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Ovarian function suppression (OFS) is a potentially life-saving treatment for young women diagnosed with high-risk hormonal-receptor (HR)+ early breast cancer (EBC), albeit one associated with significant side effects that may adversely affect quality of life. Of particular concern, this article raises a few borderline indications that were largely unaddressed in pivotal clinical trials but are still commonly encountered in daily practice. These, referred to here as 'borderline indications of OFS' remain a source of uncertainty for patients and physicians and are concisely addressed in this article.

Objectives: The Lewis-Y antigen is expressed in 44%-90% of breast cancers (BCs). The expression of the antigen in carcinoma tissue differs from that in normal tissues. This study aimed to evaluate the clinical benefit of the humanized anti-Lewis Y monoclonal antibody, hu3S193, in advanced hormone receptor-positive and Lewis Y-positive BC after administration of endocrine therapy (ET)., Methods: A single-arm phase II study was conducted in seven centers. Patients with advanced hormone receptor-positive BC who failed first-line ET were included. The inclusion criterion was the observation of tumoral expression of the Lewis Y antigen during immunohistochemistry. The treatment comprised hu3S193 antibody administration at weekly intravenous doses of 20 mg/m2 for 8-week cycles. The primary endpoint was the clinical benefit rate. ClinicalTrials.gov NCT01370239., Results: The study stopped accrual following an unplanned interim analysis as the hu3S193 antibody lacked sufficient activity to justify continuation of the study. Twenty-two patients were enrolled, of whom 21 were included in the efficacy analysis. The clinical benefit rate was 19%, with four patients presenting with stable disease after 24 weeks. One patient with prolonged stable disease received medication for over 2 years. No partial or complete responses were observed. The median time to progression and overall survival was 5.4 and 37.5 months, respectively., Conclusions: The humanized anti-Lewis Y monoclonal antibody, hu3S193, exhibited insufficient activity in this cohort. However, the possibility of activity in a more strictly selected subgroup of patients with higher levels of Lewis Y tumoral expression cannot be overlooked.

Background: In the KATHERINE study (NCT01772472), patients with residual invasive early breast cancer (EBC) after neoadjuvant chemotherapy (NACT) plus human epidermal growth factor receptor 2 (HER2)-targeted therapy had a 50% reduction in risk of recurrence or death with adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab. Here, we present additional exploratory safety and efficacy analyses., Patients and Methods: KATHERINE enrolled HER2-positive EBC patients with residual invasive disease in the breast/axilla at surgery after NACT containing a taxane (± anthracycline, ± platinum) and trastuzumab (± pertuzumab). Patients were randomized to adjuvant T-DM1 (n = 743) or trastuzumab (n = 743) for 14 cycles. The primary endpoint was invasive disease-free survival (IDFS)., Results: The incidence of peripheral neuropathy (PN) was similar regardless of neoadjuvant taxane type. Irrespective of treatment arm, baseline PN was associated with longer PN duration (median, 105-109 days longer) and lower resolution rate (∼65% versus ∼82%). Prior platinum therapy was associated with more grade 3-4 thrombocytopenia in the T-DM1 arm (13.5% versus 3.8%), but there was no grade ≥3 hemorrhage in these patients. Risk of recurrence or death was decreased with T-DM1 versus trastuzumab in patients who received anthracycline-based NACT [hazard ratio (HR) = 0.51; 95% confidence interval (CI): 0.38-0.67], non-anthracycline-based NACT (HR = 0.43; 95% CI: 0.22-0.82), presented with cT1, cN0 tumors (0 versus 6 IDFS events), or had particularly high-risk tumors (HRs ranged from 0.43 to 0.72). The central nervous system (CNS) was more often the site of first recurrence in the T-DM1 arm (5.9% versus 4.3%), but T-DM1 was not associated with a difference in overall risk of CNS recurrence., Conclusions: T-DM1 provides clinical benefit across patient subgroups, including small tumors and particularly high-risk tumors and does not increase the overall risk of CNS recurrence. NACT type had a minimal impact on safety., Competing Interests: Disclosure EPM reports consulting fees from Biotheranostics, Daiichi Sankyo, Genentech/Roche, Genomic Health, Merck, and Puma Biotechnology, and speaker bureau fees from Genentech and Genomic Health. MU reports consulting fees from the following companies, which have been paid to his institution: AbbVie, Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, Lilly Germany, Lilly International, Merck, MSD Mundipharma, Myriad Genetics, Novartis, Odonate, Pierre Fabre, Pfizer, Puma Biotechnology, F. Hoffmann-La Roche, Sanofi Aventis, and TEVA Pharmaceuticals. MSM reports honoraria for advisory boards and presentations in educational events from AstraZeneca, Lilly, MSD, Novartis, Oncologia Brasil, Pfizer, and Roche; educational support from Novartis, Pfizer, and Roche; and stock ownership in Biotoscana, Hypera Pharma, and Fleury. C-SH reports consulting fees from Amgen, Lilly, Novartis, Pfizer, and Roche; contracted research from AstraZeneca, Eirgenix, Lilly, MSD, Novartis, OBI, Pfizer, and Roche; travel expenses from Amgen, Pfizer, and Roche; and he serves on speakers bureaus for Pfizer and Roche. CEG reports consulting fees from Athenex, Celgene, Exact Science, Myriad Genetics, and Heron; uncompensated consulting for Daiichi Sankyo, Genentech, Roche, and Seattle Genetics; travel expenses from AstraZeneca, Daiichi Sankyo, and Roche; and medical writing support from AbbVie and Roche. GvM reports consulting fees from Amgen and Roche; contracted research from AbbVie, Amgen, AstraZeneca, Celgene, Myriad Genetics, Pfizer, Roche, and Vifor Pharma; and stock ownership in Cara GmbH (ARO). SK reports consulting fees from Amgen, AstraZeneca, Daiichi Sankyo, Lilly, MSD Oncology, Novartis, Pfizer, Puma Biotechnology, PFM Medical, Roche, and SOMATEX; and travel expenses from Daiichi Sankyo and Roche. MPDG reports royalties from DAKO and Neomarkers; consulting fees from Merck; and serves on a speaker’s bureau for Total Health Conferencing. BK reports speaker fees and honoraria from Roche; and has served on advisory boards for AstraZeneca, Novartis, Pfizer, and Roche. GK reports honoraria for advisory boards and presentations in educational events from Roche. TK reports honoraria from Celgene, Pfizer, and Roche. IW reports consulting fees from Cardinal Health and Vector Science; and contracted research with Lumicell, NOVADAQ, OncoSec, and Roche. MS reports consulting fees from Eisai, Lilly, MSD, Novartis, Pfizer, Roche, and Sandoz; and contracted research from AstraZeneca, Daiichi Sankyo, Eisai, Lilly, MSD, Novartis, Pfizer, Roche, and Sandoz. AB reports consulting fees from Agendia, Bayer, Bioarray Therapeutics, Biotheranostics, Celgene, Eisai, Genentech, Genomic Health, Lilly, Merck, Myriad Pharmaceuticals, NanoString Technologies, Novartis, Pfizer, Puma Biotechnology, and Roche. YY reports research funding paid to his institution from Astellas, Celgene, Janssen, Lilly, Mundipharma, Novartis, Ono, Orient EuroPharma, and Roche. SL reports research funding and/or honoraria from the following companies which have been paid to her institution: AbbVie, Amgen, AstraZeneca, Celgene, Celltrion, Cepheid, Daiichi Sankyo, EirGenix, E-vate, Roche, GH, Immunomedics, Ipsen, Medscape, Myriad Pharmaceuticals, Novartis, PEER, Pfizer, Pierre Fabre, prIME, Puma Biotechnology, SeaGen, Sividon Diagnostics, TEVA Pharmaceuticals, and Vifor. TB is an employee of Parexel International GmbH, contracted by F. Hoffmann-La Roche Ltd, during the conduct of the study. HL, DT, LHL, and CS are employees of Genentech and hold stock in Roche. MS was an employee of Genentech during the conduct of the study. All other authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Trastuzumab emtansine (T-DM1), given postoperatively for 14 cycles to patients with human epidermal growth factor receptor 2-positive (HER2-positive) early breast cancer (EBC) who failed to achieve a pathological complete response after standard chemotherapy and HER2 blockade, represents probably the greatest progress in the management of this aggressive form of breast cancer since the adjuvant trastuzumab pivotal trials. This article addresses the rationale behind the conception of the KATHERINE trial, T-DM1's structure and pharmacokinetics data, clinical efficacy data of the KATHERINE trial and of other EBC trials with T-DM1, safety aspects, implications of the KATHERINE trial results to clinical practice and future perspectives in the management of HER2-positive EBC.

Breast cancer treatment has deeply changed in the last decades, since clinical and oncological cure cannot be achieved without patient's satisfaction in term of aesthetic outcomes. Several methods have been proposed to objectively assess these results. However, Italian breast centers have not yet agreed on measurable, reproducible and validated aesthetic outcome indicators to monitor their performance., Methods: The study was designed and conducted by Senonetwork, a not-for-profit association of Italian breast centers. Ten breast centers were selected based on specific eligibility criteria. This multicentre observational prospective study recruited 6515 patients with diagnosis of in situ or invasive breast cancer who underwent breast surgery in the years 2013-2016. Thirteen indicators of aesthetic results and of related quality of care were analyzed. Data collection and analysis were conducted using a common study database., Results: On average, seven out of ten centers were able to collect data on the proposed indicators with a proportion of missing values < 25%. By expert consensus based on study results, some seven indicators have been defined as "mandatory" while the remaining six have been defined as "recommended" because they require further refinement before they can be proposed for monitoring aesthetic outcomes or because there are doubts on the feasibility of data collection. The minimum standard is reached for 5 of 13 indicators. This finding and the wide range between centers reveal that there is ample room for improvement., Conclusions: From the present study useful measurable aesthetic parameters have emerged, leading to the definition of target objectives that breast centers can use for benchmarking and improvement of quality of care., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2020 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Metastasis of rectal cancer to the breast is an extremely rare clinical event. We report the case of a 67-year-old woman with a metastatic breast tumor derived from a BRAF V600E mutant rectal carcinoma that was diagnosed and resected curatively 1 year previously. Computed tomography showed a left breast mass and multiple lung nodules suspected to be indicative of recurrent rectal cancer. The ultrasonography examination demonstrated a 10 × 10-mm hypoechoic solid lesion in the left breast with an elevation in the serum carcinoembryonic antigen level and serum carbohydrate antigen 19-9 level. Core needle biopsy was performed, and histopathologic examination showed Cytokeratin 20 and CDX-2 positivity, compatible with rectal cancer. To our knowledge, this is the first case of a metastatic breast tumor arising from rectal carcinoma with BRAF mutation. Although breast metastasis is very rare event, the possibility of breast metastasis from extra mammary sites should be considered when the breast tumor is found in cancer treatment.

Purpose: Breast cancer (BC) in young women is uncommon and tends to present with more aggressive characteristics. To better understand and characterize this scenario in Brazil through real-world data, we performed a subanalysis of AMAZONA III study (ClinicalTrials.gov identifier: NCT02663973)., Methods: The AMAZONA III study (GBECAM 0115) is a prospective registry that included 2,950 women newly diagnosed with invasive BC in Brazil from January 2016 until March 2018 at 22 sites. Valid data were obtained from 2,888 patients regarding age at diagnosis and complete baseline information. To compare epidemiologic and clinicopathological features at the time of diagnosis, patients with BC were divided into two groups according to age: ≤ 40 years and > 40 years. Quantitative variables were described as means, and categorical variables were described as frequencies and percentages and compared using the Pearson's χ 2 test., Results: Of 2,888 women diagnosed with BC, 486 (17%) were ≤ 40 years old. Young women had higher educational level, most were employed and a significant number were married ( P < . 001 for all associations). Younger patients were more symptomatic at BC diagnosis ( P < . 001), and they also presented more frequently with stage III, T3/T4, grade 3 tumors, HER-2-positive, luminal B, and triple-negative subtypes., Conclusion: Brazilian women younger than age 40 years have unfavorable clinicopathological features of BC at diagnosis, with more aggressive subtypes and advanced stage when compared with older women. These differences are not explained by socioeconomic or ethnic imbalances. The causes of a higher prevalence of BC among young women in Brazil deserve additional investigation.

Tumour-associated p53 missense mutants act as driver oncogenes affecting cancer progression, metastatic potential and drug resistance (gain-of-function) 1 . Mutant p53 protein stabilization is a prerequisite for gain-of-function manifestation; however, it does not represent an intrinsic property of p53 mutants, but rather requires secondary events 2 . Moreover, mutant p53 protein levels are often heterogeneous even within the same tumour, raising questions on the mechanisms that control local mutant p53 accumulation in some tumour cells but not in their neighbours 2,3 . By investigating the cellular pathways that induce protection of mutant p53 from ubiquitin-mediated proteolysis, we found that HDAC6/Hsp90-dependent mutant p53 accumulation is sustained by RhoA geranylgeranylation downstream of the mevalonate pathway, as well as by RhoA- and actin-dependent transduction of mechanical inputs, such as the stiffness of the extracellular environment. Our results provide evidence for an unpredicted layer of mutant p53 regulation that relies on metabolic and mechanical cues.

Objective: To evaluate whether a country's Human Development Index (HDI) can help explain the differences in the country's breast cancer and gynecological cancer incidence and mortality rates in the Pan-American region., Study Design: Ecological analysis., Methods: Pan-American region countries with publicly available data both in GLOBOCAN 2012 and the United Nations Development Report 2012 were included (n = 28). Incidence and mortality rates age-standardized per 100,000 were natural log-transformed for breast cancer, ovarian cancer, corpus uteri cancer, and cervical cancer. The mortality-to-incidence ratio (MIR) was calculated for each site. Pearson's correlation test and a simple linear regression were performed., Results: The HDI showed a positive correlation with breast cancer and ovarian cancer incidence and mortality rates, respectively, and a negative correlation with cervical cancer incidence and mortality rates. The HDI and corpus uteri cancer showed no association. MIR and the HDI showed a negative correlation for all tumor types except ovarian cancer. An increment in 1 HDI unit leads to changes in cancer rates: in breast cancer incidence β = 4.03 (95% confidence interval [CI] 2.61; 5.45) P < 0.001, breast cancer mortality β = 1.76 (95% CI 0.32; 3.21) P = 0.019, and breast cancer-MIR β = -0.705 (95% CI 0.704; 0.706) P < 0.001; in cervical cancer incidence β = -3.28 (95% CI -4.78; -1.78) P < 0.001, cervical cancer mortality β = -4.63 (95% CI -6.10; -3.17) P < 0.001, and cervical cancer-MIR β = -1.35 (95% CI -1.83; -0.87) P < 0.001; in ovarian cancer incidence β = 3.26 (95% CI 1.78; 4.75) P < 0.001, ovarian cancer mortality β = 1.82 (95% CI 0.44; 3.20) P = 0.012, and ovarian cancer-MIR β = 5.10 (95% CI 3.22; 6.97) P < 0.001; in corpus uteri cancer incidence β = 2.37 (95% CI -0.33; 5.06) P = 0.83, corpus uteri cancer mortality β = 0.68 (95% CI -2.68; 2.82) P = 0.96, and corpus uteri cancer-MIR β = -2.30 (95% CI -3.19; -1.40) P < 0.001., Conclusions: A country's HDI should be considered to understand disparities in breast cancer and gynecological cancer in the Pan-American region., (Copyright © 2017 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

Small invasion into ductal carcinoma in situ (DCIS) can easily be overlooked in resected breast specimens. To disclose useful markers predictive of invasive foci within preoperatively diagnosed DCIS lesions, a retrospective histopathological comparison was made between postoperatively diagnosed invasive ductal carcinoma with a predominant intraductal component (IDCPIC) (n=43) and pure DCIS (n=82). Through a multivariate logistic regression analysis model, 5 variables (DCIS grade, "tumor thickness," extent of retraction cleft, presence of lymph node metastasis, and HER2 score) were found to be significantly associated with the presence of invasive foci within DCIS; with a cutoff point of 0.315, sensitivity, specificity, positive predictive value, and negative predictive value were 0.93, 0.77, 0.68, and 0.95, respectively. No statistically significant difference was observed in recurrence-free survival between IDCPIC and pure DCIS, whereas the IDCPIC curve showed a slightly earlier decline than the DCIS one. In general, preoperative detection of lymph node metastasis in DCIS patients is elusive because of the extremely tiny metastatic size in most cases; thus, a 4-variable model, without lymph node metastasis, would be the actual working model. Furthermore, tumor "thickness" was found to be the most significant parameter predictive of invasive foci within DCIS. Although IDCPIC and pure DCIS showed similar recurrence-free survival curves, prediction of invasive foci within DCIS necessitates postoperative pathological analysis of surgically resected lesions., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The Hippo pathway is an oncosuppressor signalling cascade that plays a major role in the control of cell growth, tissue homoeostasis and organ size. Dysregulation of the Hippo pathway leads to aberrant activation of the transcription co-activator YAP (Yes-associated protein) that contributes to tumorigenesis in several tissues. Here we identify glucocorticoids (GCs) as hormonal activators of YAP. Stimulation of glucocorticoid receptor (GR) leads to increase of YAP protein levels, nuclear accumulation and transcriptional activity in vitro and in vivo. Mechanistically, we find that GCs increase expression and deposition of fibronectin leading to the focal adhesion-Src pathway stimulation, cytoskeleton-dependent YAP activation and expansion of chemoresistant cancer stem cells. GR activation correlates with YAP activity in human breast cancer and predicts bad prognosis in the basal-like subtype. Our results unveil a novel mechanism of YAP activation in cancer and open the possibility to target GR to prevent cancer stem cells self-renewal and chemoresistance.

We report a case of recurrent breast cancer with involvement of the right adrenal grand, which was resected using laparoscopic surgery. The patient was a 41-year-old woman who underwent duct-lobular segmentectomy for ductal carcinoma in situ. Histopathology showed microinvasion, and tested positive for ER and PR, but negative for HER2, so we applied radiation to the remaining breast and administered tamoxifen. After 9 months, local recurrence was detected and quadrantectomy with axillary lymph node dissection was performed. One year and 10 months later, local recurrence was again detected and a tumorectomy was performed. The adjuvant therapy was changed to an LH-RH analog plus anastrozole and it was administered effectively for 5 years. Left ileal metastasis appeared in the 2nd month after completion of the adjuvant chemotherapy, so radiation was applied and an LH-RH analog plus exemestane administration was started. Three years passed without recurrence, but a right adrenal tumor appeared on computed tomography. The tumor grew over 6 months, so laparoscopic right adrenalectomy was performed. Histopathologically, the tumor tested positive for ER and PR, and negative for HER2 so we diagnosed metastasis of breast cancer, and administered an LH-RH analog plus exemestane. The patient's disease has not progressed in the 3 months since surgery.

Background: Novel targeted agents and combinations have become available in multiple lines of treatment for human epidermal growth factor receptor 2-positive (HER2(+)) metastatic breast cancer (MBC). In this context, alternatives to the lapatinib (L) and capecitabine (C) regimen, evaluating L combined with other cytotoxic drugs, are warranted., Patients and Methods: In the present phase II, multicenter study, patients with HER2(+) MBC with progression after taxane were randomized between L, 1250 mg, combined with C, 2000 mg/m(2) on days 1 to 14 (LC), vinorelbine (V), 25 mg/m(2) on days 1 and 8 (LV), or gemcitabine (G), 1000 mg/m(2) on days 1 and 8 (LG), every 21 days. The primary endpoint was the overall response rate., Results: A total of 142 patients were included from 2009 to 2012. No differences were found in the patient baseline characteristics. The median age was 51 years, 69% were postmenopausal, 32% had liver metastasis, 57% were hormone receptor negative, and 48% had been previously treated with trastuzumab. The overall response rate was 49% (95% confidence interval [CI], 34.8%-63.4%), 56% (95% CI, 40%-70.4%), and 41% (95% CI, 27%-56.8%) in the LC, LV, and LG groups, respectively. The median progression-free survival was 9 months in the LC arm and 7 months in the other 2 arms (P = .28). The most common grade 3 and 4 adverse events were hand-foot syndrome (18%), diarrhea (6%), and increased alanine aminotransferase/aspartate aminotransferase (4%) in the LC arm; neutropenia (36%), diarrhea (9%), and febrile neutropenia (6%) in the LV arm; and neutropenia (47%), alanine aminotransferase/aspartate aminotransferase (13%), and rash (4%) in the LG arm., Conclusion: LV and LG seem to be active combinations in patients with HER2(+) MBC after taxane failure. The overall toxicity was manageable in all regimens., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Neoadjuvant chemotherapy has practical and theoretical advantages over adjuvant chemotherapy strategy in breast cancer (BC) management. Moreover, metronomic delivery has a more favorable toxicity profile. The present study examined the feasibility of neoadjuvant metronomic chemotherapy in two cohorts [HER2+ (TraQme) and HER2- (TAME)] of locally advanced BC. Twenty patients were prospectively enrolled (TraQme, n=9; TAME, n=11). Both cohorts received weekly paclitaxel at 100 mg/m(2) during 8 weeks followed by weekly doxorubicin at 24 mg/m(2) for 9 weeks in combination with oral cyclophosphamide at 100 mg/day (fixed dose). The HER2+ cohort received weekly trastuzumab. The study was interrupted because of safety issues. Thirty-six percent of patients in the TAME cohort and all patients from the TraQme cohort had stage III BC. Of note, 33% from the TraQme cohort and 66% from the TAME cohort displayed hormone receptor positivity in tumor tissue. The pathological complete response rates were 55% and 18% among patients enrolled in the TraQme and TAME cohorts, respectively. Patients in the TraQme cohort had more advanced BC stages at diagnosis, higher-grade pathological classification, and more tumors lacking hormone receptor expression, compared to the TAME cohort. The toxicity profile was also different. Two patients in the TraQme cohort developed pneumonitis, and in the TAME cohort we observed more hematological toxicity and hand-foot syndrome. The neoadjuvant metronomic chemotherapy regimen evaluated in this trial was highly effective in achieving a tumor response, especially in the HER2+ cohort. Pneumonitis was a serious, unexpected adverse event observed in this group. Further larger and randomized trials are warranted to evaluate the association between metronomic chemotherapy and trastuzumab treatment.

Targeting human epidermal growth factor receptor 2 (HER2) during or in sequence with chemotherapy improves overall survival in metastatic and early HER2-overexpressing breast cancer. In this paper we systematically review neoadjuvant clinical trial data in HER2-positive breast cancer and discuss key unanswered clinical questions. All trials of HER2-targeted neoadjuvant therapy were identified through non-date-limited searches of PubMED® and Biosis® and congress abstract book searches from 2000-2011. Eligible trials were prospective, had at least 10 patients and a clear definition of pathological complete response (pCR) rate. A total of 50 trials fulfilled the eligibility criteria; 41 single-arm phase II studies were identified, 37 with trastuzumab and 4 with lapatinib, with significant variability in baseline tumour characteristics and pCR rates (range 12-66.7%). Of 9 randomised phase II/III trials, 4 assessed the addition of trastuzumab to chemotherapy and a further 5 randomised trials assessed different HER2-targeting approaches. Four of these studies assessed dual HER2-targeting approaches, which universally increased pCR at the expense of increased non-cardiac toxicity when lapatinib, but not pertuzumab, was added to trastuzumab. Significant advances have been made in HER2 targeting, resulting in a marked increase in the number of breast cancer patients experiencing tumour pCR. Mature data from randomised neoadjuvant and adjuvant studies are awaited for survival outcomes with combination targeted approaches. Unanswered questions centre on the individualisation of therapy and include; which, if any, chemotherapy backbone should be used, and which patients need dual HER2 blockade?, (Copyright © 2013. Published by Elsevier Ltd.)

Objective: The clinical significance of preoperative chemotherapy, including trastuzumab for HER2-positive breast cancer, was examined based on hormone receptors(HR)to clarify future issues., Subjects: 104 HER2-positive breast cancer patients who completed preoperative chemotherapy and underwent surgery from May 2005 to August 2010. All patients received sequential treatment with taxane±trastuzumab for FEC(5-FU+epirubicin+cyclophosphamide)therapy, and from 2008 they received trastuzumab postoperatively for one year., Results: Concerning the histological effects, the rate of comprehensive pCR(CpCR)in the 104 patients(31 HR-negative administered trastuzumab, 15 HR-negative not administered trastuzumab, 28 HR-positive administered trastuzumab, 30 HR-positive not administered trastuzumab)was 65%, 47%, 21% and 23% for each group, respectively CpCR was a significant factor(p<0. 05)in prolonged distant disease-free survival(DDFS)in the HR-negative group. Distant metastasis occurred in 14 patients, namely, brain metastasis in 7 patients(4 HR-negative administered trastuzumab, 1 HR-negative not administered trastuzumab, 2 HR-positive administered trastuzumab). The therapeutic efficacy was pINV in 5 of these 7 patients(3HR-negative administered trastuzumab, 1 HR-negative not administered trastuzumab, 1 HR-positive administered trastuzumab), and 4 of those 5 patients received trastuzumab postoperatively., Discussion: The responsiveness to preoperative chemotherapy including trastuzumab for HER2-positive breast cancer differs between HR-positive and HR-negative. pINV patients seem to be at a high risk for brain metastasis regardless of HR, and it may be difficult to suppress its occurrence only with trastuzumab adjuvant therapy.

We report the case of a woman with a metastatic breast cancer, who started a third-line treatment with dasatinib, a new oral tyrosine kinase inhibitor, and who developed, one week later, a progressive breathless sensation. Workup demonstrated pleuropericardial effusion that turned out to be a side effect of this new investigational drug. Although this dasatinib-induced side effect is well known, this case clearly illustrates the importance of an accurate diagnosis and adequate treatment of complications of new agents which are easy to use since most of them are orally taken, and the difficulty to clearly separate drug origin and cancer morbidities. The patient recovered completely one month after discontinuation of dasatinib. In this report, we will review the differential diagnosis and management of pleuropericardial effusion.

TP53 missense mutations dramatically influence tumor progression, however, their mechanism of action is still poorly understood. Here we demonstrate the fundamental role of the prolyl isomerase Pin1 in mutant p53 oncogenic functions. Pin1 enhances tumorigenesis in a Li-Fraumeni mouse model and cooperates with mutant p53 in Ras-dependent transformation. In breast cancer cells, Pin1 promotes mutant p53 dependent inhibition of the antimetastatic factor p63 and induction of a mutant p53 transcriptional program to increase aggressiveness. Furthermore, we identified a transcriptional signature associated with poor prognosis in breast cancer and, in a cohort of patients, Pin1 overexpression influenced the prognostic value of p53 mutation. These results define a Pin1/mutant p53 axis that conveys oncogenic signals to promote aggressiveness in human cancers., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: Triple-negative breast cancers (TNBCs) do not derive benefit from molecular-targeted treatments such as endocrine therapy or anti-HER2 therapy because they lack those molecular targets. On the other hand, TNBCs have been shown to respond to neoadjuvant chemotherapy (NAC). In this study, we analyzed TNBC patients who were treated with NAC at Osaka National Hospital over a recent 5-year period to clarify the predictive factors for NAC and prognostic factors., Patients and Methods: Thirty-three TNBC patients underwent sequential NAC with anthracycline (FEC100: 5FU 500 mg/m(2), epirubicin 100 mg/m(2), and cyclophosphamide 500 mg/m(2)/q3w, 4 courses) and taxanes (paclitaxel 80 mg/m(2)/qw, 12 courses or docetaxel 75 mg/m(2)/q3w, 4 courses) from May 2003 to July 2008. Pre-therapeutical and surgical specimens were studied for expressions of ER, PgR, HER-2, EGFR, cytokeratin 5/6, Ki-67, p53 and androgen receptor by immunohistochemistry (IHC). We analyzed clinicopathological factors and molecular markers in regard to the response to NAC and prognosis., Results: Pathological complete response (pCR) was achieved in 12 TNBC patients (36%). The pCR rate in the basal-like phenotype was significantly lower than in the non-basal-like phenotype (23 vs. 64%, respectively: P = 0.02). High pre-operative expressions of Ki-67 (≥50%) and HER-2 (2+) were considered as predictive factors for a better response from NAC. Pre-operative Ki-67 expression showed a significant correlation with disease-free survival (DFS) and a lower expression of Ki-67 (<50%) after NAC was favorable for DFS among non-pCR patients., Conclusions: A non-basal-like phenotype and higher expressions of Ki-67 and HER-2 (2+) were favorable factors for NAC. However, a higher expression of Ki-67 on the surgical specimen after NAC was also a poor prognostic factor.

Background: Treatment with adjuvant trastuzumab for 1 year improves disease-free survival and overall survival in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. We aimed to assess disease-free survival and overall survival after a median follow-up of 4 years for patients enrolled on the Herceptin Adjuvant (HERA) trial., Methods: The HERA trial is an international, multicentre, randomised, open-label, phase 3 trial comparing treatment with trastuzumab for 1 and 2 years with observation after standard neoadjuvant, adjuvant chemotherapy, or both in patients with HER2-positive early breast cancer. The primary endpoint was disease-free survival. After a positive first interim analysis at a median follow-up of 1 year for the comparison of treatment with trastuzumab for 1 year with observation, event-free patients in the observation group were allowed to cross over to receive trastuzumab. We report trial outcomes for the 1-year trastuzumab and observation groups at a median follow-up of 48·4 months (IQR 42·0-56·5) and assess the effect of the extensive crossover to trastuzumab. Our analysis was by intention-to-treat. The HERA trial is registered with the European Clinical Trials Database, number 2005-002385-11., Findings: The HERA trial population comprised 1698 patients randomly assigned to the observation group and 1703 to the 1-year trastuzumab group. Intention-to-treat analysis of disease-free survival showed a significant benefit in favour of patients in the 1-year trastuzumab group (4-year disease-free survival 78·6%) compared with the observation group (4-year disease-free survival 72·2%; hazard ratio [HR] 0·76; 95% CI 0·66-0·87; p<0·0001). Intention-to-treat analysis of overall survival showed no significant difference in the risk of death (4-year overall survival 89·3%vs 87·7%, respectively; HR 0·85; 95% CI 0·70-1·04; p=0·11). Overall, 885 patients (52%) of the 1698 patients in the observation group crossed over to receive trastuzumab, and began treatment at median 22·8 months (range 4·5-52·7) from randomisation. In a non-randomised comparison, patients in the selective-crossover cohort had fewer disease-free survival events than patients remaining in the observation group (adjusted HR 0·68; 95% CI 0·51-0·90; p=0·0077). Higher incidences of grade 3-4 and fatal adverse events were noted on 1-year trastuzumab than in the observation group. The most common grade 3 or 4 adverse events, each in less than 1% of patients, were congestive cardiac failure, hypertension, arthralgia, back pain, central-line infection, hot flush, headache, and diarrhoea., Interpretation: Treatment with adjuvant trastuzumab for 1 year after chemotherapy is associated with significant clinical benefit at 4-year median follow-up. The substantial selective crossover of patients in the observation group to trastuzumab was associated with improved outcomes for this cohort., Funding: F Hoffmann-La Roche, Michelangelo Foundation., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The role of the stromal constituents in the natural history of breast cancers is still poorly defined. The aim of the present study was to evaluate the expression of proteoglycan versican, a constituent of desmoplastic stroma of invasive carcinomas, in preinvasive breast lesions. We selected 41 cases of breast carcinoma: 28 pure in situ lesions and 13 invasive lesions with in situ-associated lesions. The study provided evidence that versican is strongly expressed in the perilesional stroma of a subclass of ductal in situ carcinomas, and that the extension of versican immunostaining is statistically related to the high grade (G3) category (54% of diffuse expressors; p=0.01), and with a comedo pattern (67% of diffuse expressors, p=0.003). On the other hand, the expression of versican in the cases of classic lobular in situ carcinomas that we selected for the study was confined to the anatomical structures that usually contain the proteoglycan in adult breast tissues. In our cohort, versican synthesis was found to be associated with spindle-shaped elements with myofibroblastic phenotype, as in the stroma of invasive carcinoma. These data, taken together with evidence from previous studies on proteins strongly related to versican, suggest that various histotypes of breast in situ carcinomas could follow different pathways of epithelial stromal interactions. In particular a category of in situ lesions shows constituents of desmoplastic stroma before the manifestation of the morphological signs of invasion. Study of the connective tissue modifications that trigger the pivotal phase of invasion could provide new prospects in oncology., (Copyright © 2010 Elsevier GmbH. All rights reserved.)

To define a set of quality indicators that should be routinely measured and evaluated to confirm that the clinical outcome reaches the requested standards, Eusoma has organised a workshop during which twenty four experts from different disciplines have reviewed the international literature and selected the main process and outcome indicators available for quality assurance of breast cancer care. A review of the literature for evidence-based recommendations have been performed by the steering committee. The experts have identified the quality indicators also taking into account the usability and feasibility. For each of them it has been reported: definition, minimum and target standard, motivation for selection and level of evidence (graded according to AHRO). In overall 17 main quality indicators have been identified, respectively, 7 on diagnosis, 4 on surgery and loco-regional treatment, 2 on systemic treatment and 4 on staging, counselling, follow-up and rehabilitation. Breast Units in Europe are invited to comply with these indicators and monitor them during their periodic audit meetings., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Objective: Determinants of long-term outcome of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer who received neoadjuvant chemotherapy (NAC) are not clear. The purpose of this study was to explore the prognostic factors of HER2-positive breast cancer patients administered NAC., Methods: A retrospective analysis of 125 HER2-positive breast cancer patients treated by NAC using an anthracycline plus taxane with (HCN group, n = 54) or without trastuzumab (non-HCN group, n = 71) was performed. The clinical parameters, including the pathological complete remission (pCR) rate, disease-free survival (DFS) and organ-specific recurrence-free survival, were measured., Results: According to the results of the univariate analyses, age, clinical stage, pCR and axillary lymph node status were the factors significantly associated with the DFS. The inclusion of trastuzumab in the NAC regimen did not yield a significant difference in the DFS. Only the axillary lymph node status and age were found to be the significant factors affecting the DFS in a multivariate model. There were no significant differences in the patient/tumor characteristics between the HCN and non-HCN groups except for the pCR rate (50% in the HCN group vs. 24% in the non-HCN group) and the median follow-up time (738 days in the HCN group vs. 1579 days in the non-HCN group). Within the first 2 years from the initiation of NAC treatment, the central nervous system (CNS) was the most common site of first recurrence in the HCN group, whereas no cases of CNS metastasis were observed in the non-HCN group., Conclusions: The pathological axillary node status and age were found to be the significant prognostic factors in HER2-positive breast cancer patients who received NAC. The pattern of recurrence may be different between HCN-treated and non-HCN-treated patients.

Purpose: Accurate assessment of metastasis in sentinel lymph nodes (SLN) of breast cancer is important but involves a heavy workload for the pathologist. We conducted a multicenter clinical trial in Japan to evaluate a new automated assay system for cytokeratin 19 mRNA, the one-step nucleic acid amplification (OSNA) assay (Sysmex), to detect lymph node metastasis of breast cancer., Experimental Design: Surgically obtained axillary lymph nodes were sectioned into four pieces, two of which were examined with the OSNA assay. The other two adjacent pieces were examined with H&E and immunohistochemical staining for cytokeratin 19. Serial sections at 0.2-mm intervals were used in trial 1 to determine the specificity of the OSNA assay, and three pairs of sections cut from the sliced surfaces of the pieces were used in trial 2 to compare the accuracy of the OSNA assay with that of a routine pathologic examination for SLNs in Japan., Results: In trial 1, the sensitivity and specificity were 95.0% [95% confidence interval (95% CI), 75.1-99.9%] and 97.1% (95% CI, 91.8-99.4%), respectively, for 124 axillary lymph nodes obtained from 34 patients. In trial 2, the agreement between findings of the assay and of the pathologic examination was 92.9% (95% CI, 90.1-95.1%) for 450 axillary lymph nodes obtained from 164 patients., Conclusion: The OSNA assay can detect lymph node metastasis as accurately as can conventional pathology and thus can be an effective addition to or alternative for rapid intraoperative examination of SLNs.

Background: The Breast Cancer Risk Assessment Tool of the National Cancer Institute (NCI) is widely used for counseling and determining eligibility for breast cancer prevention trials, although its validity for projecting risk in African American women is uncertain. We developed a model for projecting absolute risk of invasive breast cancer in African American women and compared its projections with those from the Breast Cancer Risk Assessment Tool., Methods: Data from 1607 African American women with invasive breast cancer and 1647 African American control subjects in the Women's Contraceptive and Reproductive Experiences (CARE) Study were used to compute relative and attributable risks that were based on age at menarche, number of affected mother or sisters, and number of previous benign biopsy examinations. Absolute risks were obtained by combining this information with data on invasive breast cancer incidence in African American women from the NCI's Surveillance, Epidemiology and End Results Program and with national mortality data. Eligibility screening data from the Study of Tamoxifen and Raloxifene (STAR) trial were used to determine how the new model would affect eligibility, and independent data from the Women's Health Initiative (WHI) were used to assess how well numbers of invasive breast cancers predicted by the new model agreed with observed cancers., Results: Tables and graphs for estimating relative risks and projecting absolute invasive breast cancer risk with confidence intervals were developed for African American women. Relative risks for family history and number of biopsies and attributable risks estimated from the CARE population were lower than those from the Breast Cancer Risk Assessment Tool, as was the discriminatory accuracy (i.e., concordance). Using eligibility screening data from the STAR trial, we estimated that 30.3% of African American women would have had 5-year invasive breast cancer risks of at least 1.66% by use of the CARE model, compared with only 14.5% by use of the Breast Cancer Risk Assessment Tool. The numbers of cancers predicted by the CARE model agreed well with observed numbers of cancers (i.e., it was well calibrated) in data from the WHI, except that it underestimated risk in African American women with breast biopsy examinations., Conclusions: The CARE model usually gave higher risk estimates for African American women than the Breast Cancer Risk Assessment Tool and is recommended for counseling African American women regarding their risk of breast cancer.

Breast cancer is diagnosed at a younger age and a more advanced stage in African-American women than in White women. The authors investigated the effects of several factors, including race, on stage of breast cancer in women aged 20-54 years living in Atlanta, Georgia, and diagnosed between 1990 and 1992. A total of 251 African-American and 580 White women were interviewed and their medical records reviewed. By use of polytomous logistic regression, factors possibly influencing stage and racial differences in stage were studied. In African-American women, the odds of stage III/IV breast cancer at diagnosis were almost four times the odds in White women (odds ratio = 3.79, 95% confidence interval: 2.45, 5.89) and approximately two and one-half times for stage IIA or stage IIB disease (odds ratio = 2.57, 95% confidence interval: 1.66, 3.99; odds ratio = 1.94, 95% confidence interval: 1.31, 2.86, respectively). These racial differences appeared to be largely explained by insurance status, poverty, history of mammography, method of tumor detection, and obesity. Interventions targeting these factors could potentially lower the stage at diagnosis for African-American breast cancer patients and, in doing so, improve their survival and other outcomes.

The Ki-67 antigen is used to evaluate the proliferative activity of breast cancer (BC); however, Ki-67's role as a prognostic marker in BC is still undefined. In order to better define the prognostic value of Ki-67/MIB-1, we performed a meta-analysis of studies that evaluated the impact of Ki-67/MIB-1 on disease-free survival (DFS) and/or on overall survival (OS) in early BC. Sixty-eight studies were identified and 46 studies including 12 155 patients were evaluable for our meta-analysis; 38 studies were evaluable for the aggregation of results for DFS, and 35 studies for OS. Patients were considered to present positive tumours for the expression of Ki-67/MIB-1 according to the cut-off points defined by the authors. Ki-67/MIB-1 positivity is associated with higher probability of relapse in all patients (HR=1.93 (95% confidence interval (CI): 1.74-2.14); P<0.001), in node-negative patients (HR=2.31 (95% CI: 1.83-2.92); P<0.001) and in node-positive patients (HR=1.59 (95% CI: 1.35-1.87); P<0.001). Furthermore, Ki-67/MIB-1 positivity is associated with worse survival in all patients (HR=1.95 (95% CI: 1.70-2.24; P<0.001)), node-negative patients (HR=2.54 (95% CI: 1.65-3.91); P<0.001) and node-positive patients (HR=2.33 (95% CI: 1.83-2.95); P<0.001). Our meta-analysis suggests that Ki-67/MIB-1 positivity confers a higher risk of relapse and a worse survival in patients with early BC.

We enrolled all 2162 in situ and 21 148 invasive cases of breast cancer in 17 areas of Italy, diagnosed in 1997-2001. Rates of early cancer increased by 13.7% in the screening age group (50-69 years), and breast conserving surgery by 24.6%. Advanced cancer rates decreased by 19.4%, and mastectomy rates by 24.2%. Service screening did not increase mastectomy rates in the study population.

Vinorelbine is a semi-synthetic vinca alkaloid that has been shown active in many tumour types and is currently registered for the treatment of advanced breast cancer (ABC) and non-small cell lung cancer (NSCLC). This agent has a generally favourable safety profile, and may be suitable for use in special populations such as the elderly and/or frail patient. However, with the taxanes firmly established as standard second line treatment for ABC after failure of an anthracycline, vinorelbine has been generally relegated for use as third line therapy, in competition with the oral compound capecitabine. More recently, the exciting results observed with the combination of vinorelbine and trastuzumab in patients with Her-2 overexpressing/amplified tumours, as well as the development of a reliable formulation and revised schedule of oral vinorelbine with proven activity in ABC appear to have revived the interest in this compound in the management of this disease. There are still a number of unanswered questions that will have to be addressed by properly designed, adequately powered randomised clinical trials.

Elderly patients are more likely to present with locally advanced breast cancer than younger patients. Furthermore, due to the accelerated aging of the western population, the incidence of breast cancer in this population is expected to steadily rise in the coming decades. So far, no guidelines are available for the management of octogenarian patients presenting with inoperable disease, what frequently results in a dilemma for the treating physician. For the time being, these patients should be ideally treated within the context of a clinical trial. In all other cases, the treatment has to be individualised, frequently based on data extrapolated from different population of patients, or retrospective series. This article reviews the current evidence, options, and most promising approaches for these patients.

Topoisomerase-IIalpha (topo-II) is a molecular target for topo-II inhibitors, which makes it a potential predictive marker of responsiveness to these agents. We aim to correlate topo-II gene and protein status on 103 HER-2 amplified breast cancer samples. Paraffin-embedded blocks were screened by FISH for topo-II gene amplification (topo-II: CEP17 ratio >/=1.5; triple probe by Vysis inc.) and analyzed by IHC for topo-II protein expression (continuous variable; clone KiS1) and Ki-67 (positive if >25% of stained cells; clone MIB-1). Topo-II gene amplification was observed in 36.9% (38/103) of the HER-2 amplified study population. HER-2 amplification level (e.g. copy number) was not shown to be predictive for topo-II amplification. The median percentage of topo-II positively stained cells by IHC for topo-II non-amplified and amplified cases were 5% and 10%, respectively. A weak but significant correlation was observed between topo-II gene amplification level and percentage of positively stained cells (Spearman's ranks correlation coefficient of 0.23, p=0.02), the observed correlation being higher in patients with positive staining for Ki-67. Contrary to HER-2, where gene amplification is almost always correlated with protein overexpression in breast cancer, topo-II gene amplification apparently does not always lead to protein overexpression, at least when the latter is evaluated by IHC. Other factors, specifically the tumor proliferation status, may interfere with the topo-II protein status. Although the great majority of topo-II gene aberrations occur in HER-2 positive tumors, the level of HER-2 amplification does not predict for topo-II amplification.

Background: The need for further axillary treatment in patients with breast cancer with low-volume sentinel node (SN) involvement (micrometastases or smaller) is controversial., Methods: Twenty-five studies reporting on non-SN involvement associated with low-volume SN involvement were identified using Medline and a meta-analysis was performed., Results: The weighted mean estimate for the incidence of non-SN metastases after low-volume SN involvement is around 20 per cent, whereas this incidence is around 9 per cent if the SN involvement is detected by immunohistochemistry (IHC) alone. Subset analyses suggest that studies with axillary dissection after any type of SN involvement result in somewhat higher estimates than studies allowing omission of axillary clearance, as do studies with more detailed histological evaluation of the SN compared with those with a less intensive histological protocol. Higher-quality papers yield lower pooled estimates than lower-quality papers., Conclusion: The risk of non-SN metastasis with a low-volume metastasis in the SN is around 10-15 per cent, depending on the method of detection of SN involvement. This should be taken into account when assessing the risk of omission of axillary dissection after a positive SN biopsy yielding micrometastatic or immunohistochemically positive SNs., (Copyright (c) 2004 British Journal of Surgery Society Ltd)

The first generation of randomised trials assessing the role of primary chemotherapy in breast cancer has failed to demonstrate the expected survival benefit. However, it has established the role of this treatment in 'downstaging' tumours of patients with locally advanced disease and, consequently, in improving breast conservation rates. Also, a number of surrogates of outcome have been identified, which will hopefully lead to earlier results in breast cancer clinical trials. Encouraging results have also been reported in trials investigating a number of novel approaches., (Copyright 2004 European Society for Medical Oncology)

We report on the case of a patient with a diagnosis of a HER2-overexpressing metastatic breast cancer which was refractory to a combination of a Raf kinase inhibitor and docetaxel, but highly sensitive to trastuzumab, a HER2-targeted monoclonal antibody. Interestingly, there was no evidence of Ras-Raf-MAPK or PI3K-Akt pathways activation.

The object of this study was to assess quality of care and adherence to treatment guidelines of screen-detected lesions in Italy using a new audit system. Data on screen-detected cases surgically treated in 1997 were collected using a system (QT 2.3) developed within the Italian Group for Planning and Evaluating Mammographic Screening Programmes (GISMa) and the European Breast Cancer Screening Network. Results of 18 performance parameters were considered compared with the reference standards. In 1997, 515 lesions (335 invasive, 60 in situ and 120 benign) in 496 patients were collected from 14 departments in the Central and Northern area of Italy. The 18 indicators were analysed and grouped according to six quality objectives. Some results were good and others were excellent, such as intraoperative identification, breast conservation surgery, adequate axillary procedures and completeness of pathology reports, but most of them failed: waiting times, preoperative diagnosis, employment of frozen section on small lesions and avoiding axillary procedures in ductal carcinoma-in-situ. This work is a first attempt in Italy to evaluate and uniform the criteria adopted for quality control of breast cancer treatment, using a standardised system. Some results are good or excellent, the overall level of compliance with quality indicators is not satisfactory and corrective actions should be undertaken for a number of issues. A continuous monitoring should be performed and appropriate action taken in order to verify the effectiveness of the corrective actions and to provide screen-detected patients with the best quality of care.

In recent years, strategy in cancer therapy in general, and breast cancer in particular, has been the use of maximum tolerated doses of toxic non-specific agents as well as the investigation of a range of new agents that specifically target tumor-related molecules, in a variety of biological pathways. The trial of chemotherapy (CT) versus chemotherapy+trastuzumab (Herceptin) in HER-2-overexpressing metastatic breast cancer (MBC) was one of the first to use a biological agent in combination with chemotherapy with success and, together with some trials of taxanes in anthracycline-resistance patients one of the few to demonstrate an overall survival (OS) advantage in MBC. Five main molecular pathways are of particular interest in terms of new drug development in breast cancer: the estrogen receptor (ER) pathway, the tyrosine kinase signal transduction pathway, the cell cycle regulation pathway, the apoptosis pathway and the angiogenesis pathway. This review will focus on new agents, cytotoxic, hormonal and molecular-targeted, which are in advanced clinical stages of development for the treatment of MBC.

Background: Alkylating agents and topoisomerase-II inhibitors have been associated with the occurrence of secondary leukemias and myelodysplastic syndromes in breast cancer patients treated with adjuvant chemotherapy. Conversely, data on the occurrence of second solid malignancies in this setting are scarce., Patients and Methods: This study retrospectively evaluates the occurrence of second hematological and solid malignancies in the context of a prospective multicenter phase III trial comparing epirubicin-cyclophosphamide at intermediate doses (EC), or at full doses (HEC), with classical cyclophosphamide, methotrexate and 5-fluorouracil (CMF) in 777 patients with early breast cancer., Results: At a median follow-up of 73 months, the following 8-year actuarial rates of second solid primaries were observed: CMF 5.5% [95% confidence interval (CI) 1.5% to 9.5%], EC 4.1% (95% CI 0.1% to 8.1%), and HEC 7.2% (95% CI 3.2% to 11.2%) (P = 0.79 by log rank test). Three secondary acute myeloid leukemias (AML) were reported, all in the HEC arm (incidence = 1.2%, 95% CI 0.0% to 2.5%), which by a three arm comparison allows us to conclude that HEC is statistically different (borderline significance) from CMF and EC (P = 0.05)., Conclusions: HEC, as delivered in this trial, cannot be recommended in clinical practice because of the lack of superiority over classic CMF and because of the increased risk of AML observed in this arm. Prolongation of conventional anthracycline-based treatment beyond the current standard of four to six cycles is not recommended in clinical practice.

A breast unit is a cancer centre specialised in the diagnosis and treatment of patients with breast cancer. The high level of specialised skills involved in running a breast unit makes it an expensive pattern of care. The European Society of Mastology (EUSOMA) recommends a minimum caseload of 150 cases sufficient to maintain expertise for each team member and to ensure cost-effective working of the breast unit. Specific economic analysis evaluating main diagnostic services (radiology and pathology) and treatment are needed. The present study assesses the activity level at which the breast unit represents good value for money in surgically-treated patients. Cost assessment is realised by defining a cost function according to the following assumptions: cost function input is personnel costs and technical equipment and output is the number of newly diagnosed cases of primary breast cancer admitted to the breast care unit each year. The increase from 50 new cancer cases per year to 100 will reduce average costs by almost 50%. Cost reduction is important up to a volume of 200 new cases per year. For economic investment to be justified, it is desirable that intake rises to at least 200 new cases per year. Our result is in-line with the EUSOMA recommendation.

In the present article, an extensive review of the current knowledge regarding predictive molecular markers in breast cancer is presented. The main emphasis has been given to the adjuvant therapy setting, because of the lack of well-designed studies evaluating predictive markers in the metastatic setting. In the first part of the article some general concepts have been summarized, mainly to emphasize the difference between prognostic and predictive markers. In the second part of the article, studies evaluating molecular markers with predictive value for the most commonly used drugs or regimens (i.e., cyclophosphamide, methotrexate, 5-fluorouracil [CMF], anthracyclines, taxanes, and herceptin) have been reviewed and discussed. An attempt has been made to provide for each single predictive marker the currently available level of evidence, to allow the reader to have immediate information regarding the impact of the evaluated marker in daily clinical practice. In the last part of the article, the most important findings have been summarized and future avenues of research have been outlined.

Aims: To evaluate which pathological and clinical parameters modify the relation between tumour size and lymph node metastases in invasive breast carcinomas < 20 mm., Methods: In a retrospective study, 1075 patients with pT1 invasive breast carcinoma and with known nodal status were analysed. The size of the infiltrating tumour was microscopically evaluated, and the in situ component was not considered. The additional pathological parameters considered were: tumour grade, peritumoral vascular invasion, multicentricity, and angiogenesis. The immunophenotype of the tumour was determined as: the expression of oestrogen (ER) and progesterone (PR) receptors, p53, and c-erbB2. The patients were grouped by age as follows: < 50, 51-70, and > 70 years old., Results: Three hundred and seventy four patients (34.8%) were node positive. Univariate analysis showed that nodal positivity was significantly correlated with large tumour size (> 10 mm), vascular invasion, grade 2-3, multicentricity, and high angiogenesis (> 100 microvessels/x20 high power frame). No significant correlation was found between nodal positivity and ER, PR, p53, or c-erbB2 status. Interestingly, the association with in situ carcinoma was correlated with lower nodal positivity in tumours presenting equally sized infiltrating components. Age was an independent variable and significantly modified the risk of nodal positivity in tumours < 1 cm. In fact, in patients under 51 years of age, the proportion of nodal positivity in pT1a tumours was sevenfold higher than in older patients. In patients from 51 to 70 years old, nodal positivity correlated with tumour size, and multicentricity was an additional risk factor., Conclusions: These data suggest that, together with tumour size, the presence of in situ carcinoma, and vascular invasion, age is one of the most important predictors of metastatic diffusion in breast carcinomas.

From January of 1990 to December of 1992, 6,954 consecutive cytologic breast fine-needle aspiration biopsies (FNAB) were performed at the Laboratory of Pathology of Sant'Anna Hospital in Turin. Of these cases 62% were solid nodes, 35% were cystic nodes, and 2.7% were nonpalpable breast lesions (stereotaxic or ultrasound guided FNAB). We verified 4,110 cases: 913 cases underwent surgery and 3,197 were evaluated clinically, and/or cytologically, and/or with mammography at least 1 yr after the first diagnosis, or checked with the database of the Tumor Registry of Turin. In our series the FNAB sensitivity was 94.6%, specificity was 99.9%, accuracy was 98.8%, inadequate samples were 6.4%, false-negative rate was 1.4%, and false-positive rate was 0.3%. Our results indicate that the use of cell block improves sensitivity (from 85.2 to 94.6%) and strongly reduces false-negative results (from 3.9 to 1.4%). We conclude that FNAB is a discriminant procedure to the surgical biopsy in cases with clinical, ultrasound, or mammographic low or intermediate suspect, contributing to allow a high malignant/benign surgical biopsy rate and to reduce the need for frozen section diagnosis and medical costs.

Estrogen receptors (ER) were evaluated in 634 breast cancer patients by the dextran-coated charcoal method (DCC). In 206, ER and progesterone receptors (PR) were also tested by cytochemistry (Lee method), and in 124 ER were tested by immunofluorescence (Pertschuk method). The median follow-up is 3.7 years. Comparisons have been made between receptor content and: anatomical and clinical features, disease-free survival (DFS), and survival. The following conclusions can be drawn: there is no correlation between ER determinations by DCC and by immunofluorescence or cytochemical methods; there is no evidence of association between ER and PR determined by Lee's method and anatomical and clinical features; a highly significant positive association was found between ER rich specimens and age, post-menopausal status, lobular and tubular histologic types; there is no association between ER values and TNM stage, WHO grading, pathologic prognostic factors of primary tumor and of lymph nodes; and the DFS was not affected by ER status, except for tumors with more than 50 fmol/mg protein.