihood of distant recurrence and benefit of chemotherapy in lymph node-negative, estrogen receptor (ER)-positive, HER2-negative breast cancer patients. The RS categories are associated with the risk of locoregional recurrence (LRR) in some, but not all studies. Methods: We reviewed the institutional database to identify consecutive female patients with node-negative, ER+/HER2− breast carcinoma tested for the 21-gene RS assay and treated at our center from 2008 to 2013. We collected data on clinicopathologic features, treatment, and outcome. Statistical analysis was performed using SAS version 9.4 or R version 3.3.2. Results: Of 2326 patients, 60% (1394) were in the low RS group, 33.4% (777) in the intermediate RS group, and 6.6% (155) in the high RS group. Median follow-up was 53 months. A total of 44 LRRs were observed, with a cumulative incidence of 0.17% at 12 months and 1.6% at 48 months. The cumulative incidence of LRR at 48 months was 0.84%, 2.72% and 2.80% for low, intermediate, and high RS groups, respectively ( p < 0.01). Univariate analysis showed that the risk of LRR was associated with the RS categories ( p < 0.01), T stage ( p < 0.01) and lymphovascular invasion (LVI) ( p = 0.009). There was no difference in LRR rates by initial local treatment (total mastectomy vs. breast-conserving surgery plus radiation therapy). The RS remained significantly associated with LRR after adjusting for LVI and T stage. Compared to patients with low RS, the risk of LRR was increased more than 4-fold (hazard ratio: 4.61, 95% CI 1.90-11.19, p < 0.01), and 3-fold (hazard ratio: 2.81, 95% CI 1.41-5.56, p < 0.01) for high and intermediate risk categories, respectively. Conclusions: Our study confirms that RS is significantly associated with the risk of LRR in node-negative, ER+/HER2− breast cancer patients. Our findings suggest that in addition to its value for prognostic stage grouping and decision-making regarding adjuvant systemic therapy, the role of the RS in identifying patients not requiring radiotherapy should be studied. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity caused by several chemotherapeutic agents. Currently, CIPN is managed by empirical dose modifications at the discretion of the treating physician. The goal of this research is to quantitate the dose-CIPN relationship to inform the optimal strategies for dose modification. Data were obtained from the Cancer and Leukemia Group B (CALGB) 40502 trial, a randomized phase III trial of paclitaxel vs. nab-paclitaxel vs. ixabepilone as first-line chemotherapy for locally recurrent or metastatic breast cancer. CIPN was measured using a subset of the Functional Assessment of Cancer Therapy-Gynecologic Oncology Group Neurotoxicity (FACT-GOG-NTX) scale. A kinetic-pharmacodynamic (K-PD) model was utilized to quantitate the dose-CIPN relationship simultaneously for the three drugs. Indirect response models with linear and S drug effects were evaluated. The model was evaluated by comparing the predicted proportion of patients with CIPN (score ≥8 or score ≥12) to the observed proportion. An indirect response model with linear drug effect was able to describe the longitudinal CIPN data reasonably well. The proportion of patients that were falsely predicted to have CIPN or were falsely predicted not to have CIPN was 20% or less at any cycle. The model will be utilized to identify an early time point that can predict CIPN at later time points. This strategy will be utilized to inform dose adjustments to prospectively manage CIPN. Clinicaltrials.gov ID: NCT00785291 [ABSTRACT FROM AUTHOR]

Background/purpose: The 21-gene recurrence score (RS) assay predicts the likelihood of distant recurrence and chemotherapy benefit in early-stage, estrogen receptor (ER)-positive, HER2-negative breast cancer. Data on the RS of special histologic subtypes of invasive breast carcinoma with favorable prognosis are limited. Methods: We reviewed our institutional database to identify patients with special histologic subtypes of breast cancer associated with favorable prognosis and available RS results. Our cohort consists of fifty-seven women: thirty-three patients with pure mucinous carcinoma (MC), ten with tubular carcinoma (TC), nine with encapsulated papillary carcinoma (EPC), and five with solid papillary carcinoma (SPC). Results: Most (44/57, 77.2%) carcinomas had low RS (≤17), and none had high RS (≥31). All EPCs had low RS, but other subtypes had RS 18-30. Higher RS was associated with lower progesterone receptor (PR) expression by immunohistochemistry and lower PR mRNA scores ( P ≤ 0.007). No morphologic feature (tumor grade, biopsy site changes, cellular stroma, inflammatory cells) was associated with RS ≥ 18. At a median follow-up of 40 months, the distant recurrence-free survival was 100%. One patient with SPC developed locoregional recurrence at 22 months. Conclusions: As the largest series to date, our study raises the question of whether the RS assay is necessary for breast cancers with favorable histology. Reflex testing of node-negative, ER+/HER2− breast cancers may be deferred for these special histologic subtypes, emphasizing the need for multidisciplinary discussions between breast pathologists and other members of the breast cancer team. [ABSTRACT FROM AUTHOR]

Purpose: Breast cancer patients aged 65+ ('older') vary in frailty status. We tested whether a deficits accumulation frailty index predicted long-term mortality. Methods: Older patients ( n = 1280) with non-metastatic, invasive breast cancer were recruited from 78 Alliance sites from 2004 to 2011, with follow-up to 2015. Frailty categories (robust, pre-frail, and frail) were based on 35 baseline illness and function items. Cox proportional hazards and competing risk models were used to calculate all-cause and breast cancer-specific mortality for up to 7 years, respectively. Potential covariates included demographic, psychosocial, and clinical factors, diagnosis year, and care setting. Results: Patients were 65-91 years old. Most (76.6%) were robust; 18.3% were pre-frail, and 5.1% frail. Robust patients tended to receive more chemotherapy ± hormonal therapy (vs. hormonal) than pre-frail or frail patients (45% vs. 37 and 36%, p = 0.06), and had the highest adherence to hormonal therapy. The adjusted hazard ratios for all-cause mortality ( n = 209 deaths) were 1.7 (95% CI 1.2-2.4) and 2.4 (95% CI 1.5-4.0) for pre-frail and frail versus robust women, respectively, with an absolute mortality difference of 23.5%. The adjusted hazard of breast cancer death ( n−99) was 3.1 (95% CI 1.6-5.8) times higher for frail versus robust patients (absolute difference of 14%). Treatment differences did not account for the relationships between frailty and mortality. Conclusions: Most older breast cancer patients are robust and could consider chemotherapy where otherwise indicated. Patients who are frail or pre-frail have elevated long-term all-cause and breast cancer mortality. Frailty indices could be useful for treatment decision-making and care planning with older patients. [ABSTRACT FROM AUTHOR]

Purpose: Tools to estimate survival, such as ePrognosis (), were developed for general, not cancer, populations. In older patients with breast cancer, accurate overall survival estimates would facilitate discussions about adjuvant therapies. Methods: Secondary analyses were performed of data from two parallel breast cancer studies (CALGB/Alliance 49907/NCT000224102 and CALGB/Alliance 369901/NCT00068328). We included patients ( n = 971) who were age 70 years and older with complete baseline quality of life data (194 from 49907; 777 from 369901). Estimated versus observed all-cause two-year mortality rates were compared. ePrognosis score was calculated based on age, sex, and daily function (derived from EORTC QLQ-C30). ePrognosis scores range from 0 to 10, with higher scores indicating worse prognosis based on mortality of community-dwelling elders and were categorized into three groups (0-2, 3-6, 7-10). Observed mortality rates were estimated using Kaplan-Meier methods. Results: Patient mean age was 75.8 years (range 70-91) and 73% had stage I-IIA disease. Most patients were classified by ePrognosis as good prognosis ( n = 562, 58% 0-2) and few ( n = 18, 2% 7-10) poor prognosis. Two-year observed mortality rates were significantly lower than ePrognosis estimates for patients scoring 0-2 (2% vs 5%, p = 0.001) and 3-6 (8% vs 12%, p = 0.01). The same trend was seen with scores of 7-10 (23% vs 36%, p = 0.25). Conclusions: ePrognosis tool only modestly overestimates mortality rate in older breast cancer patients enrolled in two cooperative group studies. This tool, which estimates non-cancer mortality risk based on readily available clinical information may inform adjuvant therapy decisions but should be validated in non-clinical trial populations. [ABSTRACT FROM AUTHOR]

Background: OncotypeDX, a multi-gene expression assay, has been incorporated into clinical practice as a prognostic and predictive tool. However, its use in resource-constrained international healthcare systems is limited. Here we develop and validate a simplified model using clinicopathologic criteria to predict OncotypeDX score. Methods: Patients with estrogen receptor (ER) and/or progesterone receptor (PR)-positive and HER2-negative invasive ductal carcinoma for whom the OncotypeDX test was successfully performed between 09/2008 and 12/2011 were retrospectively identified. Tumor size, nuclear and histologic grade, lymphovascular invasion, and ER and PR status were extracted from pathology reports. Data were split into a training dataset comprising women tested 09/2008-04/2011, and a validation dataset comprising women tested 04/2011-12/2011. Using the training dataset, linear regression analysis was used to identify factors associated with OncotypeDX score, and to create a simplified risk score and identify risk cutoffs. Results: Estrogen and progesterone receptors, tumor size, nuclear and histologic grades, and lymphovascular involvement were independently associated with OncotypeDX. The full model explained 39% of the variation in the test data, and the simplified risk score and cutoffs assigned 57% of patients in the test data to the correct risk category (OncotypeDX score <18, 18-30, >30). 41% of patients were predicted to have OncotypeDX score <18, of these 83, 16, and 2% had true scores of <18, 18-30, and >30, respectively. Conclusions: Awaiting an inexpensive test that is prognostic and predictive, our simplified tool allows clinicians to identify a fairly large group of patients (41%) with very low chance of having high-risk disease (2%). [ABSTRACT FROM AUTHOR]

Purpose: A joint American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology panel convened to develop a focused update of the American Society of Clinical Oncology guideline concerning use of postmastectomy radiotherapy (PMRT). Methods: A recent systematic literature review by Cancer Care Ontario provided the primary evidentiary basis. The joint panel also reviewed targeted literature searches to identify new, potentially practice-changing data. Recommendations: The panel unanimously agreed that available evidence shows that PMRT reduces the risks of locoregional failure (LRF), any recurrence, and breast cancer mortality for patients with T1-2 breast cancer with one to three positive axillary nodes. However, some subsets of these patients are likely to have such a low risk of LRF that the absolute benefit of PMRT is outweighed by its potential toxicities. In addition, the acceptable ratio of benefit to toxicity varies among patients and physicians. Thus, the decision to recommend PMRT requires a great deal of clinical judgment. The panel agreed clinicians making such recommendations for individual patients should consider factors that may decrease the risk of LRF, attenuate the benefit of reduced breast cancer-specific mortality, and/or increase risk of complications resulting from PMRT. When clinicians and patients elect to omit axillary dissection after a positive sentinel node biopsy, the panel recommends that these patients receive PMRT only if there is already sufficient information to justify its use without needing to know additional axillary nodes are involved. Patients with axillary nodal involvement after neoadjuvant systemic therapy should receive PMRT. The panel recommends treatment generally be administered to both the internal mammary nodes and the supraclavicular-axillary apical nodes in addition to the chest wall or reconstructed breast. [ABSTRACT FROM AUTHOR]

Objective: It had been previously shown that patients who receive neoadjuvant systemic therapy (NST) are more likely to undergo breast-conserving therapy (BCT) than those who have primary surgery. However, the frequency with which patients who are not BCT-eligible prior to NST convert to BCT-eligible with treatment is unknown. To document this conversion rate in a subset of patients expected to have a high clinical response rate to NST, we studied surgical assessment and management of patients enrolled on a randomized neoadjuvant trial for stage II-III HER2-positive breast cancer (HER2 + BC)(CALGB 40601). Methods: The treating surgeon assessed BCT candidacy based on clinico-radiographic criteria both before and after NST. Definitive breast surgical management was at surgeon and patient discretion. We sought to determine (1) the conversion rate from BCT-ineligible to BCT-eligible (2) the percentage of BCT-eligible patients who chose breast conservation, and (3) the rate of successful BCT. We also evaluated surgeon-determined factors for BCT-ineligibility and the correlation between BCT eligibility and pathologic complete response (pCR). Results: Of 292 patients with pre- and post-NST surgical assessments, 59 % were non-BCT candidates at baseline. Of the 43 % of these patients who converted with NST, 67 % opted for BCT, with an 80 % success rate. NST increased the BCT-eligible rate from 41 to 64 %. Common factors cited for BCT-ineligibility prior to NST including tumor size (56 %) and probable poor cosmetic outcome (26 %) were reduced by 67 and 75 %, respectively, with treatment, while multicentricity, the second most common factor (33 %), fell by only 16 %. Since 23 % of the BCT-eligible patients chose mastectomy, BCT was the final surgical procedure in just 40 % of the patients. Patients considered BCT-eligible both at baseline and after NST had a pCR rate of 55 %, while patients who were BCT-ineligible prior to NST had the same pCR rate (44 %) whether they converted to BCT-eligible or not. Conclusions: Many patients with HER2 + BC deemed ineligible for BCT at baseline can be converted to BCT-eligible with NST; excluding patients with multicentric disease substantially increases that percentage. In converted patients who opt for BCT, the success rate is similar to that of patients considered BCT-eligible at baseline. Whether a BCT-ineligible patient converts to BCT eligibility or not does not appear to affect the likelihood of achieving a pCR. Despite the efficacy of NST in this patient cohort, only 40 % of patients had successful BCT; further research into why BCT-eligible patients often opt for mastectomy is needed. [ABSTRACT FROM AUTHOR]

Background: Lobular neoplasia (LN) represents a spectrum of atypical proliferative lesions, including atypical lobular hyperplasia and lobular carcinoma-in-situ. The need for excision for LN found on core biopsy (CB) is controversial. We conducted a prospective multi-institutional trial (TBCRC 20) to determine the rate of upgrade to cancer after excision for pure LN on CB. Methods: Patients with a CB diagnosis of pure LN were prospectively identified and consented to excision. Cases with discordant imaging and those with additional lesions requiring excision were excluded. Upgrade rates to cancer were quantified on the basis of local and central pathology review. Confidence intervals and sample size were based on exact binomial calculations. Results: A total of 77 of 79 registered patients underwent excision (median age 51 years, range 27-82 years). Two cases (3 %; 95 % confidence interval 0.3-9) were upgraded to cancer (one tubular carcinoma, one ductal carcinoma-in-situ) at excision per local pathology. Central pathology review of 76 cases confirmed pure LN in the CB in all but two cases. In one case, the tubular carcinoma identified at excision was also found in the CB specimen, and in the other, LN was not identified, yielding an upgrade rate of one case (1 %; 95 % CI 0.01-7) by central pathology review. Conclusions: In this prospective study of 77 patients with pure LN on CB, the upgrade rate was 3 % by local pathology and 1 % by central pathology review, demonstrating that routine excision is not indicated for patients with pure LN on CB and concordant imaging findings. [ABSTRACT FROM AUTHOR]

Obesity is a major global health problem with a rising worldwide burden. In addition to its association with several diseases, obesity is associated with increased incidence and worse prognosis for many malignances. Many possible mechanisms that contribute to the obesity-cancer link have been proposed, but key pathways likely include steroid hormone signaling, altered gut microbiota, insulin and insulin growth factor interactions, levels of circulating adipokines, and local and systemic inflammation. By understanding these mechanisms and their interactions, we may be able to intervene to improve the public health burden imposed by obesity. Equally critical to the development of targeted intervention strategies is the identification of accurate biomarkers to better detect populations that are more or less likely to benefit from specific interventions. [ABSTRACT FROM AUTHOR]

The rates of overweight and obesity are increasing worldwide in both developed and developing countries. Obesity is a major public health problem as it is associated with many diseases, including diabetes, hypertension, dyslipidemia, atherosclerosis, and some types of cancer. Breast cancer is a malignancy in which both the risk of development and the prognosis are negatively impacted by the obese state. The precise mechanisms pathophysiologically linking obesity and cancer are still under investigation. The biological basis for these associations includes both systemic and local tissue effects and white adipose tissue inflammation appears to be a critical component. A comprehensive understanding of the mechanisms linking obesity, inflammation and cancer may provide an opportunity for the development of strategies to attenuate the negative impact of obesity. [ABSTRACT FROM AUTHOR]

Purpose: To determine if the histology of a breast malignancy influences the appearance of untreated osseous metastases on FDG PET/CT. Methods: This retrospective study was performed under IRB waiver. Our Hospital Information System was screened for breast cancer patients who presented with osseous metastases, who underwent FDG PET/CT prior to systemic therapy or radiotherapy from 2009 to 2012. Patients with invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), or mixed ductal/lobular (MDL) histology were included. Patients with a history of other malignancies were excluded. PET/CT was evaluated, blinded to histology, to classify osseous metastases on a per-patient basis as sclerotic, lytic, mixed lytic/sclerotic, or occult on CT, and to record SUVmax for osseous metastases on PET. Results: Following screening, 95 patients who met the inclusion criteria (74 IDC, 13 ILC, and 8 MDL) were included. ILC osseous metastases were more commonly sclerotic and demonstrated lower SUVmax than IDC metastases. In all IDC and MDL patients with osseous metastases, at least one was FDG-avid. For ILC, all patients with lytic or mixed osseous metastases demonstrated at least one FDG-avid metastasis; however, in only three of seven patients were sclerotic osseous metastases apparent on FDG PET. Conclusion: The histologic subtype of breast cancer affects the appearance of untreated osseous metastases on FDG PET/CT. In particular, non-FDG-avid sclerotic osseous metastases were more common in patients with ILC than in patients with IDC. Breast cancer histology should be considered when interpreting non-FDG-avid sclerotic osseous lesions on PET/CT, which may be more suspicious for metastases (rather than benign lesions) in patients with ILC. [ABSTRACT FROM AUTHOR]

Chemotherapy-related amenorrhea (CRA) is associated with infertility and menopausal symptoms. Learning how frequently paclitaxel and trastuzumab cause amenorrhea is important. Most other adjuvant breast cancer therapies induce CRA in approximately 50 % of all premenopausal recipients []. 410 patients enrolled on the APT Trial, a single-arm phase 2 adjuvant study of 12 weeks of paclitaxel and trastuzumab followed by nine months of trastuzumab monotherapy. Eligible patients had ≤3 cm node-negative HER2 + breast cancers. Premenopausal enrollees were asked to complete menstrual surveys every 3-12 months for 72 months. Women who responded to at least one survey at least 15 months after chemotherapy initiation (and who did not undergo hysterectomy and/or bilateral oophorectomy or receive ovarian suppressing medications prior to 15 months) were included in this analysis. A participant was defined as having amenorrhea in follow-up if her self-reported last menstrual period at last follow-up was greater than 12 months prior to the survey. Among the 64 women in the evaluable population (median age at study entry 44 years, range 27-52 years), the median time between chemotherapy initiation and last menstrual survey was 51 months (range 16-79). 18 of 64 women (28 %, 95 % CI 18-41 %) were amenorrheic at that time point. Amenorrhea rates among premenopausal women treated with adjuvant paclitaxel and trastuzumab for early stage breast cancer appear lower than those seen historically with standard alkylator-based breast cancer regimens. Future studies are needed to understand the impact of this regimen on related issues of fertility and menopausal symptoms. [ABSTRACT FROM AUTHOR]

Trastuzumab improves outcomes among patients with HER2-positive breast cancer but is associated with a risk of treatment-induced cardiotoxicity (TIC). It is unclear how frequently TIC leads to trastuzumab interruption outside of prospective trials, and how TIC is managed in clinical practice. Patients with HER2-postive breast cancer receiving adjuvant trastuzumab from 2005 to 2010 were identified ( n = 608). We evaluated the incidence, risk factors, and management of trastuzumab interruption due to TIC. In total, 488 (80 %) patients were treated with anthracycline prior to trastuzumab. Trastuzumab was interrupted in 108 (18 %) patients. Cumulative trastuzumab dose was lower in the interrupted group (median 86 vs. 108 mg/kg, p < 0.0001). The most common reason for interruption was TIC (66 of 108 patients): 20 had symptomatic heart failure and 46 had asymptomatic left ventricular ejection fraction (LVEF) decline. Patients with trastuzumab interruption for TIC were older (54 vs. 50 years, p = 0.014) with lower LVEF before anthracycline (63 vs. 67 %, p < 0.0001) and trastuzumab (62 vs. 67 %, p < 0.0001) therapy. Mean LVEF at baseline, TIC diagnosis, and follow-up after trastuzumab interruption was 63, 45, and 55 %, respectively. Thirty-three of 66 patients with TIC were re-challenged with trastuzumab, and five patients had recurrent LVEF decline. In clinical practice, trastuzumab interruption is common and most often due to TIC, with most patients receiving anthracycline prior to trastuzumab. Cardiac dysfunction improves after trastuzumab interruption but may not fully recover to baseline. Strategies to minimize cardiotoxicity and treatment interruption should be investigated to prevent persistent left ventricular dysfunction in affected patients. [ABSTRACT FROM AUTHOR]

Purpose: Survivorship care plans (SCP) are recommended for all cancer patients and could be especially useful to survivors 65 years and over ('older'). This study examined receipt of SCPs among older breast cancer survivors and whether SCPs were associated with improved patient-reported outcomes. Methods: Three hundred and twenty-eight older women diagnosed with invasive, nonmetastatic breast cancer between 2007-2011 were recruited from 78 cooperative-group sites. Participants completed telephone interviews at baseline and 1-year posttreatment. Regression analyses examined SCP receipt (yes/no) and functioning (EORTC-QLQ-C30), cancer worry, and experiences of survivorship care (care coordination, knowledge). Results: Only 35 % of women received SCPs. For each 1-year increase in age, there was a 5 % lower odds of receiving an SCP (odds ratio (OR) = 0.94, 95 % confidence interval (CI) 0.91-0.98, p = 0.007). Besides age, no other factor predicted SCPs. SCP receipt was associated with greater knowledge and understanding of requisite follow-up care ( p < 0.05); however, functioning was not significantly different among those with vs. without SCPs. Conclusions: Receipt of care plans was limited. SCPs improved understanding of breast cancer follow-up care among older survivors, but did not impact functioning one year post-treatment. Implications for Cancer Survivors: To impact functioning and salient needs of the growing cohort of older survivors, survivorship care plans likely should be tailored to geriatric-specific issues. To improve functioning, SCP content should expand to include exercise, nutrition, polypharmacy, social support and management of symptom burden from cancer, and other comorbid conditions. To improve follow-up care for cancer survivors, SCPs should delineate shared care roles between oncology and primary care in managing recurrence surveillance, screening, and cancer sequelae. [ABSTRACT FROM AUTHOR]

Seventy percent of breast cancers express estrogen receptor (ER), and most of these are sensitive to ER inhibition. However, many such tumors for unknown reasons become refractory to inhibition of estrogen action in the metastatic setting. We conducted a comprehensive genetic analysis of two independent cohorts of metastatic ER-positive breast tumors and identified mutations in ESR1 affecting the ligand-binding domain (LBD) in 14 of 80 cases. These included highly recurrent mutations encoding p.Tyr537Ser, p.Tyr537Asn and p.Asp538Gly alterations. Molecular dynamics simulations suggest that the structures of the Tyr537Ser and Asp538Gly mutants involve hydrogen bonding of the mutant amino acids with Asp351, thus favoring the agonist conformation of the receptor. Consistent with this model, mutant receptors drive ER-dependent transcription and proliferation in the absence of hormone and reduce the efficacy of ER antagonists. These data implicate LBD-mutant forms of ER in mediating clinical resistance to hormonal therapy and suggest that more potent ER antagonists may be of substantial therapeutic benefit. [ABSTRACT FROM AUTHOR]

The quantity and makeup of dietary fat intake are known to affect human health. A variety of purported health benefits, including cancer prevention, have focused increased attention on use of omega-3 (ω-3) polyunsaturated fatty acid (PUFA) supplements. Preclinical evidence has been encouraging, and recent studies have increased our understanding of mechanisms by means of which ω-3 PUFAs may protect against breast cancer. However, epidemiological studies have yielded mixed results. Recent population studies have attempted to determine factors, for example total fat intake and the ratio of ω-3 to ω-6 PUFA intake, that may affect the action of ω-3 PUFAs. Several clinical trials, some currently ongoing, are investigating strategies to favorably alter endogenous fatty acid profiles in an attempt to develop clinically feasible prevention methods. Identification of well-defined subpopulations who are most likely to benefit from a targeted prevention approach will probably be crucial to this effort. [ABSTRACT FROM AUTHOR]

Cognitive changes in older women receiving chemotherapy are poorly understood. We examined self-reported cognitive function for older women who received adjuvant chemotherapy on Cancer and Leukemia Group B (CALGB) 49907. CALGB 49907 randomized 633 women aged ≥65 with stage I-III breast cancer to standard adjuvant chemotherapy (cyclophosphamide-methotrexate-5-fluorouracil or doxorubicin-cyclophosphamide) versus capecitabine. We examined self-reported cognitive function in 297 women (CALGB 361002) who enrolled on the quality of life substudy and had no gross impairment on cognitive screening. Women were evaluated using an 18-item instrument at six time points (baseline through 24 months). At each time point for each patient, we calculated a cognitive function score (CFS) defined as the mean response of items 1-18 and defined impairment as a score >1.5 standard deviations above the overall average baseline score. Differences in scores by patient characteristics were evaluated using a Kruskal-Wallis test. A linear mixed-effects model was used to assess CFSs by treatment over time. Among 297 women, the median age was 71.5 (range 65-85) and 73 % had performance status of 0. Baseline depression and fatigue were reported in 6 and 14 % of patients, respectively. The average CFS at baseline was 2.08 (corresponding to 'normal ability'), and baseline cognitive function did not differ by treatment regimen ( p = 0.350). Over 24 months, women reported minimal changes at each time point and insignificant differences by treatment arm were observed. In a healthy group of older women, chemotherapy was not associated with longitudinal changes in self-reported cognitive function. [ABSTRACT FROM AUTHOR]

Heat shock protein 90 (Hsp90) facilitates maturation and stability of HER2. Combining an Hsp90 inhibitor and trastuzumab has demonstrated anti-tumor effects in patients with HER2+ breast cancer. Adults with measurable, locally advanced or metastatic HER2+ breast cancer and prior trastuzumab treatment were enrolled in a phase 2 trial employing weekly 300 mg/m retaspimycin HCl, a potent Hsp90 inhibitor, with 6 mg/kg trastuzumab every 3 weeks. A Simon's two-stage design determined trial expansion by dose-limiting toxicity (DLT) and response rates. Pharmacokinetics and electrocardiograms were evaluated. Twenty-six patients with median age 52.5 years (range 33-72) enrolled with a median of six prior chemotherapeutic regimens (range 2-20). On study, patients received a median of three treatment cycles (range 1-12). No DLTs were observed. Most adverse events (AEs) were grade 1 or 2; common treatment-related AEs included fatigue (46 %), nausea (31 %), and diarrhea (23 %). One patient had treatment-related serious AEs of grade 1 diarrhea and grade 3 hypokalemia. grade 3 transaminase elevation occurred in one patient (4 %) who also had metastatic liver disease. Sixteen patients (62 %) had stable disease, with a median on-study duration of 2.4 months (range 1.1-8.2). No confirmed responses were observed. Retaspimycin HCl at 300 mg/m² weekly in combination with trastuzumab was well tolerated and without significant toxicities. Modest clinical activity was observed, but did not meet criteria for trial expansion. The safety profile for patients on study raises the possibility of retaspimycin HCl underdosing that limited efficacy. Studies employing higher doses are ongoing. [ABSTRACT FROM AUTHOR]

Breast cancer is the most prevalent life-threatening cancer in women and the second leading cause of cancer associated deaths. Consequently, optimizing breast cancer therapy to increase cure rates in early stage disease and improve life expectancy and palliation for patients with metastasis is a critical need and major area of research in medical oncology. This article focuses on the development of personalized therapy in breast cancer though the use of targeted therapies and their associated biomarkers. Topics reviewed include the historic advances in targeting the HER2 receptor and the current avenues being studied to circumvent resistance; new developments in the management of triple negative and metastatic breast cancer; and the challenges and pitfalls associated with targeting angiogenesis. Using these as examples, many of the innovations and challenges in the treatment of women with breast cancer are explored. [ABSTRACT FROM AUTHOR]

Preclinical data have demonstrated that the combination of antihuman epidermal growth factor receptor-2 (anti-HER2) and antivascular endothelial growth factor (anti-VEGF)-targeted agents has antitumor activity; these data indicate certain patients with HER2-overexpressing breast cancer may derive clinical benefit from this combination. The purpose of this single-arm phase II study was to determine the efficacy and safety of the dual-targeting combination of lapatinib and bevacizumab. Women with HER2-overexpressing advanced breast cancer received 1,500 mg oral lapatinib daily plus 10 mg/kg IV bevacizumab every 2 weeks. The primary endpoint was progression-free survival (PFS) at week 12; secondary endpoints included overall tumor response rate (ORR), clinical benefit rate (CBR), duration of response, time-to-response, PFS, and safety. Circulating tumor cells (CTC) and circulating endothelial cells (CEC) were measured at baseline and during study treatment as potential response markers. Fifty-two patients with stage IV disease were enrolled. The 12-week investigator-assessed PFS rate was 69.2% (95% confidence interval [CI]: 54.9, 81.3). Median PFS was 24.7 weeks (95% CI: 20.4, 35.1), and the CBR was 30.8% (95% CI: 18.7, 45.1). Of 45 patients with measurable disease, 6 were determined to have a partial response per Response Evaluation Criteria in Solid Tumors (ORR: 13.3%; 95% CI: 5.1, 26.8). The most common adverse events (AEs) included diarrhea, rash, and fatigue; most of these were either grade 1 or 2. Clinical responses were correlated with decreases in CTC and CEC. Lapatinib plus bevacizumab was active in patients with HER2-overexpressing breast cancer. The AE profile of the combination was consistent with the known profiles for these agents. [ABSTRACT FROM AUTHOR]

Neoadjuvant chemotherapy for breast cancer allows individual tumor response to be assessed depending on molecular subtype, and to judge the impact of response to therapy on recurrence-free survival (RFS). The multicenter I-SPY 1 TRIAL evaluated patients with ≥3 cm tumors by using early imaging and molecular signatures, with outcomes of pathologic complete response (pCR) and RFS. The current analysis was performed using data from patients who had molecular profiles and did not receive trastuzumab. The various molecular classifiers tested were highly correlated. Categorization of breast cancer by molecular signatures enhanced the ability of pCR to predict improvement in RFS compared to the population as a whole. In multivariate analysis, the molecular signatures that added to the ability of HR and HER2 receptors, clinical stage, and pCR in predicting RFS included 70-gene signature, wound healing signature, p53 mutation signature, and PAM50 risk of recurrence. The low risk signatures were associated with significantly better prognosis, and also identified additional patients with a good prognosis within the no pCR group, primarily in the hormone receptor positive, HER-2 negative subgroup. The I-SPY 1 population is enriched for tumors with a poor prognosis but is still heterogeneous in terms of rates of pCR and RFS. The ability of pCR to predict RFS is better by subset than it is for the whole group. Molecular markers improve prediction of RFS by identifying additional patients with excellent prognosis within the no pCR group. [ABSTRACT FROM AUTHOR]

Our group applied mathematical modeling to capecitabine dosing and predicted 7 days of treatment followed by 7 days of rest (7-7) would improve efficacy and minimize toxicity. The conventional schedule of capecitabine limits full dosing in combination with other agents due to toxicity. Lapatinib inhibits the tyrosine kinase of HER2 and has activity when added to conventionally scheduled capecitabine for the treatment of patients with trastuzumab-refractory, HER2-positive, metastatic breast cancer (MBC). We performed this study to evaluate the activity and tolerability of capecitabine 7-7 with lapatinib in patients with trastuzumab-refractory MBC. Eligible patients had measurable, HER2-positive, MBC that progressed following exposure to trastuzumab. Treatment consisted of capecitabine 2,000 mg orally twice daily, 7-7 and lapatinib 1,250 mg orally daily. The primary endpoint was response rate. Secondary endpoints included toxicity, progression-free survival, and stable disease ≥6 months. Twenty-three patients were treated on study. More than 60% had prior chemotherapy for MBC and all had prior trastuzumab. After a median of 23 weeks (range 2-96+), five patients had partial responses (23; 95 CI, 7-44%) and six (27; 95 CI, 10-48%) had stable disease ≥6 months. Median progression-free survival was 9.4 months. The most common treatment-related toxicities ≥ grade (gr) 2 were hand-foot syndrome (gr 2 43%; gr 3 4% gr 4 0%), diarrhea (gr 2 26%; gr 3/4 0%), elevated liver chemistries (gr 2 17%; gr 3/4 0%), and anemia (gr 2 13%; gr 3 4%; gr 4 4%). No grade ≥3 nausea, vomiting, or diarrhea events occurred. This study demonstrated feasibility and after meeting biostatistical requirements for continued accrual was terminated in anticipation of slow enrollment. Capecitabine 7-7 with lapatinib was well tolerated with minimal gastrointestinal toxicity. Antitumor activity was observed in patients with trastuzumab-refractory MBC. [ABSTRACT FROM AUTHOR]

Purpose Granulocyte-colony stimulating factor (G-CSF) was used in CALGB 9741 to support dose-dense sequential chemotherapy with doxorubicin and cyclophosphamide (AC) followed by paclitaxel (P) (Citron et al. J Clin Oncol 21:1431–1439, 2003). However, myelosuppression is not known to be dose or schedule limiting for paclitaxel. We therefore conducted this trial to determine the need for routine G-CSF, using the pegylated product (pG-CSF), support during the paclitaxel component of dose-dense sequential chemotherapy in women with early stage breast carcinoma (BC). Patients and methods Eligible patients received dose-dense chemotherapy consisting of four cycles of AC followed by four cycles of P at two week intervals. pG-CSF (NeulastaTM) was administered after each of four cycles of AC but was held after P. Planned enrollment was 59 pts. Results Of the first 15 patients, nine completed therapy without delays due to neutropenia but 6 (40%) did not, leading to implementation of the pre-specified early termination rule. Overall, 85% of P doses were successfully delivered on time. The mean treatment delay for the entire group due to neutropenia was 0.75 days. There was no significant correlation between neutropenia and prior WBC, ANC, or concurrent treatment with trastuzumab. Pts with neutropenia tended to be younger (Mean age 43.5) and have a lower BSA (1.65 m2). There were no febrile episodes due to omission of pG-CSF. Conclusion When paclitaxel is administered in a dose-dense fashion without growth factor support brief treatment delays are common. Further study is needed to identify the minimal pG-CSF administration that will avoid treatment delays. [ABSTRACT FROM AUTHOR]

Anthracyclines have been widely used in the adjuvant treatment of breast cancer and are part of most adjuvant regimens for the treatment of high-risk disease. The 2000 Early Breast Cancer Trialists Collaborative Group overview of polychemotherapy in breast cancer demonstrated that anthracycline-based regimens are superior to non-anthracycline-based therapies in terms of disease-free and overall survival. However, recently, there has been controversy related to anthracycline based on retrospective analyses which showed that only patients with human epidermal growth factor receptor 2 (HER2)-amplified tumors benefited from anthracyclines. However, caution must be used in basing treatments on retrospective data. HER2 should not be the only target used when considering an anthracycline because there may be other suspected molecular predictors of response, such as topoisomerase II alpha ( TOPO II α) gene aberrations (amplifications and deletions), TOPO II α protein overexpression, and DNA repair dysfunction, as well as others as yet undiscovered. Further, TOPO II α gene amplifications and gene deletions have been seen in HER2-negative tumors. This review argues against the use of HER2 as the sole target for predicting response to anthracyclines. [ABSTRACT FROM AUTHOR]

Several reports have suggested that breast cancer patients with elevated serum levels of interleukin-6 (IL-6) have a worse prognosis than patients with lower levels. We have studied IL-6 in breast cancer cell lines and have shown that autocrine production of IL-6 can confer multi-drug resistance in vitro by inducing multidrug resistance gene-1 transcription with subsequent overexpression of P-glycoprotein (PGP). Both IL-6 and PGP expression can be measured in malignant cells using immunohistochemical (IHC) techniques. We hypothesized that patients whose tumors expressed higher amounts of IL-6 or PGP would be less likely to respond to paclitaxel, an agent affected by the PGP pathway. If so, then IL-6 could serve as a predictive factor for paclitaxel sensitivity. Both IL-6 and PGP expression were measured in patients treated in a randomized trial that compared three doses of single agent paclitaxel (175, 210, and 250 mg/m over 3 h every 3 weeks) in 469 women with metastatic breast cancer (CALGB 9342). No difference in complete and partial response was found among the three treatment arms. Tissue blocks in this trial were analyzed for IL-6 (154 patients) and PGP (149 patients) in paraffin-embedded sections from tumor samples; clinical characteristics of these patients were similar to the total sample of 469 patients. There were no significant differences among IL-6 or PGP scores whether measured as continuous or dichotomous variables, or by other scoring, and response to paclitaxel. In multivariate analysis neither IL-6 nor PGP was a significant predictor of time to progression or overall survival. IHC expression of IL-6 and PGP levels in tumor cells is not a predictive marker for response to paclitaxel in women with metastatic breast cancer. [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]

For patients with hormone-unresponsive or higher-risk operable early-stage breast cancer, adjuvant chemotherapy significantly reduces the risks of relapse and death. The prognosis for such patients, especially those presenting with extensive axillary lymph node involvement, remains poor. New chemotherapy agents and novel administration schedules have recently been shown to improve clinical outcome. This overview provides a summary of the state of the art and the most recent developments regarding adjuvant chemotherapy for primary breast carcinoma. [ABSTRACT FROM AUTHOR]

High-dose chemotherapy is based on the scientific hypothesis that escalating the dose of drug will overcome drug resistance and improve outcome. Autologous bone marrow transplantation and, more recently, peripheral stem cell transplantation used as a means to restore marrow, made this a viable treatment for patients with selected tumours such as haematological malignancies. The role in breast cancer is less certain. Given the known as well as the potential toxicities, the objective of high-dose chemotherapy should be cure as opposed to palliation. However, the natural history of breast cancer can be protracted, with relapses occurring 15–20 years after treatment or within months of curative surgery. In breast cancer there is a positive correlation between recurrence-free and long-term survival. Therefore, the recurrence-free survival can be considered a surrogate endpoint in clinical trials. In patients with metastatic disease where cure is rare, at best, duration of a disease-free state may be a surrogate for overall benefit. Alternatively, time to progression may be another endpoint in the evaluation of treatment for metastatic disease. This is based on the assumption that quality of life is enhanced without progression of disease. Toxicity is the significant issue in the use of high-dose chemotherapy. The most common toxicity is myeloablation, potentially requiring prolonged hospitalisation. The only justification for these toxicities would be evidence of significant and meaningful benefit. A clinically relevant benefit with high-dose chemotherapy has not been seen in major randomised clinical trials of breast cancer in both the adjuvant and metastatic setting. In patients with advanced breast cancer, a small percentage may achieve long-term, disease-free survival, although there is no improvement in overall survival. Nonetheless, some investigators believe that high-dose chemotherapy holds promise, although currently this treatment is not recommended outside of a well designed prospective trial. These studies have provided useful information regarding cancer treatment. However, ongoing study of drug administration intervals, that is, dose-dense therapies, may lead to an approach that allows superior and less toxic treatment for breast cancer. [ABSTRACT FROM AUTHOR]

Gossypol has demonstrated in vitro effects on cell cycle regulation and anti-tumor activity against mammary carcinoma cell lines. This Phase I/II study assesses both the effect of gossypol on cell cycle regulatory proteins in vivo and the clinical effect. Twenty women with refractory metastatic breast cancer received oral gossypol at daily doses between 30 and 50mg per day. Gossypol plasma levels were measured ( n=8) and the modulation of the retinoblastoma (Rb) gene protein and Cyclin D1 was assessed by serial biopsies ( n=4). Grade I–II toxicities with gossypol treatment included nausea in 30% of patients, fatigue 15%, emesis 15%, altered taste sensation 15% and diarrhea in 10% of patients. Two of the three patients receiving 50mg/day experienced dose limiting dermatologic toxicity (grade III). One patient had a minor response and two patients had stable disease with >50 decline in serial assessments of the serum tumor markers. Immunohistochemical analysis of cyclin D1 and Rb expression in serial biopsies of four patients revealed both a concurrent decrease in cyclin D1 expression and an increase in nuclear Rb expression in three patients. The maximal tolerated dose (MTD) of gossypol was 40mg/day. Gossypol appears to affect the expression of Rb protein and cyclin D1 in breast cancer metastases at doses achievable, yet had negligible antitumor activity against anthracycline and taxane refractory metastatic breast cancer. The cell cycle regulatory effects of gossypol suggest a potential role for gossypol as a modulating agent in conjunction with other cell cycle specific compounds. [ABSTRACT FROM AUTHOR]

The rates of obesity are increasing worldwide and this condition is now recognized as a leading preventable cause of cancer. Several diseases are directly related to obesity, including diabetes, hypertension, atherosclerosis, stroke, musculoskeletal disorders, and a diverse range of malignances—such as breast cancer. Obesity is associated with an increased risk of postmenopausal estrogen receptor-positive breast cancer and worse cancer-related outcomes for all breast tumor subtypes. Several mechanisms have been proposed to contribute to the obesity-cancer link, including high levels of circulating and local estrogens, altered amounts of adipokines (leptin and adiponectin), disrupted insulin/IGF signaling, modifications within the microbiome, and local and systemic effects of inflammation. Here we will review recent advances in our understanding of the complex signaling pathways underlying the obesity-cancer link. An improved understanding of these processes is anticipated to propel novel and effective intervention strategies to reduce the global obesity-cancer burden. [ABSTRACT FROM AUTHOR]

The article discusses the randomised phase III trial conducted by Arbeitsgemeinschaft Gynakologische Onkologie (AGO) Breast Study Group on women with high-risk early-stage breast cancer. The patients were assigned to sequential intense dose-dense (IDD) chemotherapy with epirubicin, paclitaxel and cyclophosphamide. A brief background on the use of adjuvant chemotherapy for women with early-stage breast cancer is presented, as well as a chart showing the efficacy of dose-dense chemotherapy.

The article reports on the outcome of the NOAH clinical trial in the U.S. It notes that the impact of treatment with trastuzumab in the locally advanced breast cancer (LABC) setting was evaluated in the open-label NOAH study. It also mentions the results of the study which revealed that trastuzumab treatment for locally advanced breast cancer was associated with increased complete and overall response rate and improved event-free survival.

Ixabepilone (Ixempra; Bristol-Myers Squibb), a cytotoxic microtubule inhibitor, was approved by the US FDA for the treatment of metastatic breast cancer in October 2007. It is the first member of the epothilone family of anticancer agents to be approved. [ABSTRACT FROM AUTHOR]