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Background Job loss after a cancer diagnosis can lead to long-term financial toxicity and its attendant adverse clinical consequences, including decreased treatment adherence. Among women undergoing (neo)adjuvant chemotherapy for breast cancer, access to work accommodations (e.g., sick leave) is associated with higher job retention after treatment completion. However, low-income and/or minority women are less likely to have access to work accommodations and, therefore, are at higher risk of job loss. Given the time and transportation barriers that low-income working patients commonly face, it is crucial to develop an intervention that is convenient and easy to use. Methods We designed an intervention to promote job retention during and after (neo)adjuvant chemotherapy for breast cancer by improving access to relevant accommodations. Talking to Employers And Medical staff about Work (TEAMWork) is an English/Spanish mobile application (app) that provides (1) suggestions for work accommodations tailored to specific job demands, (2) coaching/strategies for negotiating with an employer, (3) advice for symptom self-management, and (4) tools to improve communication with the medical oncology team. This study is a randomized controlled trial to evaluate the app as a job-retention tool compared to a control condition that provides the app content in an informational paper booklet. The primary outcome of the study is work status after treatment completion. Secondary outcomes include work status 1 and 2 years later, participant self-efficacy to ask an employer for accommodations, receipt of workplace accommodations during and following adjuvant therapy, patient self-efficacy to communicate with the oncology provider, self-reported symptom burden during and following adjuvant therapy, and cancer treatment adherence. Discussion This study will assess the use of mobile technology to improve vulnerable breast cancer patients’ ability to communicate with their employers and oncology providers, work during treatment and retain their jobs in the long term, thereby diminishing the potential consequences of job loss, including decreased treatment adherence, debt, and bankruptcy. Trial registration ClincalTrials.gov NCT03572374. Registered on 08 June 2018.

Breast cancer brain metastases (BCBM) are a common and devastating complication of metastatic breast cancer with conventional systemic therapies demonstrating limited effectiveness. Consequently, radiotherapy (RT) ± surgery remains the cornerstone of BCBM management. Because preclinical and clinical evidence indicate that immune checkpoint blockade (ICB) may synergize with RT to promote systemic tumor regression, we explored the safety and efficacy of RT and concurrent tremelimumab-mediated cytotoxic T-lymphocyte associated protein 4 (CTLA-4) ICB with tremelimumab ± HER2-directed therapy with trastuzumab for BCBM. Eligible patients had BCBM indicated for brain RT. A Simon two-stage design was adopted to evaluate the efficacy of tremelimumab and RT in 20 patients with human epidermal growth factor receptor normal (HER2−) BCBM. The safety of concurrent RT, tremelimumab, and trastuzumab was evaluated in a cohort of 6 HER2+ patients. The primary endpoint was 12-week non-central nervous system (CNS) disease control rate (DCR). Secondary endpoints included safety, survival, and CNS response. Exploratory correlatives included characterization of peripheral blood immune responses among exceptional responders. Tremelimumab plus RT ± trastuzumab was tolerated with no treatment-related grade 4 adverse events reported. The 12-week non-CNS DCR was 10% (2/20) in the HER2− cohort and 33% (2/6) in the HER2+ cohort. One patient with HER2+ disease experienced a durable partial response with evidence of peripheral T-cell activation. Thus, tremelimumab and RT ± trastuzumab was tolerated. Although modest clinical activity was observed in the HER2- efficacy cohort, encouraging responses were observed in the HER2+ safety cohort. Consequently, a trial to determine efficacy in HER2+ BCBM is planned.Clinical Trial Registration Number: NCT02563925.

The addition of pertuzumab (P) to trastuzumab (H) and neoadjuvant chemotherapy (NAC) has decreased the risk of distant recurrence in early stage HER2-positive breast cancer. The incidence of brain metastases (BM) in patients who achieved pathological complete response (pCR) versus those who do not is unknown. In this study, we sought the incidence of BM in patients receiving HP-containing NAC as well as survival outcome. We reviewed the medical records of 526 early stage HER2-positive patients treated with an HP-based regimen at Memorial Sloan Kettering Cancer Center (MSKCC), between September 1, 2013 to November 1, 2019. The primary endpoint was to estimate the cumulative incidence of BM in pCR versus non-pCR patients; secondary endpoints included disease free-survival (DFS) and overall survival (OS). After a median follow-up of 3.2 years, 7 out of 286 patients with pCR had a BM while 5 out of 240 non-pCR patients had a BM. The 3-year DFS was significantly higher in the pCR group compared to non-pCR group (95% vs 91 %, p = 0.03) and the same trend was observed for overall survival. In our cohort, despite the better survival outcomes of patients who achieved pCR, we did not observe appreciable differences in the incidence of BM by pCR/non-pCR status. This finding suggests that the BM incidence could not be associated with pCR. Future trials with new small molecules able to cross the blood brain barrier should use more specific biomarkers rather than pCR for patients’ selection.

PURPOSE: Racial/ethnic minorities experience greater job loss than whites during periods of economic downturn and after a cancer diagnosis. Therefore, race/ethnicity-matched controls are needed to distinguish the impact of illness on job loss from secular trends. METHODS: Surveys were administered during and 4 months post-completion of breast cancer treatment. Patients were pre-diagnosis employed women aged 18–64, undergoing treatment for stage I-III breast cancer, who spoke English, Chinese, Korean, or Spanish. Each patient was asked to: 1) nominate peers who were surveyed in a corresponding timeframe (active controls), 2) report a friend’s work status at baseline and follow-up (passive controls). Both types of controls were healthy, employed at baseline, and shared the nominating patient’s race/ethnicity, language, and age. The primary outcome was number of evaluable patient-control pairs by type of control. A patient-control pair was evaluable if work status at follow-up was reported for both individuals. RESULTS: Of 180 patients, 25% had evaluable active controls (45 patient-control pairs); 84% had evaluable passive controls (151 patient-control pairs). Although patients with controls differed from those without controls under each strategy, there was no difference in the percentage of controls who were working at follow-up (96% of active controls; 91% of passive controls). However, only 65% of patients were working at follow-up. CONCLUSIONS: The majority of patients had evaluable passive controls. There was no significant difference in outcome between controls ascertained through either method. IMPLICATIONS FOR CANCER SURVIVORS: Passive controls are a low-cost, higher-yield option to control for secular trends in racially/ethnically diverse samples.

Alpelisib is a selective inhibitor of PI3Kα, shown to improve outcomes for PIK3CA mutant, hormone receptor positive (HR+) metastatic breast cancers (MBC) when combined with antiestrogen therapy. To uncover mechanisms of resistance, we conducted a detailed, longitudinal analysis of tumor and plasma circulating tumor DNA among such patients from a phase I/II trial combining alpelisib with an aromatase inhibitor (AI) (NCT01870505). The trial's primary objective was to establish safety with maculopapular rash emerging as the most common grade 3 adverse event (33%). Among 44 evaluable patients, the observed clinical benefit rate was 52%. Correlating genetic alterations with outcome, we identified loss-of-function PTEN mutations in 25% of patients with resistance. ESR1 activating mutations also expanded in number and allele fraction during treatment and were associated with resistance. These data indicate that genomic alterations that mediate resistance to alpelisib or antiestrogen may promote disease progression and highlight PTEN loss as a recurrent mechanism of resistance to PI3Kα inhibition.

In the ACOSOG (American College of Surgeons Oncology Group) Z0011 trial and the AMAROS (After Mapping of the Axilla: Radiotherapy or Surgery?) trial, matted nodes with gross extracapsular extension (ECE), a risk factor for locoregional recurrence, were an indication for axillary lymph node dissection (ALND), but the effect of microscopic ECE (mECE) in the sentinel lymph nodes (SLNs) on recurrence was not examined. Between 2010 and 2017, 811 patients with cT1-2N0 breast cancer and SLN metastasis were prospectively managed according to Z0011 criteria, with ALND for those with more than two positive SLNs or gross ECE. Management of mECE was not specified. In this study, we compare outcomes of patients with one to two positive SLNs with and without mECE, treated with SLN biopsy alone (n = 685). Median patient age was 58 years, and median tumor size was 1.7 cm. mECE was identified in 210 (31%) patients. Patients with mECE were older, had larger tumors, and were more likely to be hormone receptor positive and HER2 negative, have two positive SLNs, and receive nodal radiation. At a median follow-up of 41 months, no isolated axillary failures were observed. There were 11 nodal recurrences; two supraclavicular ± axillary, four synchronous with breast, and five with distant failure. The five-year rate of any nodal recurrence was 1.6% and did not differ by mECE (2.3% vs. 1.3%; p = 0.84). No differences were observed in local (p = 0.08) or distant (p = 0.31) recurrence rates by mECE status. In Z0011-eligible patients, nodal recurrence rates in patients with mECE are low after treatment with SLN biopsy alone, even in the absence of routine nodal radiation. The presence of mECE should not be considered a routine indication for ALND.

PURPOSE: CIPN is a common, debilitating, and dose-limiting side effect of chemotherapy. Here, we describe characteristics of patients with CIPN using both patient-reported outcomes (PRO) and quantitative sensory testing (QST). METHODS: Breast cancer survivors with persistent moderate to severe CIPN defined by a rating of 4 or greater on a 0–10 Numeric Rating Scale (NRS) from two ongoing clinical trials were included. PROs included the Neuropathic Pain Scale (NPS) and Functional Assessment of Cancer Therapy-Gynecologic Oncology Group/Neurotoxicity (FACT/GOG-Ntx). QST included tactile and vibration detection threshold measurements. Data were analyzed using descriptive statistics and Spearman correlation coefficients. RESULTS: 49 female patients with a mean age of 61 years were assessed; 63% were Caucasian. Mean NRS scores were 4.2, 5.7, and 4.3 on 0–10 scale for pain, numbness, and tingling, respectively. Mean NPS score was 41.0 on a 0–100 scale, and the mean FACT/GOG-Ntx score was 25.8 on a 0–44 scale. QST showed mild to moderate impairments in tactile and vibration perception. The FACT/GOG-Ntx subscale for numbness was negatively correlated with tactile and vibration thresholds in both hands and feet (both p < 0.05). NPS was positively correlated with tactile thresholds in the hands and feet (p < 0.05). CONCLUSION: Patients with moderate to severe CIPN report moderate pain, numbness, and tingling, and exhibit reduced tactile and vibration perception on QST. Weak to moderate correlations were observed between PRO and QST. These data suggest that QST outcomes are associated with CIPN symptoms and may be useful in helping monitor and manage CIPN treatment.

BACKGROUND: Pathologic complete response (pCR) is associated with better prognosis and guides management for patients with advanced rectal cancer. Response rates vary between series for unclear reasons. We examine whether the thoroughness of pathologic assessment explains differences in pCR rates. METHODS: We retrospectively reviewed pathology reports from patients with stage II/III rectal cancer who underwent chemoradiation and resection in a prospective, multicenter trial. We utilized a novel measure for the thoroughness of pathologic assessment by dividing residual tumor size by the number of cassettes evaluated (tumor size to cassette ratio, TSCR), and evaluated whether TSCR is associated with pCR. We validated our findings using a separate cohort. RESULTS: From the trial cohort, 71 of 247 (29%) patients achieved pCR. The pCR rate ranged from 0 to 45% and mean TSCR ranged 0.29 to 0.87 across 12 institutions. Within each institution, a lower TSCR was associated with pCR, demonstrating a higher degree of thoroughness used for tumors that achieved pCR. Moreover, across all samples, low TSCR was independently associated with pCR on multivariable analysis. This finding was corroborated in a separate cohort of 201 tumors evaluated by five pathologists; each pathologist had a lower mean TSCR for pCR calls compared with non-pCR calls. However, the mean TSCR for an institution was not associated with its overall pCR rate. CONCLUSIONS: Pathologists assess rectal cancers that have responded significantly to neoadjuvant therapy more thoroughly. Thoroughness does not appear to explain differences in pCR rates between institutions. Our results suggest pCR is not a sampling artifact.

Guidelines concur that postmastectomy radiation therapy (PMRT) in T1-2 tumors with one to three positive (+) lymph nodes (LNs) decreases locoregional recurrence (LRR) but advise limiting PMRT to patients at highest risk to balance against potential harms. In this study, we identify the risks of LRR after mastectomy in patients with T1-2N1 disease, treated with modern chemotherapy, and identify predictors of LRR when omitting PMRT. Patients with T1-2N1 breast cancer undergoing mastectomy between 1995 and 2006 were categorized by receipt of PMRT. The Chi square test compared the clinicopathologic features between both groups, and Kaplan–Meier and Cox regression analysis was used to determine the rates of LRR, recurrence-free survival (RFS), and overall survival (OS). Overall, 1087 patients (924 no PMRT, 163 PMRT) were included in the study, with a median follow-up of 10.8 years (range 0–21). We identified 63 LRRs (56 no PMRT, 7 PMRT), and 10-year rates of LRR with and without PMRT were 4.0% and 7.0%, respectively. Patients receiving PMRT were younger (p = 0.019), had larger tumors (p = 0.0013), higher histologic grade (p = 0.029), more positive LNs (p

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 ~1,900 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

Women with ductal carcinoma in situ (DCIS) are increasingly choosing bilateral mastectomy. We sought to quantify rates of contralateral breast cancer (CBC) and ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery (BCS) for DCIS, and to compare risk factors for CBC and IBTR. From 1978 to 2011, DCIS patients undergoing BCS with a contralateral breast at risk were identified from a prospectively maintained database. The association of clinicopathologic and treatment factors with CBC and IBTR were evaluated using Kaplan–Meier analysis, multivariable Cox regression, and competing risk regression (CRR). Of 2759 patients identified, 151 developed CBC and 344 developed IBTR. Five- and 10-year Kaplan–Meier CBC rates were 3.2 and 6.4%. Overall, 10-year IBTR rates were 2.5-fold higher than CBC rates, and, without radiation, 4-fold higher. On CRR, 5- and 10-year rates were 2.9 and 5.8% for CBC, and 7.8 and 14.5% for IBTR. CBC risk and invasive CBC risk were not significantly associated with age, family history, presentation, nuclear grade, year of surgery, or radiation. By multivariable Cox regression, endocrine therapy was associated with lower CBC risk (hazard ratio 0.57, p = 0.03). Ten-year risk of subsequent CBC in the subset of patients who developed IBTR was similar to the cohort as a whole (8.1 vs. 6.4%). CBC rates were low across all groups, including those who experienced IBTR. CBC was not associated with factors that increase IBTR risk. While factors associated with IBTR risk are important in decision making regarding management of the index DCIS, they are not an indication for contralateral prophylactic mastectomy.

Randomized trials demonstrate equivalent locoregional control with sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND) for T1–2 micrometastatic breast cancer, but include few mastectomy patients. Consensus is lacking on indications for post-mastectomy radiotherapy (PMRT) in this population. Herein, we evaluate locoregional recurrence (LRR) in an unselected, modern cohort of T1–2 breast cancer patients with micrometastases or isolated tumor cells (ITCs; N0i+/N1mi) having a mastectomy. We identified patients with T1–2N0i+/N1mi breast cancer treated with mastectomy from January 2006 to December 2011. Recurrent, bilateral, and neoadjuvant cases were excluded. The primary outcome of interest was LRR. Overall, 352 patients [211 (60%) with ITCs and 141 (40%) with micrometastases] were identified. 162 (46%) patients had SLNB alone and one node was positive in 295 (84%) cases; 31 (9%) patients had PMRT and 95% had systemic therapy. At a median 6 years of follow-up, the overall crude LRR rate was 2.8% (n = 9), with no axillary recurrences, and the crude LRR rate was 3.9% among those who had SNB alone. Those with LRR had a median age of 55 years, median tumor size of 1.7 cm, and ductal histology; the majority were high-grade (89%) and estrogen receptor positive (78%), with one positive node (89%). There was no association between LRR and receipt of PMRT (p = 0.4), SLNB versus ALND (p = 0.2), or number of positive nodes (p = 0.7) using the log-rank test. LRR was infrequent among T1–2N0i+/N1mi patients treated with mastectomy without PMRT, with no axillary failures, suggesting that PMRT or nodal radiotherapy are not routinely indicated in this population.

This study aimed to determine the relationship between mammographic calcifications and magnetic resonance imaging (MRI) tumoral enhancement before and after neoadjuvant chemotherapy (NAC) and to assess the impact of these findings on surgical management. This Institutional Review Board-approved, Health Insurance Portability and Accountability Act (HIPAA)-compliant retrospective study involved breast cancer patients who underwent NAC between 2009 and 2015. The study cohort comprised 90 patients with pre- and posttreatment MRI and mammograms demonstrating calcifications within the tumor bed either at presentation or after treatment. The data gathered included pre- and post-NAC imaging findings and post-NAC histopathology, particularly findings associated with calcifications. Comparisons were made using Fisher’s exact test, with p values lower than 0.05 considered significant. Complete resolution of MRI enhancement occurred for 44% of the patients, and a pathologic complete response (pCR) was achieved for 32% of the patients. No statistically significant correlation between changes in mammographic calcifications and MRI enhancement was found (p = 0.12). Resolution of enhancement was strongly correlated with pCR (p < 0.0001). The majority of the patients with pCR demonstrated complete resolution of enhancement (79%, 23/29). No statistically significant relationship was found between changes in calcifications and rates of pCR (p = 0.06). A pCR was achieved most frequently for patients with resolution of enhancement and new, increasing, or unchanged calcifications (p < 0.0001). Although calcifications seen on post-NAC mammography may be associated with benign disease, loss of MRI enhancement does not predict the absence of residual tumor with sufficient accuracy to leave calcifications in place. Complete excision of tumor bed calcifications remains standard practice and a substantial limitation to NAC use for downstaging patients to be eligible for breast conservation treatment.

Identifying DCIS patients at low risk for disease progression could obviate need for standard therapy. The LORIS (surgery versus active monitoring for low-risk DCIS) trial is studying the safety of monitoring low-risk DCIS, although ipsilateral breast tumor recurrence (IBTR) rates in patients meeting enrollment criteria after complete surgical excision are unknown. Women with pure DCIS treated with breast-conserving surgery (BCS) with/without radiation therapy (RT) from 1/1996–1/2011 were included from a prospectively maintained database. IBTR rates were compared between those who did and did not meet LORIS eligibility criteria (age ≥ 46 years, screen-detected calcifications, nipple discharge absence, minimal family history, non-high-grade DCIS) after complete surgical excision. A total of 2394 women were identified; 401 met LORIS criteria. Median follow-up was 5.9 years; 431 had ≥10 years follow-up. LORIS cohort median age was 61 years (range 46–86 years); 207 (52 %) underwent RT, 79 (20 %) received endocrine therapy. Of 401 patients, 24 experienced an IBTR. Overall 10-year IBTR rates were 10.3 % (LORIS) versus 15.4 % (non-LORIS) (p = 0.08); without RT, 12.1 versus 21.4 %, respectively (p = 0.06). The 10-year invasive-IBTR rates for women meeting LORIS criteria were: 5.3 % BCS overall, 6.0 % without RT. Women meeting LORIS criteria (after complete surgical excision) are at somewhat lower risk for IBTR. Among such women undergoing excision without RT, the 10-year invasive-IBTR rate was 6 %. Given that approximately 20 % of women with core biopsy-proven non-high-grade DCIS have invasive cancer at excision, women managed without excision would be expected to incur higher invasive cancer rates. Additional criteria are needed to identify women not requiring intervention for DCIS.

Transient, multi-protein complexes are important facilitators of cellular functions. This includes the chaperome, an abundant protein family comprising chaperones, co-chaperones, adaptors, and folding enzymes—dynamic complexes of which regulate cellular homeostasis together with the protein degradation machinery1–6. Numerous studies have addressed the role of chaperome members in isolation, yet little is known about their relationships regarding how they interact and function together in malignancy7–17. As function is probably highly dependent on endogenous conditions found in native tumours, chaperomes have resisted investigation, mainly due to the limitations of methods needed to disrupt or engineer the cellular environment to facilitate analysis. Such limitations have led to a bottleneck in our understanding of chaperome-related disease biology and in the development of chaperome-targeted cancer treatment. Here we examined the chaperome complexes in a large set of tumour specimens. The methods used maintained the endogenous native state of tumours and we exploited this to investigate the molecular characteristics and composition of the chaperome in cancer, the molecular factors that drive chaperome networks to crosstalk in tumours, the distinguishing factors of the chaperome in tumours sensitive to pharmacologic inhibition, and the characteristics of tumours that may benefit from chaperome therapy. We find that under conditions of stress, such as malignant transformation fuelled by MYC, the chaperome becomes biochemically ‘rewired’ to form a network of stable, survival-facilitating, high-molecular-weight complexes. The chaperones heat shock protein 90 (HSP90) and heat shock cognate protein 70 (HSC70) are nucleating sites for these physically and functionally integrated complexes. The results indicate that these tightly integrated chaperome units, here termed the epichaperome, can function as a network to enhance cellular survival, irrespective of tissue of origin or genetic background. The epichaperome, present in over half of all cancers tested, has implications for diagnostics and also provides potential vulnerability as a target for drug intervention.

The American College of Surgeons Oncology Group Z0011 trial demonstrated the safety of omitting axillary lymph node dissection (ALND) for women with fewer than three positive sentinel lymph nodes (SLNs) who are undergoing breast-conservation therapy (BCT). Because most of the women were postmenopausal with estrogen receptor (ER) positive cancers, applicability of ALND for younger patients and those with triple-negative (TN) or human epidermal growth factor receptor 2 (HER2) overexpressing (HER2+) tumors remains controversial.From August 2010 to December 2015, patients undergoing BCT for cT1-2N0 disease and found to have positive SLNs were prospectively followed. Axillary lymph node dissection was indicated for more than two positive SLNs or gross extracapsular extension. Clinicopathologic characteristics, axillary surgery, nodal burden, and outcomes were compared between the high-risk patients (TN, HER2+, or age 50 years) and the remaining patients, termed average risk patients.Among 701 consecutive patients, 242 (35 %) were high risk: 31 (13 %) with TN, 48 (20 %) with HER2+, 130 (54 %) with age less than 50 years, and 33 (14 %) with more than one high-risk feature. The remaining 459 patients (65 %) were average risk. The high-risk patients were younger, had higher-grade tumors (p 0.0001), and more often had abnormal nodes imaged (p = 0.02). In this study, SLNB alone was performed for 85 % high-risk versus 82 % average-risk cases (p = 0.39). A median of four versus three SLNs were excised (p = 0.04), and both groups had a median of one positive SLN. Additional positive nodes at ALND were found in 62 % high-risk patients versus 65 % average-risk patients (p = 0.8), with a median of three positive nodes in both groups. During a median follow-up period of 31 months, no patients experienced isolated axillary recurrences.Axillary lymph node dissection was no more likely to be indicated for high-risk patients. For patients undergoing ALND, the nodal burden was similar. For patients otherwise meeting the American College of Surgeons Oncology Group (ACOSOG) Z0011 clinical eligibility criteria, ALND is not indicated on the basis of age or subtype.

The American Society of Clinical Oncology (ASCO) guidelines include incorporation of fertility preservation guidelines in the care of breast oncology patients. This study aimed to examine the baseline knowledge and preferences concerning fertility preservation among women of childbearing age with newly diagnosed breast cancer at the time of their initial visit to Memorial Sloan Kettering Cancer Center (MSKCC).A questionnaire on reproductive history, fertility knowledge, and preservation options was administered to women 18-45 years of age with newly diagnosed breast cancer at MSKCC between May and September 2011.The inclusion criteria were met by 60 women eligible for analysis who had a median age of 40 years (range 20-45 years). The findings showed that 50 % of the women either desired children in the future or were unsure whether they wanted children, with 9 % reporting that they received information about fertility preservation options before their MSKCC visit. Women who had never been pregnant were more likely than those with prior pregnancies to consider having children in the future (p = 0.001) and to contemplate fertility preservation options both before (p = 0.001) and after (p = 0.0002) cancer treatment.Early referral allows patients to take advantage of fertility preservation options while preventing delay in the initiation of systemic therapy. Referral by the breast surgical oncologist at the time of the initial visit has the potential to increase fertility knowledge because it appears that many women have not yet received fertility information at this early treatment stage.

Bilateral breast cancer (BBC) may present as synchronous (SBC) or metachronous breast cancer (MBC). Optimal surgical management of BBC patients is not well-defined. In this study, we report on histopathology, treatment, and outcomes in BBC patients. Upon Institutional Review Board approval, we identified BBC patients diagnosed and treated for invasive breast cancer between 1999 and 2007. Retrospective chart review for demographics, histopathology, treatment, and outcomes was performed, and factors associated with BCS choice were collected. Contraindication to BCS was defined as any of the following one-breast findings: multicentric disease, tumor considered too large for BCS, and a patient without a nominal breast size for acceptable cosmetic results. McNemar’s test for matched pairs (binary variables) or the paired t test (continuous variables) were used to examine if a pathologic characteristic differed within a cancer pair. Kaplan–Meier methods estimated overall survival (OS). A total of 203 BBC patients (119 SBC, 84 MBC) comprised our study group. Histopathologic characteristics of the first and second cancers diagnosed in both the SBC and MBC patients were very similar in histologic type and molecular profiles. Overall, 57 % of MBC patients underwent breast-conserving surgery (BCS) at initial diagnosis versus 34 % of patients with SBC. BCS contraindications were similar in both groups: 16 (34 %) MBC patients and 28 (36 %) SBC patients. Kaplan–Meier OS estimates at 5 and 10 years were 86 and 78 % for MBC, and 87 and 77 % for SBC patients, respectively. OS was excellent for both the MBC and SBC groups. Contraindications to BCS did not differ between groups. However, patients with SBC were less likely to undergo BCS compared with patients with MBC at the time of initial diagnosis.

This study was designed to describe patient, disease, and treatment characteristics of women diagnosed with breast cancer at the Breast Examination Center of Harlem (BECH) and to determine whether these characteristics have changed over time.Retrospective chart review of women diagnosed with breast cancer at BECH from 2000 to 2008 was performed. Comparisons were made to data from an earlier study period (1995-2000).From 2000 to 2008, 339 women were diagnosed with breast cancer following attendance at BECH-55 % were black, 39 % Hispanic, 5 % of other race/ethnicity; 52 % had no health insurance. Hispanic patients were significantly more likely to have no health insurance compared with black patients (p = 0.0091); 29 % of patients had preinvasive disease and 36.5 % had stage I disease. Almost 40 % of the entire group was followed for1 year. Five-year overall survival for the entire group was 83 % (95 % CI, 75-89 %) and 79 % for 188 Black women (95 % CI, 68-87 %). Compared with the earlier study period (1995-2000), fewer patients presented with palpable masses (45.4 vs. 67 %), and more had either stage 0 or stage I disease (65.6 vs. 46 %).Women diagnosed with breast cancer at BECH are predominantly Black and Hispanic, and most of these patients do not have health insurance. An increasing proportion of women diagnosed with breast cancer are presenting with nonpalpable, early-stage disease. Despite improved access to breast cancer screening, early stage at diagnosis, and access to appropriate management, these ethnic minorities continue to have poor outcomes and are poorly compliant with follow-up.

Postmastectomy radiation (PMRT) in T1–T2 tumors with 1–3 positive axillary lymph nodes (ALNs) is controversial. Impact of molecular subtype (MST) on locoregional recurrence (LRR) and PMRT benefit is uncertain. We examined the association between MST and LRR, recurrence-free survival (RFS), and overall survival (OS), in T1–T2 tumors with 1–3 positive ALNs. From an institutional database, we identified mastectomy patients with 1–3 positive ALNs between 1995 and 2006. Patients who received neoadjuvant chemotherapy, had T3–T4 tumors, or ≥4 positive ALNs were excluded. MST was defined as: hormone receptor (HR)+/HER2−(luminal A/B), HR+/HER2+(luminal HER2), HR−/HER2+(HER2), and HR−/HER2−(basal). Kaplan–Meier method and Cox regression analysis were used to examine association between MST and LRR, RFS, and OS. This study included 884 patients (700 no PMRT, 141 PMRT): 72.8 % luminal A/B, 7.8 % luminal HER2, 6.8 % HER2, and 12.6 % basal. Median follow-up was 6.3 years; 39 LRRs occurred. Luminal A/B subtype had the smallest tumors (p = 0.03), lowest intraductal component (p = 0.01), histologic grade (p

The effect of increasing negative margin width after breast-conserving therapy (BCT) on local recurrence (LR) is controversial. LR rates vary by subtype, with the highest rates seen in triple-negative breast cancer (TNBC). This study examined LR rates in relationship to margin width in TNBC treated with BCT.Women with TNBC who underwent BCT between 1999 and 2009 were identified. Margins were defined as positive (ink on tumor), 0.1-2.0, and 2 mm. Patients with positive margins were excluded. Statistical comparisons were by t test, Fisher's exact test, and Wilcoxon rank sum test. Cumulative incidence of LR was compared by competing-risks methodology.Of 535 cancers, 71 had margins ≤2 mm and 464 had margins2 mm. At a median follow-up of 84 months (range 8-165 months), there were 37 local, 18 regional, and 77 distant recurrences or deaths as first events. Ten patients had a locoregional recurrence before planned radiotherapy and were excluded from cumulative incidence analyses. The cumulative incidence of LR at 60 months for margins ≤2 mm was 4.7 % (95 % confidence interval 0-10.0) and for2 mm was 3.7 % (1.8, 5.5) (p = 0.11). After controlling for chemotherapy and tumor size, there was no difference in LR between the two margin groups (p = 0.06). A difference in the risk of distant recurrence or death was not observed (p = 0.53).Margin width of2 mm was not associated with reduced LR rates. These data support a negative margin definition of no ink on tumor, even in this high-risk TNBC cohort.

Postmastectomy radiotherapy (PMRT) is well established in patients with ≥4 positive axillary lymph nodes (ALN); indications in 1 to 3 positive ALN remains controversial. We examined clinicopathologic criteria used for PMRT selection and compared locoregional recurrence (LRR), recurrence-free survival (RFS), and overall survival (OS) among patients with and without PMRT.Between 1995 and 2006, a total of 1,331 patients with T1-T2 tumors and 1 to 3 positive ALN underwent mastectomy. We excluded T3/T4 tumors and neoadjuvant chemotherapy; we analyzed 1,087 patients (924 without PMRT, 163 with PMRT). Chi square testing compared clinicopathologic features between groups. The Kaplan-Meier method and Cox regression analysis examined the association between PMRT and LRR, RFS, and OS.PMRT patients were more likely to be ≤50 years old (p = 0.001) and to have larger tumors (p = 0.01), disease of a higher histologic grade (p = 0.03), lymphovascular invasion (LVI) (p0.0001), a greater number of positive ALN (p0.0001), extranodal invasion (p0.0001), and macroscopic ALN metastases (p0.0001). With a median follow-up of 7 years, PMRT and no-PMRT groups were similar in LRR (p = 0.57), RFS (p = 0.70), and OS (p = 0.28). On multivariate analysis of the no-PMRT group, age ≤50 years (p = 0.002) and presence of LVI (p0.0001) were associated with LRR. Stratified by age and LVI, patients ≤50 years old and with LVI had the highest 5-year LRR, 10.1 versus 1.1 %, than in patients50 years old without LVI (p0.001).By using clinicopathologic features, clinicians delivered PMRT to a select group of patients with T1-T2 tumors and 1 to 3 positive ALN, resulting in similarly low rates of 5-year LRR. Among patients not receiving PMRT, age ≤50 years and LVI were associated with increased LRR rates and warrant PMRT consideration.

Capecitabine is widely used in the management of metastatic breast cancer; however, drug delivery is limited by gastrointestinal and other toxicity. We employed mathematical modeling to rationally design an optimized dose and schedule for capecitabine of 2,000 mg twice daily, flat dosing, 7 days on, 7 days off. Preclinical data suggested increased efficacy and tolerability with this novel dosing, and three early-phase clinical trials have suggested a favorable toxicity profile. To further define the tolerability of this regimen, we conducted a systematic review of the gastrointestinal adverse events of patients on these studies. This review demonstrated a favorable gastrointestinal toxicity profile with capecitabine in this novel schedule when given as single agent or in combination therapy with either bevacizumab or lapatinib. No patients discontinued therapy for gastrointestinal toxicity, and there were no grade 4 or 5 gastrointestinal toxicities reported. Grade 3 or greater diarrhea occurred in two (2%); grade 2 or greater mucositis, constipation, and vomiting were reported in three (4%) patients. We conclude that capecitabine administered on a 7 days on, 7 days off schedule has limited gastrointestinal toxicity. Our methodology was based on an analysis of individual patient toxicity data from one phase I single-agent capecitabine and two phase II capecitabine combination studies (with bevacizumab and lapatinib, respectively), focusing specifically on gastrointestinal toxicity.

Targeted treatment with antiangiogenic therapy has become standard of care for the treatment of most patients with metastatic clear cell renal cell carcinoma (mRCC) based upon improvements in progression-free survival (PFS) in several randomised phase III clinical trials (Escudier et al, 2007a, 2007b; Motzer et al, 2007; Sternberg et al, 2010). With more than one choice of therapy available for patients with mRCC, clinical decision making is more complex, and data on other outcomes in addition to efficacy, such as quality of life and safety, have become increasingly important. Most often, treatments are compared by a head-to-head analysis of each trial endpoint separately. For purposes of a primary analysis, this approach is reasonable. However, this approach may not be ideal if there are important tradeoffs between endpoints such as an increased time with side effects of treatment but longer time to progression in one arm compared with the other. One method that allows integration of both the quality and quantity of survival time is the Time Without Symptoms of disease progression or Toxicity of treatment or TWiST analysis, and its extension the quality-adjusted TWiST or Q-TWiST (Gelber and Goldhirsch, 1986; Goldhirsch et al, 1989). The primary hypothesis of these methods is that patients with no disease symptoms or treatment toxicity have better health-related quality of life than those who have disease symptoms and toxicity. Q-TWiST was first used to evaluate adjuvant therapy for breast cancer (Gelber et al, 1991), and has since been widely applied to other settings and cancers (Gelber et al, 1996; Rosendahl et al, 1999; Sherrill et al, 2008; Marcus et al, 2010; Zbrozek et al, 2010). In this paper, we report the results of a Q-TWiST analysis from a phase III randomised clinical trial comparing the oral antiangiogenic compound sunitinib (SUTENT; Pfizer, Inc; New York, NY, USA), with interferon-α (IFN-α) as first-line treatment for patients with mRCC (Motzer et al, 2007; Motzer et al, 2009). In this trial, sunitinib showed superior PFS compared with IFN-α (median PFS 11 vs 5 months, P

BRCA1 germline mutation carriers usually develop ER, PR and HER2 negative breast carcinoma. Somatic BRCA1 mutations are rare in sporadic breast cancers, but other mechanisms could impair BRCA1 functions in these tumors, particularly in triple-negative breast carcinomas (TNBCs). Id4, a helix-loop-helix DNA binding factor, blocks BRCA1 gene transcription in vitro and could downregulate BRCA1 in vivo. We compared Id4 immunoreactivity in 101 TNBCs versus 113 non-TNBCs, and correlated the results with tumor morphology and immunoreactivity for CK5/6, CK14, EGFR, and androgen receptor (AR). Id4 was present in 76 out of 101 (75 %) TNBCs: 40 (40 %) TNBCs displayed Id4 positivity in >50 % of neoplastic cells, 23 (23 %) in 5–50 %, and 13 (13 %) in

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.

PIK3CA gene mutations are the most common activating mutations in human breast cancer. Its association with hormone receptor-positive breast cancer makes it a prime target for clinical therapeutic advances to maintain anti-estrogen responsiveness. In anticipation of this therapeutic approach, we have evaluated intratumoral heterogeneity in primary breast cancers with regard to PIK3CA mutation status. In addition, we have assessed for the presence of the mutation in paired pre-invasive breast cancer and metastases. To assess for intratumoral heterogeneity, separate tumor blocks from primary breast cancers (n = 63) were genotyped for PIK3CA mutations. Available paired tissue samples from breast tumors known to harbor mutations underwent massARRAY genotyping (n = 70) to identify PIK3CA and AKT1(E17K) mutations. Cores were macro-dissected from matched tissue, including normal breast, benign lymph nodes (LN), ductal carcinoma in situ, regional LN metastases, and distant metastases. Matched samples underwent genetic fingerprinting by multiple SNP genotyping to confirm genetic identity. Intratumoral heterogeneity is minimal with a concordance rate of 95.2% between two different blocks from primary breast cancers. Complete concordance of PIK3CA mutations is noted between primary breast cancer and DCIS. PIK3CA mutations in primary breast cancer are detected in matched regional LNs (91.7%) and distant metastases (100%). Mutation detection by massARRAY genotyping is sensitive but may be affected by sample quality. Intratumoral heterogeneity as measured by PIK3CA genotype is rare; PIK3CA mutations occur early and are selected for in breast cancer progression. HapMap analysis is an essential control for paired sample analysis. This data is clinically important, particularly, for the design of therapies targeting the PI3K/AKT pathway, as it offers confidence that the detection of PIK3CA mutations in the invasive primary tumor will accurately reflect breast cancer biology.

Data from randomized controlled trials support use of a diverting stoma in rectal cancer patients with low anastomoses, but there is little data on how this impacts patient quality of life (QOL). This study prospectively evaluates QOL in stage I-III rectal cancer patients undergoing sphincter-preserving surgery (SPS) with a temporary diverting stoma.Patents were identified from a prospective single-institution study of stage I-III rectal cancer patients undergoing SPS. Patients completed the EORTC C30/CR38 QOL scale preoperatively, at stoma closure, and at 6 months. The Stoma Quality of Life (SQOL) was administered at stoma closure. Subscales of the EORTC hypothesized to be affected by a diverting stoma were identified a priori. Longitudinal trends were analyzed using repeated measures ANOVA. Frequencies for responses on specific SQOL items were tabulated, and correlations between SQOL subscales and EORTC Global QOL assessed with Pearson correlation coefficient.Global QOL was reportedly good (mean score 70.2) and did not change with a temporary stoma (P = .83). Physical (P = .33), role (P = .07), and social function (P = .48) were also stable. Decreased body image was observed (P = .03). Stoma-related difficulties identified by the SQOL included sexual activity (53%), leakage (39%), discomfort in clothing (34%), concerns regarding privacy to empty pouch (32%), and feeling unattractive (31%). "Overall satisfaction with life," Work/social function (P.001), sexuality/body image (P = .01), and stoma function (P = .01) subscales of the SQOL correlated strongly with the EORTC Global QOL score (P.001).In this longitudinal study of QOL in rectal cancer patients with a temporary stoma, Global QOL was good despite significant stoma-related difficulties. Use of alternative research methodology is necessary to provide insight into why this contradiction exists.

Radiation from medical imaging may induce cellular damage and increase the risk of cancer. While health care workers are restricted to an annual dose of 50 milliSieverts (mSv), the exposure to patients is not typically recorded. After breast-conservation therapy (BCT), patients are subjected to screening mammography, diagnostic breast imaging, and systemic surveillance imaging (SSI). Our objectives are to determine the cumulative radiation exposure of breast cancer survivors after completion of BCT, and to compare exposure levels in two historical cohorts. We also evaluated the indications of SSI. We performed a retrospective study of 68 patients with stage I or II breast cancer who received BCT in 1997 or 2002. Cumulative radiation exposure during follow-up from all imaging attributable to the breast cancer diagnosis was recorded, including both breast and nonbreast imaging. The indications for SSI were recorded. In the first 5 years after BCT, patients received a median annual dose of 0.92 mSv with no difference between the 1997 and 2002 cohorts. A median of 90% of radiation exposure was due to mammography. From 1997 to 2002, the percentage of patients receiving computed tomography (CT) scans increased. Additional SSI occurred in 65% of patients, with the majority of tests ordered in the asymptomatic patient. Patients with nodal positivity were more likely to receive SSI (p = 0.03). In the first 5 years after BCT, annual radiation exposure due to imaging was low. However, it seems prudent to consider the risks of radiation exposure when ordering potentially low-yield screening studies in asymptomatic patients.

Volume of disease in the sentinel lymph node (SLN) is a significant predictor of additional nodal metastasis. This study assesses incidence of residual non-SLN disease in a large cohort of women with minimal SLN metastases and compares three methods of SLN micrometastasis volume measurement to determine which best predicts residual disease on completion axillary lymph node dissection (cALND).A total of 505 patients with invasive breast cancer and minimal SLN metastasis (pN1mi or pN0(i+)) underwent cALND and had complete data. All SLNs were evaluated by three measurement methods for volume of metastasis: (1) method of detection (frozen section, routine hematoxylin and eosin, serial hematoxylin and eosin, immunohistochemistry), (2) American Joint Committee on Cancer's AJCC Cancer Staging Manual, 7th edition, N category, and (3) number of metastatic cells (1-100, 101-999, ≥1000). Multivariable logistic regression models were used to predict the presence of additional non-SLN disease.A total of 251 patients (50%) had pN0(i+) and 254 patients (50%) had pN1mi disease. Twelve percent of those with pN0(i+) and 20% with pN1mi had additional non-SLN disease. On multivariate analyses including eight variables, only lymphovascular invasion (odds ratio 2.2, P 0.01) and volume of nodal metastasis as assessed by any method of measurement (method of detection, AJCC, and cell count) were significantly correlated with additional non-SLN disease (P = 0.04, 0.03, and 0.02, respectively). All three models had similar goodness of fit and discrimination (Akaike information criterion = 442, 442, 441; -2log likelihood = 416, 420, 417; concordance index = 0.680, 0.675, 0.676, respectively).A significant proportion of women with minimal SLN metastases have additional non-SLN disease at cALND. Assessments of SLN volume of disease by three different methods of measurement are equivalent for prediction of additional non-SLN metastases.

Axillary lymph node dissection (ALND) in patients with immunohistochemistry (IHC)-determined metastases to the sentinel lymph node (SLN) is controversial. The goal of this study was to examine factors associated with ALND in IHC-only patients.Retrospective review of an institutional SLN database from July 1997 to July 2003 was performed. We compared sociodemographic, pathologic, and therapeutic variables between IHC-only patients who had SLN biopsy alone and those that had ALND.Our study group consisted of 171 patients with IHC-only metastases to the SLN. Young age, estrogen receptor negative status, high Memorial Sloan-Kettering Cancer Center nomogram score, and chemotherapy were associated with ALND. Among patients who had ALND (n = 95), 18% had a positive non-SLN. Rates of systemic therapy were similar between those with and without positive non-SLNs at ALND. No axillary recurrences were observed in this series with a median follow-up of 6.4 years. The percentage of patients who were recurrence-free after 5 years was 97% (95% confidence interval, 92.1-98.6).On the basis of our findings and the lack of prospective randomized data, the practice of selectively limiting ALND to IHC-only patients thought to be at high risk and to patients for whom the identification of additional positive nodes may change systemic therapy recommendations seems to be a safe and reasonable approach.

Completion axillary lymph node dissection (CALND) is routinely performed in breast cancer patients with positive sentinel lymph nodes (SLN). We sought to determine the sociodemographic, pathologic, and therapeutic variables that were associated with CALND.From 7/1997 to 7/2003, 1,470 patients with invasive breast cancer were SLN positive by intraoperative frozen section or final pathologic exam by hematoxylin-eosin and/or immunohistochemistry (IHC). A comorbidity score was assigned using Adult Comorbidity Evaluation-27 system. Fisher's exact, Wilcoxon tests, and multivariate logistic regression analysis were used.CALND was performed less often in patients with ageor= 70 years compared with age70 years, moderate or severe comorbidities compared with no or mild, IHC-only positive SLN and breast conservation therapy (BCT compared with mastectomy. Patients who did not undergo CALND were less likely than CALND patients to have grade III disease, lymphovascular invasion multifocal disease, tumor size2 cm or to receive adjuvant chemotherapy. However, they were more likely to undergo axillary radiotherapy (RT). On multivariate analysis, ageor= 70 years [odds ratio (OR) 0.4, 95% confidence interval (CI) 0.26-0.63], IHC-only positive SLN (OR 0.13, 95%CI 0.09-0.19), presence of moderate to severe comorbidities (OR 0.64, 95%CI 0.41-0.99), tumor sizeor= 2 cm (OR 0.44, 95%CI 0.29-0.66), axillary RT (OR 0.39, 95%CI 0.20-0.78), and BCT (OR 0.54, 95%CI 0.37-0.79) were all independently associated with lower odds of CALND.The decision to perform CALND following positive SLN biopsy was multifactorial. Patient factors were a primary determinant for the use of CALND in our study. The decreased use of CALND in the BCT patients probably reflects reliance on the radiotherapy tangents to maintain local control in the axilla.

Introduction The objective of this study was to examine the feasibility and toxicity of adjuvant dose-dense chemotherapy in older women with breast cancer. Methods A search of the Memorial Sloan-Kettering Cancer Center (MSKCC) breast cancer database was performed to identify all patients age 60 and older who underwent an initial consultation with a breast medical oncologist between October 1, 2002 and June 28, 2005. Inclusion criteria were: (1) age ≥ 60, (2) follow-up care obtained at MSKCC, (3) intent to treat with adjuvant dose-dense AC-T (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 2 weeks for 4 cycles followed by paclitaxel 175 mg/m2 every 2 weeks for 4 cycles, with white blood cell growth factor support). Results One hundred sixty-two patients (mean age 66, range 60–76) with breast cancer, stages I (n = 5), II (n = 111), and III (n = 46) according to the sixth edition of the AJCC staging system, were included in this analysis. Forty-one percent (n = 67) experienced a grade 3 or 4 toxicity, 9% a grade 3 infection (n = 14), 6% grade 3 fatigue (n = 9), 5% neutropenic fever (n = 8), and 4% thromboembolic events (n = 7). Twenty-two percent (n = 36) did not complete the planned 8 cycles of treatment. There was no statistically significant association between age and either toxicity or treatment discontinuation. In multivariate analysis including age, pretreatment hemoglobin, and comorbidity, the presence of comorbidity (Charlson score ≥ 1) and a lower baseline hemoglobin score were associated with an increased risk of any grade 3 or 4 toxicity. Conclusions We found that the risk of toxicity depended more on comorbid medical conditions and baseline hemoglobin value than age in this cohort of older adults receiving dose-dense adjuvant chemotherapy.

Phyllodes tumors (PT) are rare fibroepithelial neoplasms of the breast with unpredictable behavior. We reviewed our single institution experience with PT over 51 years to identify factors predictive of local recurrence (LR) and metastasis. From 1954 to 2005, a total of 352 cases of PT were identified; 293 had follow-up. All available pathology slides (90%) were rereviewed for margins, borders, fibroproliferation in the surrounding breast tissue, stromal pattern, stromal cellularity, frequency of mitoses, and necrosis. All cases occurred in women, with a median age of 42, with 203 originally categorized as benign and 90 as malignant. Median follow-up was 7.9 years. A total of 35 patients developed LR at a median of 2 years. In univariate analyses, a higher actuarial LR rate was associated with positive margins (P = .04), fibroproliferation (P = .001), and necrosis (P = .006). PT classified as malignant did not have a higher risk of LR (P = .79). Five patients developed distant disease at a median of 1.2 years. These patients constituted 71% of the seven patients who had uniformly aggressive pathologic features, including large tumor size (≥7.0 cm), infiltrative borders, marked stromal overgrowth, marked stromal cellularity, high mitotic count, and necrosis. Positive margins, fibroproliferation in the surrounding breast tissue, and necrosis are associated with a marked increase in LR rates. Efforts should be made to achieve negative surgical margins to reduce risk of LR. Death from PT is rare (2%), and only PT that demonstrate uniformly aggressive pathologic features seem to be associated with mortality.

151Eu-Mossbauer investigations have been made on Eu(Cu1−xAux)2Si2 (x=0, 0.1, 0.15, 0.20) as a function of temperature. Intr⤩uction of gold in the matrix not only pr⤩uces significant variations in the isomer shift but also leads to a slowing down of valence fluctuations.

The series Eu2M3Si5 (M=Ni, Cu, Pd, Rh) have been synthesised for the first time. The Ni, Cu, Pd systems form in U2Co3Si5 type structure.151Eu Mossbauer spectroscopy shows that Eu is in valence fluctuating (VF) state in Ni system, while in Cu and Pd systems it is in stable divalent state. These observations are further confirmed by magnetic susceptibility studies. The material Eu2Rh3Si5 shows two lines in the Mossbauer resonance, one of which shows VF behaviour.