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Pathologic complete response (pCR) after Primary Systemic Treatment (PST) for breast cancer is associated with excellent long-term outcomes. With increasing use of PST, the indication for regional nodal irradiation (RNI) has been challenged. The aim of this paper is to review the literature on de-escalation of RNI in patients treated with PST.We found no level 1 evidence on de-escalation of RNI after PST, but several randomized trials are ongoing. Consequently, current de-escalation strategies are based on cohort studies. These studies showed that in patients with low nodal tumour burden (LNTB) (

Background We conducted a prospective cohort study in the Netherlands (RAPCHEM: NCT01279304, BOOG 2010-03) in breast cancer (BC) patients treated with primary systemic therapy (PST), followed by surgery and post-operative radiation therapy (RT) according to a predefined consensus-based study-guideline (SG). The aim of the current analysis is to evaluate adherence to the SG. Methods From January 2011 to January 2015, patients with cT1-2N1 BC treated in 17 Dutch RT Centres were included. Patients with four or more suspicious nodes at imaging were excluded. SG recommended whole breast RT for patients treated with breast conserving therapy. SG on loco(-regional) RT were defined for three risk groups based on the ypN status: (1) ypN0 (low-risk): RT breast and no RT after mastectomy; (2) ypN1 (intermediate-risk): RT breast or chest wall; (3) ypN2 (high-risk): RT breast or chest wall, including regional lymph nodes. Results We included 848 patients: 292 in the low-risk group; 374 in the intermediate-risk group; 182 in the high-risk group. Overall, 64% of the patients was treated according to the SG; 11% received less RT than the predefined target volumes and 25% received more extensive RT than according to the SG. The largest variation was seen in the intermediate risk group, where only 54% was treated according to the SG. Conclusion Substantial deviation from the SG for post-operative RT was observed after PST, especially in patients with an intermediate-risk. Future analyses will evaluate outcome of these patients in relation to risk factors and the actual RT given.

In our study, we investigated the predictive properties of LVI (lymphovascular invasion) and PNI (perineural invasion) on survival times from pathology specimens obtained from surgical operation after neoadjuvant chemotherapy (NAC) with breast cancer patients. Two hundered eleven female patients were included in this study. We evaluated the relationship between potential prognostic factors and mean recurrence-free survival (RFS) and overall survival (OS) times using Kaplan-Meier methodology and Cox proportional hazard modelling.The mean follow-up time was 27.3 months.PNI positive patients had shorter RFS and OS times than PNI negatives (p< 0.001, p= 0.002, respectively), and LVI positive patients had shorter RFS and OS times than LVI negatives (p< 0.001, p< 0.001, re-spectively). In the multivariate analysis performed, the presence of pN stage and PNI were found to be predictive for RFS (p= 0.047, p< 0.001, respectively), while pT stage and PNI positivity were found to be predictive for OS (p= 0.035, p= 0.017, respectively). LVI did not show the property of being an independent predictive marker for survival. PNI caused significant survival differences in all subtypes for both RFS (log-rank p< 0.001, p= 0.003, p= 0.001, respectively) and OS(log-rank p= 0.035, p= 0.006, p= 0.020 respectively) in HR+/Her2-, Her2+ and Triple negative breast cancer subtyping. LVI, on the other hand, caused survival distribution difference for RFS (p= 0.021) in the HR+/Her2-subtype and for both RFS and OS in the Triple-negative subtype (p< 0.001, p= 0.025, respectively). PNI is strongly and significantly associated with RFS and OS. We suggest that it can be used in identifying high-risk patients for recurrence of PNI and in new staging systems.

Simple Summary Invasive lobular breast cancer (ILC) is a special type of breast cancer (BC) that was first described in 1941. The diagnosis of ILC is made by microscopy of tumor specimens, which reveals a distinct morphology. This review recapitulates the developments in the microscopic assessment of ILC from 1941 until today. We discuss different concepts of ILC, provide an overview on ILC variants, and highlight advances which have contributed to a better understanding of ILC as a special histologic spectrum of tumors. Abstract Invasive lobular breast cancer (ILC) is the most common special histological type of breast cancer (BC). This review recapitulates developments in the histomorphologic assessment of ILC from its beginnings with the seminal work of Foote and Stewart, which was published in 1941, until today. We discuss different concepts of ILC and their implications. These concepts include (i) BC arising from mammary lobules, (ii) BC growing in dissociated cells and single files, and (iii) BC defined as a morpho-molecular spectrum of tumors with distinct histological and molecular characteristics related to impaired cell adhesion. This review also provides a comprehensive overview of ILC variants, their histomorphology, and differential diagnosis. Furthermore, this review highlights recent advances which have contributed to a better understanding of the histomorphology of ILC, such as the role of the basal lamina component laminin, the molecular specificities of triple-negative ILC, and E-cadherin to P-cadherin expression switching as the molecular determinant of tubular elements in CDH1-deficient ILC. Last but not least, we provide a detailed account of the tumor microenvironment in ILC, including tumor infiltrating lymphocyte (TIL) levels, which are comparatively low in ILC compared to other BCs, but correlate with clinical outcome. The distinct histomorphology of ILC clearly reflects a special tumor biology. In the clinic, special treatment strategies have been established for triple-negative, HER2-positive, and ER-positive BC. Treatment specialization for patients diagnosed with ILC is just in its beginnings. Accordingly, ILC deserves greater attention as a special tumor entity in BC diagnostics, patient care, and cancer research.

Purpose In patients with ipsilateral breast tumor recurrence (IBTR), the detection of distant disease determines whether the intention of the treatment is curative or palliative. Therefore, adequate preoperative staging is imperative for optimal treatment planning. The aim of this study is to evaluate the impact of conventional imaging techniques, including chest X-ray and/or CT thorax-(abdomen), liver ultrasonography(US), and skeletal scintigraphy, on the distant recurrence-free interval (DRFI) in patients with IBTR, and to compare conventional imaging with 18F-FDG PET-CT or no imaging at all. Methods This study was exclusively based on the information available at time of diagnoses of IBTR. To adjust for differences in baseline characteristics between the three imaging groups, a propensity score (PS) weighted method was used. Results Of the 495 patients included in the study, 229 (46.3%) were staged with conventional imaging, 89 patients (19.8%) were staged with 18F-FDG PET-CT, and in 168 of the patients (33.9%) no imaging was used (N = 168). After a follow-up of approximately 5 years, 14.5% of all patients developed a distant recurrence as first event after IBTR. After adjusting for the PS weights, the Cox regression analyses showed that the different staging methods had no significant impact on the DRFI. Conclusions This study showed a wide variation in the use of imaging modalities for staging IBTR patients in the Netherlands. After using PS weighting, no statistically significant impact of the different imaging modalities on DRFI was shown. Based on these results, it is not possible to recommend staging for distant metastases using 18F-FDG PET-CT over conventional imaging techniques. Electronic supplementary material The online version of this article (10.1007/s10549-019-05205-z) contains supplementary material, which is available to authorized users.

This systematic review and meta-analysis pools data from studies in the neoadjuvant setting on axillary pathologic complete response rates for different breast cancer subtypes in patients with initial clinically node-positive disease.Importance An overview of rates of axillary pathologic complete response (pCR) for all breast cancer subtypes, both for patients with and without pathologically proven clinically node-positive disease, is lacking. Objective To provide pooled data of all studies in the neoadjuvant setting on axillary pCR rates for different breast cancer subtypes in patients with initially clinically node-positive disease. Data Sources The electronic databases Embase and PubMed were used to conduct a systematic literature search on July 16, 2020. The references of the included studies were manually checked to identify other eligible studies. Study Selection Studies in the neoadjuvant therapy setting were identified regarding axillary pCR for different breast cancer subtypes in patients with initially clinically node-positive disease (ie, defined as node-positive before the initiation of neoadjuvant systemic therapy). Data Extraction and Synthesis Two reviewers independently selected eligible studies according to the inclusion criteria and extracted all data. All discrepant results were resolved during a consensus meeting. To identify the different subtypes, the subtype definitions as reported by the included articles were used. The random-effects model was used to calculate the overall pooled estimate of axillary pCR for each breast cancer subtype. Main Outcomes and Measures The main outcome of this study was the rate of axillary pCR and residual axillary lymph node disease after neoadjuvant systemic therapy for different breast cancer subtypes, differentiating studies with and without patients with pathologically proven clinically node-positive disease. Results This pooled analysis included 33 unique studies with 57 531 unique patients and showed the following axillary pCR rates for each of the 7 reported subtypes in decreasing order: 60% for hormone receptor (HR)-negative/ERBB2 (formerly HER2)-positive, 59% for ERBB2-positive (HR-negative or HR-positive), 48% for triple-negative, 45% for HR-positive/ERBB2-positive, 35% for luminal B, 18% for HR-positive/ERBB2-negative, and 13% for luminal A breast cancer. No major differences were found in the axillary pCR rates per subtype by analyzing separately the studies of patients with and without pathologically proven clinically node-positive disease before neoadjuvant systemic therapy. Conclusions and Relevance The HR-negative/ERBB2-positive subtype was associated with the highest axillary pCR rate. These data may help estimate axillary treatment response in the neoadjuvant setting and thus select patients for more or less invasive axillary procedures.Question What are the rates of axillary pathologic complete response (pCR) for different breast cancer subtypes in patients with initially clinically node-positive breast cancer? Findings This systematic review and meta-analysis, including 33 unique studies with 57 531 unique patients, showed that the hormone receptor (HR)-negative/ERBB2-positive subtype was associated with the highest axillary pCR rate (60%). The remaining subtypes were associated with the following axillary pCR rates in decreasing order: 59% for ERBB2-positive, 48% for triple-negative, 45% for HR-positive/ERBB2-positive, 35% for luminal B, 18% for HR-positive/ERBB2-negative, and 13% for luminal A breast cancer. Meaning These data can help estimate axillary treatment response in the neoadjuvant setting and thus select patients for more or less invasive axillary procedures.

We report on the second Assisi Think Tank Meeting (ATTM) on breast cancer which was held under the auspices of the European Society for RadioTherapy & Oncology (ESTRO). In discussing in-depth current evidence and practice it was designed to identify grey areas in diverse forms of the disease. It aimed at addressing uncertainties and proposing future trials to improve patient care.Before the meeting, three key topics were selected: 1) primary systemic therapy, mastectomy, breast reconstruction and post-mastectomy radiation therapy, 2) therapeutic options in ductal carcinoma in situ, and 3) therapy de-escalation in early stage breast cancer. Clinical practice in these areas was investigated by means of an online questionnaire. The time lapse period between the survey and the meeting was used to review the literature and on-going clinical trials. At the ATTM both were discussed in depth and research protocols were proposed.

Background Ipsilateral breast tumour recurrence (IBTR) has an unfavourable prognosis, with a significant subsequent risk of distant recurrence. Repeat sentinel lymph node biopsy (rSLNB) has recently been demonstrated to be technically feasible and useful in tailoring adjuvant treatment plans in patients with IBTR. The prognostic impact of rSLNB in patients with IBTR remains unclear. This study analysed the risk of distant recurrence after IBTR, and evaluated the prognostic impact of rSLNB and other patient and tumour characteristics on distant recurrence-free survival. Methods Data were obtained from the SNARB (Sentinel Node and Recurrent Breast Cancer) study. Cox proportional hazards analyses were performed to assess the prognostic effect of tumour, patient and treatment factors on distant recurrence-free survival. Results Of the 515 included patients, 230 (44·7 per cent) had a tumour-negative rSLNB and 46 (8·9 per cent) a tumour-positive rSLNB. In 239 patients (46·4 per cent) the rSLNB procedure was unsuccessful. After a median follow-up of 5·1 years, 115 patients (22·3 per cent) had developed a recurrence. The overall 5-year distant recurrence-free survival rate was 84·2 (95 per cent c.i. 80·7 to 87·7) per cent. An interval of less than 2 years between primary breast cancer treatment and ipsilateral recurrence (P = 0·018), triple-negative IBTR (P = 0·045) and absence of adjuvant chemotherapy after IBTR (P = 0·010) were independently associated with poor distant recurrence-free survival. The association between the outcome of rSLNB and distant recurrence-free survival was not statistically significant (P = 0·682). Conclusion The outcome of rSLNB is not an important prognostic factor for distant recurrence, and its value as a staging tool in patients with IBTR seems disputable.

Extended endocrine therapy can reduce recurrences occurring more than 5 years after diagnosis (late recurrences) in estrogen receptor (ER)-positive breast cancer. Given the side effects of endocrine therapy, optimal patient selection for extended treatment is crucial. Enhanced understanding of late recurrence biology could optimize patient selection in this setting. We therefore summarized the current knowledge of late recurrence biology, clinical trials on extended endocrine therapy, and tools for predicting late recurrence and benefit from treatment extension. Extending 5 years of tamoxifen therapy with 5 years of tamoxifen or an aromatase inhibitor (AI) reduces late recurrence risk by 2-5%, but results of extending AI-based therapy are inconsistent. Although several clinicopathological parameters and multigene assays are prognostic for late recurrence, selection tools predicting benefit from extended endocrine therapy are sparse. Therefore, we additionally performed a pooled analysis using 2231 mRNA profiles of patients with ER-positive/human epidermal growth factor receptor 2 negative breast cancer. Gene Set Enrichment Analysis was applied on genes ranked according to their association with early and late recurrence risk. Higher expression of estrogen-responsive genes was associated with a high recurrence risk beyond 5 years after diagnosis when patients had received no systemic therapy. Although 5 years of endocrine therapy reduced this risk, this effect disappeared after treatment cessation. This suggests that late recurrences of tumors with high expression of estrogen-responsive genes are likely ER-driven. Long-term intervention in this pathway by means of extended endocrine therapy might reduce late recurrences in patients with tumors showing high expression of estrogen-responsive genes.

Extended endocrine therapy can reduce recurrences occurring more than 5 years after diagnosis (late recurrences) in estrogen receptor (ER)-positive breast cancer. Given the side effects of endocrine therapy, optimal patient selection for extended treatment is crucial. Enhanced understanding of late recurrence biology could optimize patient selection in this setting. We therefore summarized the current knowledge of late recurrence biology, clinical trials on extended endocrine therapy, and tools for predicting late recurrence and benefit from treatment extension. Extending 5 years of tamoxifen therapy with 5 years of tamoxifen or an aromatase inhibitor (AI) reduces late recurrence risk by 2-5%, but results of extending AI-based therapy are inconsistent. Although several clinicopathological parameters and multigene assays are prognostic for late recurrence, selection tools predicting benefit from extended endocrine therapy are sparse. Therefore, we additionally performed a pooled analysis using 2231 mRNA profiles of patients with ER-positive/human epidermal growth factor receptor 2 negative breast cancer. Gene Set Enrichment Analysis was applied on genes ranked according to their association with early and late recurrence risk. Higher expression of estrogen-responsive genes was associated with a high recurrence risk beyond 5 years after diagnosis when patients had received no systemic therapy. Although 5 years of endocrine therapy reduced this risk, this effect disappeared after treatment cessation. This suggests that late recurrences of tumors with high expression of estrogen-responsive genes are likely ER-driven. Long-term intervention in this pathway by means of extended endocrine therapy might reduce late recurrences in patients with tumors showing high expression of estrogen-responsive genes.

An increasing number of women is surviving breast cancer and due to that at risk of developing an isolated ipsilateral breast tumor recurrence (IBTR) or a contralateral breast cancer (CBC). Patients' main concern is cancer recurrence. Patient counseling on breast cancer recurrence is challenging. In order to provide healthcare professionals and patients more guidance, a systematic literature review of the incidence of isolated IBTR and CBC in women diagnosed with early invasive breast cancer was performed. Medline, EMBASE and the Cochrane Library were searched from 2000 until October 2015. Multicenter studies reporting an IBTR or CBC rate in curatively treated adult females diagnosed with invasive breast cancer were included. The initial search yielded 6998 potentially relevant articles. Twenty were eligible for inclusion, representing 25 recurrence incidence rates. Both isolated IBTR and CBC incidence rates steadily increased with the length of follow-up, indicating that IBTR and CBC occur even more than 15 years after diagnosis. The annual incidence rate of isolated IBTR and CBC in women diagnosed with an early invasive breast cancer was 0.6% (range: 0.4-1.1%) and 0.5% (range: 0.2-0.7%), respectively. Analyzed data were lacking information about important risk factors and given treatment with regard to the incidence of recurrence, which hampers the prediction of patient tailored recurrence risks. The presented rates are therefore the best available estimates of isolated IBTR and CBC annual incidence rates based on the current literature. Healthcare professionals could use these rates in their communication with patients diagnosed with early invasive breast cancer. (C) 2018 Elsevier Ltd. All rights reserved.

Sentinel lymph node biopsy (SLNB) is the standard of care for axillary staging in clinically node-negative (cN0) breast cancer patients without neoadjuvant chemotherapy (NAC). The application of SLNB in patients receiving NAC has also been explored. Evidence supports its use after NAC in pretreatment cN0 patients. Nonetheless, its routine use in all the pretreatment node-positive patients who become cN0 after NAC is unjustified due to the unacceptably high false-negative rate, which can be improved in a subset of patients. Axillary surgery omission in selected patients with a low risk of ALN metastasis has gained more and more research interest because the SLNs are tumor-free in more than 70% of all patients. To avoid drawbacks of conventional mapping methods, novel techniques for SLN detection have been developed and shown to be highly accurate in patients with early breast cancer. This article reviews the progress in SLNB in patients with breast cancer.

This systematic review and meta-analysis pools data from studies in the neoadjuvant setting on axillary pathologic complete response rates for different breast cancer subtypes in patients with initial clinically node-positive disease.Importance An overview of rates of axillary pathologic complete response (pCR) for all breast cancer subtypes, both for patients with and without pathologically proven clinically node-positive disease, is lacking. Objective To provide pooled data of all studies in the neoadjuvant setting on axillary pCR rates for different breast cancer subtypes in patients with initially clinically node-positive disease. Data Sources The electronic databases Embase and PubMed were used to conduct a systematic literature search on July 16, 2020. The references of the included studies were manually checked to identify other eligible studies. Study Selection Studies in the neoadjuvant therapy setting were identified regarding axillary pCR for different breast cancer subtypes in patients with initially clinically node-positive disease (ie, defined as node-positive before the initiation of neoadjuvant systemic therapy). Data Extraction and Synthesis Two reviewers independently selected eligible studies according to the inclusion criteria and extracted all data. All discrepant results were resolved during a consensus meeting. To identify the different subtypes, the subtype definitions as reported by the included articles were used. The random-effects model was used to calculate the overall pooled estimate of axillary pCR for each breast cancer subtype. Main Outcomes and Measures The main outcome of this study was the rate of axillary pCR and residual axillary lymph node disease after neoadjuvant systemic therapy for different breast cancer subtypes, differentiating studies with and without patients with pathologically proven clinically node-positive disease. Results This pooled analysis included 33 unique studies with 57 531 unique patients and showed the following axillary pCR rates for each of the 7 reported subtypes in decreasing order: 60% for hormone receptor (HR)-negative/ERBB2 (formerly HER2)-positive, 59% for ERBB2-positive (HR-negative or HR-positive), 48% for triple-negative, 45% for HR-positive/ERBB2-positive, 35% for luminal B, 18% for HR-positive/ERBB2-negative, and 13% for luminal A breast cancer. No major differences were found in the axillary pCR rates per subtype by analyzing separately the studies of patients with and without pathologically proven clinically node-positive disease before neoadjuvant systemic therapy. Conclusions and Relevance The HR-negative/ERBB2-positive subtype was associated with the highest axillary pCR rate. These data may help estimate axillary treatment response in the neoadjuvant setting and thus select patients for more or less invasive axillary procedures.Question What are the rates of axillary pathologic complete response (pCR) for different breast cancer subtypes in patients with initially clinically node-positive breast cancer? Findings This systematic review and meta-analysis, including 33 unique studies with 57 531 unique patients, showed that the hormone receptor (HR)-negative/ERBB2-positive subtype was associated with the highest axillary pCR rate (60%). The remaining subtypes were associated with the following axillary pCR rates in decreasing order: 59% for ERBB2-positive, 48% for triple-negative, 45% for HR-positive/ERBB2-positive, 35% for luminal B, 18% for HR-positive/ERBB2-negative, and 13% for luminal A breast cancer. Meaning These data can help estimate axillary treatment response in the neoadjuvant setting and thus select patients for more or less invasive axillary procedures.

Background The administration of endocrine therapy for 5 years substantially reduces recurrence rates during and after treatment in women with early-stage, estrogen-receptor (ER)–positive breast cancer. Extending such therapy beyond 5 years offers further protection but has additional side effects. Obtaining data on the absolute risk of subsequent distant recurrence if therapy stops at 5 years could help determine whether to extend treatment. Methods In this meta-analysis of the results of 88 trials involving 62,923 women with ER-positive breast cancer who were disease-free after 5 years of scheduled endocrine therapy, we used Kaplan–Meier and Cox regression analyses, stratified according to trial and treatment, to assess the associations of tumor diameter and nodal status (TN), tumor grade, and other factors with patients’ outcomes during the period from 5 to 20 years. Results Breast-cancer recurrences occurred at a steady rate throughout the study period from 5 to 20 years. The risk of distant recurrence was strongly correlated with the original TN status. Among the patients with stage T1 disease, the risk of distant recurrence was 13% with no nodal involvement (T1N0), 20% with one to three nodes involved (T1N1–3), and 34% with four to nine nodes involved (T1N4–9); among those with stage T2 disease, the risks were 19% with T2N0, 26% with T2N1–3, and 41% with T2N4–9. The risk of death from breast cancer was similarly dependent on TN status, but the risk of contralateral breast cancer was not. Given the TN status, the factors of tumor grade (available in 43,590 patients) and Ki-67 status (available in 7692 patients), which are strongly correlated with each other, were of only moderate independent predictive value for distant recurrence, but the status regarding the progesterone receptor (in 54,115 patients) and human epidermal growth factor receptor type 2 (HER2) (in 15,418 patients in trials with no use of trastuzumab) was not predictive. During the study period from 5 to 20 years, the absolute risk of distant recurrence among patients with T1N0 breast cancer was 10% for low-grade disease, 13% for moderate-grade disease, and 17% for high-grade disease; the corresponding risks of any recurrence or a contralateral breast cancer were 17%, 22%, and 26%, respectively. Conclusions After 5 years of adjuvant endocrine therapy, breast-cancer recurrences continued to occur steadily throughout the study period from 5 to 20 years. The risk of distant recurrence was strongly correlated with the original TN status, with risks ranging from 10 to 41%, depending on TN status and tumor grade. (Funded by Cancer Research UK and others.)

Sentinel lymph node biopsy (SLNB) is the standard of care for axillary staging in clinically node-negative (cN0) breast cancer patients without neoadjuvant chemotherapy (NAC). The application of SLNB in patients receiving NAC has also been explored. Evidence supports its use after NAC in pretreatment cN0 patients. Nonetheless, its routine use in all the pretreatment node-positive patients who become cN0 after NAC is unjustified due to the unacceptably high false-negative rate, which can be improved in a subset of patients. Axillary surgery omission in selected patients with a low risk of ALN metastasis has gained more and more research interest because the SLNs are tumor-free in more than 70% of all patients. To avoid drawbacks of conventional mapping methods, novel techniques for SLN detection have been developed and shown to be highly accurate in patients with early breast cancer. This article reviews the progress in SLNB in patients with breast cancer.

Purpose The INTENS study was designed to determine whether delivering neoadjuvant chemotherapy at a higher dose in a shorter period of time improves outcome of breast cancer patients. Methods Women with newly diagnosed breast cancer were randomly assigned to neoadjuvant chemotherapy consisting of four cycles of doxorubicin and cyclophosphamide followed by four cycles of docetaxel (AC 60/600–T 100 mg/m2) or six cycles of TAC as triplet chemotherapy (75/50/500 mg/m2) every 3 weeks. The primary outcome was the pathologic complete response (pCR), with disease-free and overall survival as secondary endpoints. Results In total, 201 patients were included. The pCR rates were 28% for patients treated with AC-T and 19% for patients treated with TAC, with an odds ratio of 1.60 (95% CI 0.90–3.21). With a median follow-up of 6 years (range 0.04–8.41 years), the five-year disease-free survival was 81% for patients treated with sequentially AC-T and 71% for patients treated with concurrent triplet TAC chemotherapy with a stratified hazard ratio (HR) of 0.50 (95% CI 0.29–0.86). Five-year overall survival was 84% versus 76%, respectively, with a stratified HR of 0.55 (95% CI 0.29–1.03). Conclusions No differences were observed between the two treatment arms with respect to pCR rate, but the sequentially delivered chemotherapy outperformed the triplet combination chemotherapy in terms of survival, despite a lower cumulative dose per agent. GOV nr NCT00314977.

Encapsulating peritoneal sclerosis (EPS) represents a rare complication of long-term peritoneal dialysis (PD). It is characterised by diffuse peritoneal membrane fibrosis, progressive intestinal encapsulation and the clinical spectrum of intestinal obstruction. The pathogenesis is as yet not well understood but includes inflammation, angiogenesis and fibrosis. The current diagnosis of EPS lacks specificity and relies on clinical, radiographic or macroscopic evaluation. There is no general agreement on managing EPS although accumulating clinical data suggest drug treatment (steroids, tamoxifen), surgery (enterolysis) or a combination of both. Here, we provide a short overview on the current knowledge of EPS, with a focus on treatment. Moreover, we present a diagnostic and a therapeutic algorithm for EPS based on the best available published data and our combined experience.

BACKGROUND: Pre-clinical studies have demonstrated synergistic anti-tumour effects of chemotherapy (CT) and zoledronic acid (ZOL). Within the AZURE trial, designed to determine whether the addition of ZOL to neoadjuvant therapy improves disease outcomes, a subgroup received neoadjuvant CT. We report a retrospective evaluation comparing pathological response in the primary tumour between treatment groups. METHODS: In total, 205 patients received neoadjuvant CT±ZOL (CT þZOL, n ¼102; CT, n ¼103). The primary end point was pathologically assessed residual invasive tumour size (RITS) at surgery. Secondary end points were pathological complete response (pCR) rate and axillary nodal involvement. Following review of surgical pathology reports (n ¼195), outcome differences between groups were assessed adjusting for potential response modifiers. RESULTS: Baseline characteristics and CT treatments were similar. In multivariate analysis, allowing for biological and clinical factors known to influence tumour response, the adjusted mean RITS in CT and CT þZOL groups were 27.4 and 15.5mm, respectively, giving a difference in means of 12mm (95% confidence interval: 3.5–20.4mm; P ¼0.006). The pCR rate was 6.9% in the CT group and 11.7% in the CT þZOL group (P ¼0.146). There was no difference in axillary nodal involvement (P ¼0.6315). CONCLUSION: These data suggest a possible direct anti-tumour effect of ZOL in combination with CT, warranting formal evaluation in prospective studies.

Many hormonal modalities are available for breast cancer treatment, such as selective oestrogen receptor modulators (SERMs), aromatase inhibitors, progestins and luteinising hormone-releasing hormone (LHRH) agonists. The Long-term impact of these endocrine manipulations is an issue, because the duration of adjuvant treatment is still increasing, as is the number of breast cancer survivors. Premature menopause is induced at a young age, and may often be permanent after chemotherapy. The purpose of this review is to provide a literature-based overview of the side effects of endocrine treatment in pre- and postmenopausal breast cancer patients and the influence on HRQoL, especially on sexual functioning. The collection of health-related quality of life (HRQoL) data can result in better treatment recommendations during endocrine therapy.Methods: This review was Limited to prospective randomised studies in English Literature from between 1977 and 2007 and provides an overview of the effects on HRQoL and sexuality of various hormonal treatment in pre- and postmenopausal breast cancer patients, both in the adjuvant and palliative setting. Relevant clinical studies were identified by using the Medline database.Results: HRQoL mostly is severely influenced by chemotherapy and part of these symptoms may be tasting, especially when associated with the induction of premature menopause. Similar symptoms may be encountered during ovarian suppression therapy by LHRH analogs, but they will. usually prove to be reversible. The varying side effect profiles of tamoxifen and aromatase inhibitors did not lead to significant difference in overall HRQoL. HRQoL during progestins and the SERM fulvestrant has been compared to this during aromatase inhibitors, and a large number of studies on HRQoL during endocrine therapy wilt be discussed. (C) 2008 Elsevier Ltd. All rights reserved.

Breast cancer is the most frequently diagnosed malignancy amongst females worldwide. In recent years the management of this disease has transformed considerably, including the administration of chemotherapy in the neoadjuvant setting. Aside from increasing rates of breast conserving surgery and enabling surgery via tumour burden reduction, use of chemotherapy in the neoadjuvant setting allows monitoring of in vivo tumour response to chemotherapeutics. Currently, there is no effective means of identifying chemotherapeutic responders from non-responders. Whilst some patients achieve complete pathological response (pCR) to chemotherapy, a good prognostic index, a proportion of patients derive little or no benefit, being exposed to the deleterious effects of systemic treatment without any knowledge of whether they will receive benefit. The identification of predictive and prognostic biomarkers could confer multiple benefits in this setting, specifically the individualization of breast cancer management and more effective administration of chemotherapeutics. In addition, biomarkers could potentially expedite the identification of novel chemotherapeutic agents or increase their efficacy. Micro-RNAs (miRNAs) are small non-coding RNA molecules. With their tissue-specific expression, correlation with clinicopathological prognostic indices and known dysregulation in breast cancer, miRNAs have quickly become an important avenue in the search for novel breast cancer biomarkers. We provide a brief history of breast cancer chemotherapeutics and explore the emerging field of circulating (blood-borne) miRNAs as breast cancer biomarkers for the neoadjuvant treatment of breast cancer. Established molecular markers of breast cancer are outlined, while the potential role of circulating miRNAs as chemotherapeutic response predictors, prognosticators or potential therapeutic targets is discussed.

Anti-estrogens, in particular tissue selective anti-estrogens, have been the bedrock of adjuvant therapy for patients with estrogen receptor alpha (ERα) positive breast cancer. Though current therapies have greatly enhanced patient prognosis, there continues to be an impetus for the development of improved anti-estrogens. ERα is a nuclear receptor transcription factor which activates gene expression through the recruitment of transcriptional coactivator proteins. The SRC family of coactivators, which includes AIB1, has been shown to be of particular importance for ERα mediated transcription. ERα-AIB1 interactions are indicative of gene expression and are inhibited by anti-estrogen treatment. We have exploited the interaction between ERα and AIB1 as a novel method for imaging ERα activity using a split luciferase molecular sensor. By producing a range of ERα ligand binding domain (ER-LBD) and AIB1 nuclear receptor interacting domain (AIB-RID) N- and C-terminal firefly luciferase fragment fusion proteins, constructs which exhibited more than a 10-fold increase in luciferase activity with E2 stimulation were identified. The specificity of the E2-stimulated luciferase activity to ERα-AIB1 interaction was validated through Y537S and L539/540A ER-LBD fusion protein mutants. The primed nature of the split luciferase assay allowed changes in ERα activity, with respect to the protein-protein interactions preceding transcription, to be assessed soon after drug treatment. The novel assay split luciferase detailed in this report enabled modulation of ERα activity to be sensitively imaged in vitro and in living subjects and potentially holds much promise for imaging the efficacy of novel ERα specific therapies.

The present study evaluated the efficacy and safety of oxaliplatin, UFT, and leucovorin in metastatic gastric cancer.Patients received intravenous oxaliplatin 130 mg/m(2) on day 1, followed by oral UFT capsules (350 mg/m(2) per day) and leucovorin tablets (90 mg/day), every 8 h, for 14 days, in a 3-week cycle.Twenty-three patients (61% with a parts per thousand yen2 metastatic sites), median age of 60 years (range, 39-69 years) were entered. Based on intention-to-treat analysis, one complete response and seven partial responses were found, resulting in an overall response rate (RR) of 35% (95% confidence interval [CI], 16-54), a median time to progression of 4 months (95% CI, 0.5-7.5), and a median overall survival (OS) of 8 months (95% CI, 4.5-11.5). The 1-year survival rate was 26%. Three patients did not complete the first course of 2 weeks; 1 died suddenly on day 16 with fatal lung embolism; 1 had rapid progressive disease and 1 experienced gastric hemorrhage on day 15 - both these patients withdrew. In the 20 patients assessable for toxicity no grade 4 toxicity occurred, grade 3 toxicity consisted of anemia in 1, diarrhea in 2, and neurotoxicity in 3 patients. No hand-foot syndrome (HFS) occurred.Oxaliplatin is an effective drug in gastric cancer, but, as previously reported, its feasibility in combination with capecitabine is hampered due to combined hand-foot-based toxicity. The present phase II study of a combination of oxaliplatin with UFT and leucovorin appears to have efficacy and tolerability comparable to two other drug regimens used in gastric cancer, without the HFS problem.

Tamoxifen increases the risk of uterine corpus cancer. Since only few, mostly small, studies have examined prognosis of uterine corpus cancer following tamoxifen, we conducted a large retrospective cohort study to further investigate this. We examined histopathologic and immunohistochemical characteristics of 332 patients with uterine corpus cancer following breast cancer, according to tamoxifen use. Survival was examined in the same patients combined with 309 patients from a previous study with updated follow-up. Histological review of all cancers was performed. Long-term tamoxifen users showed a higher proportion of non-endometrioid tumors than non-users (32.7% vs. 17.4%, P = 0.004), especially serous adenocarcinomas and carcinosarcomas. An increased proportion of FIGO stage III and IV tumors was also observed (20.0% vs. 11.3%, P = 0.049). Within FIGO stage I, both short-term and long-term tamoxifen users showed a higher proportion of tumors limited to the endometrium than non-users (35.7% vs. 22.9%, P = 0.049 and 0.004 respectively). Uterine corpus cancers in long-term tamoxifen users were more often steroid receptor-negative (ER alpha, PRA and PRB, P = 2 years tamoxifen = 2.4; 95% CI = 1.2-4.6). In conclusion, this large study clearly shows that tamoxifen-associated tumors have less favorable histological features and a worse survival. Our results can be applied when weighing risks and benefits of tamoxifen versus other hormonal agents used in the prevention and treatment of breast cancer.

Cancer in the older person is an increasingly common problem, due to the progressive prolongation of the life-expectancy of the Western population. This article reviews the mechanisms associating aging and cancer, age-related changes in cancer biology, assessment of the older person to estimate life-expectancy, treatment tolerance, and medical and social conditions that may interfere with cancer treatment, effectiveness of cancer prevention and cancer treatment in older individuals. A comprehensive geriatric assessment (CGA) is commonly used to predict life-expectancy and functional reserve and to unearth conditions that may jeopardize cancer prevention and treatment. In the interest of cost and time, shortened forms of CGA are being explored. Chemoprevention of cancer is a promising form of prevention that at present has no conclusive clinical indications. Early diagnosis of breast and colon cancer through screening of asymptomatic patients at risk may be beneficial for individuals with a life-expectancy of 5 years or longer. Early detection of lung cancer in ex-smokers is undergoing clinical trials, as this disease is becoming more and more common. Age should not prevent appropriate treatment of cancer in older individuals, especially in those with adequate life-expectancy and functional reserve. The National Cancer Center Network (NCCN) has issued a series of guidelines to minimize the toxicity and promote the effectiveness of cancer in older patients. Important interventions include prevention of neutropaenic infections with filgrastim and peg-filgrastim, prevention of anaemia with epoietin or darbepoietin, and prevention and early management of mucositis.

Objective. To define by transvaginal ultrasonography an optimal cutoff for endometrial thickness measurements to be used in screening for endometrial pathologies in asymptomatic breast cancer patients on tamoxifen, and to evaluate the incorporation of saline infusion sonohysterography and Doppler studies into the diagnostic scheme. Methods. Sixty tamoxifen-treated women examined by transvaginal ultrasonography with saline infusion were included in this retrospective study. Variables of interest were endometrial thickness and texture, and the presence of intracavitary fluid at ultrasonography, total endometrial thickness, defined as the sum of the two endometrial layers and the presence of polypoid masses at sonohysterography, and uterine artery flow indices at Doppler ultrasonography. The dilatation and curettage performed after the sonographic scan detected pathological endometrial changes in nine cases, including six endometrial polyps, two endometrial hyperplasias, and one endometrial cancer. All parameters evaluated were compared between patients with benign and pathological endometria. Continuous variables that differed significantly between the groups were investigated further by receiver operating characteristics curve analyses and the diagnostic value of combinations of various parameters by binary logistic regression. Results. The endometrial thickness in patients with proven endometrial pathologies was significantly greater compared with women with benign endometria, both by transvaginal ultrasonography (12.7 +/- 5.5 vs. 7.0 +/- 4.5 mm; P = 0.003) and by sonohysterography (6.3 +/- 2.8 vs. 4.1 +/- 1.7 mm; P = 0.036). While saline infusion sonohysterography also revealed a significantly higher frequency of polypoid masses in the former group (67% vs. 2%; P < 0.001), no other significant differences were defined between the groups in regard to any other sonographic or Doppler parameter evaluated. For the diagnosis of any endometrial pathology, the optimal cutoffs of endometrial thickness at ultrasonography and total endometrial thickness at sonohysterography were 9.5 and 5.5 mm, with sensitivities of 89% and 78% and specificities of 78% and 84%, respectively. A logistic regression model including polypoid lesions (B = -4.935; P < 0.001) and total endometrial thickness at sonohysterography (B = 0.432; P = 0.027) as the only two independent variables had a sensitivity of 100% and specificity of 84%. Conclusion. Saline infusion sonohysterography does, yet Doppler ultrasonography does not, add to the value of endometrial thickness measurements by transvaginal ultrasonography in the screen for endometrial pathologies in asymptomatic breast cancer patients on tamoxifen.

Introduction: Tamoxifen is an effective treatment for breast cancer but an undesirable side-effect is an increased risk of endometrial cancer, particularly rare tumor types associated with poor prognosis. We investigated whether tamoxifen therapy increases mortality among breast cancer patients subsequently diagnosed with endometrial cancer.Methods: We pooled case-patient data from the three largest case-control studies of tamoxifen in relation to endometrial cancer after breast cancer (1,875 patients: Netherlands, 765; United Kingdom, 786; United States, 324) and collected follow-up information on vital status. Breast cancers were diagnosed in 1972 to 2005 with endometrial cancers diagnosed in 1978 to 2006. We used Cox proportional hazards survival analysis to estimate hazard ratios (HRs) and 95% confidence intervals (CI).Results: A total of 1,104 deaths occurred during, on average, 5.8 years following endometrial cancer (32% attributed to breast cancer, 25% to endometrial cancer). Mortality from endometrial cancer increased significantly with unfavorable non-endometrioid morphologies (P Conclusions: Patients with endometrial cancer after breast cancer who received tamoxifen treatment for five years for breast cancer have greater endometrial cancer mortality risk than those who did not receive tamoxifen. This can be attributed to non-endometrioid histological subtypes with poorer prognosis among long term tamoxifen users.