SAA1-dependent reprogramming of adipocytes by tumor cells is associated with triple negative breast cancer aggressiveness.

Triple negative breast cancers (TNBC) are characterized by a poor prognosis and a lack of targeted treatments. Their progression depends on tumor cell intrinsic factors, the tumor microenvironment and host characteristics. Although adipocytes, the primary stromal cells of the breast, have been determined to be plastic in physiology and cancer, the tumor-derived molecular mediators of tumor-adipocyte crosstalk have not been identified yet. In this study, we report that the crosstalk between TNBC cells and adipocytes in vitro beyond adipocyte dedifferentiation, induces a unique transcriptional profile that is characterized by inflammation and pathways that are related to interaction with the tumor microenvironment. Accordingly, increased cancer stem-like features and recruitment of pro-tumorigenic immune cells are induced by this crosstalk through CXCL5 and IL-8 production. We identified serum amyloid A1 (SAA1) as a regulator of the adipocyte reprogramming through CD36 and P2XR7 signaling. In human TNBC, SAA1 expression was associated with cancer-associated adipocyte infiltration, inflammation, stimulated lipolysis, stem-like properties, and a distinct tumor immune microenvironment. Our findings constitute evidence that the interaction between tumor cells and adipocytes through the release of SAA1 is relevant to the aggressiveness of TNBC.

Sentinel Lymph Node Biopsy vs No Axillary Surgery in Patients With Small Breast Cancer and Negative Results on Ultrasonography of Axillary Lymph Nodes: The SOUND Randomized Clinical Trial.

Importance: Sentinel lymph node biopsy (SLNB) is the standard of care for axillary node staging of patients with early breast cancer (BC), but its necessity can be questioned since surgery for examination of axillary nodes is not performed with curative intent. Objective: To determine whether the omission of axillary surgery is noninferior to SLNB in patients with small BC and a negative result on preoperative axillary lymph node ultrasonography. Design, Setting, and Participants: The SOUND (Sentinel Node vs Observation After Axillary Ultra-Sound) trial was a prospective noninferiority phase 3 randomized clinical trial conducted in Italy, Switzerland, Spain, and Chile. A total of 1463 women of any age with BC up to 2 cm and a negative preoperative axillary ultrasonography result were enrolled and randomized between February 6, 2012, and June 30, 2017. Of those, 1405 were included in the intention-to-treat analysis. Data were analyzed from October 10, 2022, to January 13, 2023. Intervention: Eligible patients were randomized on a 1:1 ratio to receive SLNB (SLNB group) or no axillary surgery (no axillary surgery group). Main Outcomes and Measures: The primary end point of the study was distant disease-free survival (DDFS) at 5 years, analyzed as intention to treat. Secondary end points were the cumulative incidence of distant recurrences, the cumulative incidence of axillary recurrences, DFS, overall survival (OS), and the adjuvant treatment recommendations. Results: Among 1405 women (median [IQR] age, 60 [52-68] years) included in the intention-to-treat analysis, 708 were randomized to the SLNB group, and 697 were randomized to the no axillary surgery group. Overall, the median (IQR) tumor size was 1.1 (0.8-1.5) cm, and 1234 patients (87.8%) had estrogen receptor-positive ERBB2 (formerly HER2 or HER2/neu), nonoverexpressing BC. In the SLNB group, 97 patients (13.7%) had positive axillary nodes. The median (IQR) follow-up for disease assessment was 5.7 (5.0-6.8) years in the SLNB group and 5.7 (5.0-6.6) years in the no axillary surgery group. Five-year distant DDFS was 97.7% in the SLNB group and 98.0% in the no axillary surgery group (log-rank P = .67; hazard ratio, 0.84; 90% CI, 0.45-1.54; noninferiority P = .02). A total of 12 (1.7%) locoregional relapses, 13 (1.8%) distant metastases, and 21 (3.0%) deaths were observed in the SLNB group, and 11 (1.6%) locoregional relapses, 14 (2.0%) distant metastases, and 18 (2.6%) deaths were observed in the no axillary surgery group. Conclusions and Relevance: In this randomized clinical trial, omission of axillary surgery was noninferior to SLNB in patients with small BC and a negative result on ultrasonography of the axillary lymph nodes. These results suggest that patients with these features can be safely spared any axillary surgery whenever the lack of pathological information does not affect the postoperative treatment plan. Trial Registration: ClinicalTrials.gov Identifier: NCT02167490.

Adipocytes in Breast Cancer, the Thick and the Thin.

It is well established that breast cancer development and progression depend not only on tumor-cell intrinsic factors but also on its microenvironment and on the host characteristics. There is growing evidence that adipocytes play a role in breast cancer progression. This is supported by: i) epidemiological studies reporting the association of obesity with a higher cancer risk and poor prognosis, ii) recent studies demonstrating the existence of a cross-talk between breast cancer cells and adipocytes locally in the breast that leads to acquisition of an aggressive tumor phenotype, and iii) evidence showing that cancer cachexia applies also to fat tissue and shares similarities with stromal-carcinoma metabolic synergy. This review summarizes the current knowledge on the epidemiological link between obesity and breast cancer and outlines the results of the tumor-adipocyte crosstalk. We also focus on systemic changes in body fat in patients with cachexia developed in the course of cancer. Moreover, we discuss and compare adipocyte alterations in the three pathological conditions and the mechanisms through which breast cancer progression is induced.

Decoding Immune Heterogeneity of Triple Negative Breast Cancer and Its Association with Systemic Inflammation.

Triple negative breast cancer (TNBC) is an aggressive subtype with limited therapeutic options. New opportunities are emerging from current comprehensive characterization of tumor immune infiltration and fitness. Therefore, effectiveness of current chemotherapies and novel immunotherapies are partially dictated by host inflammatory and immune profiles. However, further progress in breast cancer immuno-oncology is required to reach a detailed awareness of the immune infiltrate landscape and to determine additional reliable and easily detectable biomarkers. In this study, by analyzing gene expression profiles of 54 TNBC cases we identified three TNBC clusters displaying unique immune features. Deep molecular characterization of immune cells cytolytic-activity and tumor-inflammation status reveled variability in the local composition of the immune infiltrate in the TNBC clusters, reconciled by tumor-infiltrating lymphocytes counts. Platelet-to-lymphocyte ratio (PLR), a blood systemic parameter of inflammation evaluated using pre-surgical blood test data, resulted negatively correlated with local tumoral cytolytic activity and T cell-inflamed microenvironment, whereas tumor aggressiveness score signature positively correlated with PLR values. These data highlighted that systemic inflammation parameters may represent reliable and informative markers of the local immune tumor microenvironment in TNBC patients and could be exploited to decipher tumor infiltrate properties and consequently to select the most appropriate therapies.

Wound Healing Fluid Reflects the Inflammatory Nature and Aggressiveness of Breast Tumors.

Wound healing fluid that originates from breast surgery increases the aggressiveness of cancer cells that remain after the surgery. We determined the effects of the extent of surgery and tumor-driven remodeling of the surrounding microenvironment on the ability of wound-healing to promote breast cancer progression. In our analysis of a panel of 34 cytokines, chemokines, and growth factors in wound healing fluid, obtained from 27 breast carcinoma patients after surgery, the levels of several small molecules were associated with the extent of cellular damage that was induced by surgery. In addition, the composition of the resulting wound healing fluid was associated with molecular features of the removed tumor. Specifically, IP-10, IL-6, G-CSF, osteopontin, MIP-1a, MIP-1b, and MCP1-MCAF were higher in more aggressive tumors. Altogether, our findings indicate that the release of factors that are induced by removal of the primary tumor and subsequent wound healing is influenced by the extent of damage due to surgery and the reactive stroma that is derived from the continuously evolving network of interactions between neoplastic cells and the microenvironment, based on the molecular characteristics of breast carcinoma cells.

Correction to: Observational study on the prognostic value of testosterone and adiposity in postmenopausal estrogen receptor positive breast cancer patients.

Following publication of the original article [1], the authors reported that the affiliation of author Annalisa Orenti was omitted.

Observational study on the prognostic value of testosterone and adiposity in postmenopausal estrogen receptor positive breast cancer patients.

BACKGROUND: Despite the clear endocrine-metabolic relationship between androgenic activity and adiposity, the role of androgens in breast cancer prognosis according to patient's adiposity is scarcely explored. Here, we aimed at investigating the prognostic value of circulating testosterone in association with patient's body mass index (BMI). METHODS: Circulating testosterone and BMI were evaluated at breast cancer diagnosis in 460 estrogen receptor (ER)-positive postmenopausal patients. Local relapse, distant metastasi(e)s and contralateral breast cancer were considered recurrence events. The Kruskal-Wallis test was performed to evaluate if testosterone levels differed within subgroups of categorical tumour characteristics. The Cox proportional hazard regression model was fitted to estimate the impact of standard prognostic factors on relapse-specific hazard ratio (HR). After backward selection, a model including continuous testosterone level, BMI categories (< 25, normal-weight; =25-30, overweight; ≥30 kg/m2, obese), tumour size and lymph nodes number was fitted. Furthermore, Cox models provided the relapse-specific HRs for median, third quartile and 95th percentile compared to the first quartile of testosterone levels, stratified by BMI categories. RESULTS: During a median follow up of 6.3 years, 45 patients relapsed. Testosterone levels significantly increased across BMI categories (p = 0.001). Both circulating testosterone and BMI were positively associated with disease free survival (p = 0.005 and p = 0.021, respectively). A significant interaction was found between testosterone and BMI (p = 0.006). For normal-weight women, testosterone concentration around median (0.403 ng/mL) or third quartile (0.532 ng/mL) showed a high significant HR of relapse (5.52; 95% CI:1.65-18.49 and 4.55; 95% CI:1.09-18.98, respectively). Overweight patients showed increased HR at increasing testosterone levels, reaching a significant high HR (4.68; 95% CI:1.39-15.70) for testosterone values of 0.782 ng/mL (95th percentile). For obese patients HR decreased (not significantly) at increased testosterone concentrations, explaining the interaction between testosterone levels and BMI categories. CONCLUSIONS: In ER-positive postmenopausal breast cancer patients, high testosterone levels are associated with worse prognosis in normal-weight and overweight women, whereas in obese seems to be associated with a better outcome. Although the results require further validation, they suggest that assessment of circulating testosterone and BMI could help to identify postmenopausal ER-positive patients at higher risk of relapse and potentially open new therapeutic strategies.

The PDGFRß/ERK1/2 pathway regulates CDCP1 expression in triple-negative breast cancer.

BACKGROUND: CDCP1, a transmembrane protein with tumor pro-metastatic activity, was recently identified as a prognostic marker in TNBC, the most aggressive breast cancer subtype still lacking an effective molecular targeted therapy. The mechanisms driving CDCP1 over-expression are not fully understood, although several stimuli derived from tumor microenvironment, such as factors present in Wound Healing Fluids (WHFs), reportedly increase CDCP1 levels. METHODS: The expression of CDCP1, PDGFRß and ERK1/2cell was tested by Western blot after stimulation of MDA-MB-231 cells with PDGF-BB and, similarly, in presence or not of ERK1/2 inhibitor in a panel of TNBC cell lines. Knock-down of PDGFRß was established in MDA-MB-231 cells to detect CDCP1 upon WHF treatment. Immunohistochemical staining was used to detect the expression of CDCP1 and PDGFRß in TNBC clinical samples. RESULTS: We discovered that PDGF-BB-mediated activation of PDGFRß increases CDCP1 protein expression through the downstream activation of ERK1/2. Inhibition of ERK1/2 activity reduced per se CDCP1 expression, evidence strengthening its role in CDCP1 expression regulation. Knock-down of PDGFRß in TNBC cells impaired CDCP1 increase induced by WHF treatment, highlighting the role if this receptor as a central player of the WHF-mediated CDCP1 induction. A significant association between CDCP1 and PDGFRß immunohistochemical staining was observed in TNBC specimens, independently of CDCP1 gene gain, thus corroborating the relevance of the PDGF-BB/PDGFRß axis in the modulation of CDCP1 expression. CONCLUSION: We have identified PDGF-BB/PDGFRß-mediated pathway as a novel player in the regulation of CDCP1 in TNCBs through ERK1/2 activation. Our results provide the basis for the potential use of PDGFRß and ERK1/2 inhibitors in targeting the aggressive features of CDCP1-positive TNBCs.

Dynamics of the hazard for distant metastases after ipsilateral breast tumor recurrence according to estrogen receptor status: An analysis of 2851 patients.

BACKGROUND: Breast cancer (BC) patients with ipsilateral breast tumor recurrence (IBTR) are at high risk of developing distant metastases (DM). We aimed to evaluate the risk pattern of developing DM, with respect to the occurrence of IBTR, in a large series of patients homogeneously treated by conservative surgery (QUART) with a considerably long follow-up. METHODS: Piecewise exponential model was used to investigate DM dynamics conditioning on known prognostic factors and IBTR occurrence as time dependent covariate. The model was extended to account for the timescale induced by IBTR, namely the time elapsed since IBTR to the endpoint. RESULTS: Among 2851 BCE patients receiving QUART, 209 were assessable for IBTR. After a median follow-up of 129 months, 588 patients presented DM (CCI = 27.3%) as first event and 92 (CCI = 48.8%) following IBTR. Primary tumor size and nodal status confirmed their prognostic value. The hazard for DM was early and high in Estrogen Receptor (ER) negative BC patients; while it was initially low but increases during follow-up in ER positive cases. Patients experiencing IBTR showed DM dynamic similar to that following primary tumor, with a sudden increased risk within 24 months from surgery, regardless the time elapsed since QUART. CONCLUSION: BC patients experiencing IBTR showed a sudden and sustained risk of DM following surgery. Our findings are consistent with the hypothesis that IBTR occurrence might act as a "time resector" for risk of DM, and provide a rationale for proper surveillance guidelines and systemic therapy for optimizing BC recurrence and appropriate choice of treatment.

Partial breast irradiation with CyberKnife after breast conserving surgery: a pilot study in early breast cancer.

BACKGROUND: Local recurrences after breast conserving treatment are mainly close to the original tumor site, and as such shorter fractionation strategies focused on and nearest mammary gland, i.e. accelerated partial breast irradiation (APBI), have been developed. Stereotactic APBI has been attempted, although there is little experience using CyberKnife (CK) for early breast cancer. METHODS: This pilot study was designed to assess the feasibility of CK-APBI on 20 evaluable patients of 29 eligible, followed for 2 years. The primary endpoint was acute/sub-acute toxicity; secondary endpoints were late toxicity and the cosmetic result. RESULTS: Mean pathological tumor size was 10.5 mm (±4.3, range 3-18), 8 of these patients were classified as LumA-like, 11 as LumB-like, and 1 as LumB-HER2-enriched. Using CK-APBI with Iris, the treatment time was approximately 60 min (range~ 35 to ~ 120). All patients received 30 Gy in five fractions delivered to the PTV. The median number of beams was 180 (IQR 107-213; range:56-325) with a median PTV isodose prescription of 86.0% (IQR 85.0-88.5; range:82-94). The median PTV was 88.1 cm3 (IQR 63.8-108.6; range:32.3-238.8). The median breast V100 and V50 was 0.6 (IQR 0.1-1.5; range:0-13) and 18.6 (IQR 13.1-21.7; range:7.5-37), respectively. The median PTV minimum dose was 26.2 Gy (IQR 24.7-27.6; range 22.3-29.3). Mild side effects were recorded during the period of observation. Cosmetic evaluations were performed by three observers from the start of radiotherapy up to 2 years. Patients' evaluation progressively increase from 60% to 85% of excellent rating; this trend was similar to that of external observer. CONCLUSIONS: These preliminary results showed the safe feasibility of CK-APBI in early breast cancer, with mild acute and late toxicity and very good cosmetic results. TRIAL REGISTRATION: The present study is registered at Clinicaltrial.gov ( NCT02896322 ). Retrospectively egistered August 4, 2016.

Ten-year results of applying an original scoring system for addressing adjuvant therapy use after breast-conserving surgery for ductal carcinoma in situ of the breast.

PURPOSE: Although large-scale randomised clinical trials have established that radiotherapy (RT) - alone or combined with hormonal therapy (HT) - is effective in reducing the risk of ipsilateral breast tumour recurrence (IBTR), overall survival does not seem to be improved by adjuvant therapies. We sought to ascertain whether specific criteria can be adopted to avoid RT with an acceptable rate of IBTR after breast-conserving surgery (BCS) achieving tumour-free margins. PATIENTS AND METHODS: This non-randomised prospective study concerned the outcome of patients who underwent BCS for ductal carcinoma in situ (DCIS) and were prospectively assessed by means of an established scoring system based on width of free margins in association with age <40, presence of comedonecrosis, high grade, ER negativity and HER2 positivity, to orient the use of any adjuvant therapies. RESULTS: From March 2000 to April 2006, a total of 224 patients were enrolled and followed up for this study. No adjuvant treatment was considered for 76 patients, while 53, 39 and 56 patients received HT alone, RT alone, and RT plus HT, respectively. After a median follow-up of 129.6 months, 25 patients developed an IBTR, corresponding to a yearly rate of 1.138% (95% CI: 0.769-1.684). CONCLUSION: When the criteria considered in the present study were applied to address the use of adjuvant therapies, no RT was administered to 57.6% of patients, 33.9% received no adjuvant treatments at all, and the rate of IBTR was low. Our findings support the conviction that the risk/benefit of omitting RT may lean on the side of the latter in selected patients.

Evaluation of Local Oncologic Safety in Nipple-Areola Complex-sparing Mastectomy After Primary Chemotherapy: A Propensity Score-matched Study.

BACKGROUND: Nipple-areola complex-sparing mastectomy (NSM), extending the concept of skin-sparing mastectomy, allows for the provision of a better cosmetic result. Large operable T2-T3 breast cancer might theoretically appear suitable for this surgical option as an alternative to conventional mastectomy or breast-conserving surgery, when a good response to primary chemotherapy has been achieved. PATIENTS AND METHODS: From January 2009 to May 2013, 422 patients with invasive breast cancer were progressively accrued to NSM. Of the 422 patients, 361 underwent NSM as first-line treatment (NSM group), and 61 underwent surgery after primary chemotherapy (NSM-PC group). A total of 151 breast cancer patients, who had undergone PC and conventional total mastectomy (TM-PC group) from 2004 to 2009 were evaluated as comparative group with respect to the NSM-PC group. Using propensity score matching, local disease-free survival (LDFS) was evaluated comparatively. RESULTS: The rate of nipple-areola involvement in the NSM and NSM-PC groups was 13.3% and 9.8%, respectively (P = .539). The nipple-areola involvement in the NSM and NSM-PC groups was significantly associated with the tumor size (odds ratio [OR], 1.48; 95% confidence interval [CI], 1.13-1.95; P = .004), plurifocal or pluricentric tumor (OR, 3.18; 95% CI, 1.72-5.89; P < .001), and the presence of an intraductal component (OR, 2.38; 95% CI, 1.22-4.64; P = .011). The LDFS in the NSM-PC and TM-PC matched cohorts did not show a significant difference, with a 4-year LDFS of 0.89 (95% CI, 0.77-0.95) and 0.93 (95% CI, 0.83-0.97), respectively (hazard ratio [HR], 1.31; 95% CI, 0.40-4.35; P = .655). The NSM-PC cohort was also compared with the NSM cohort in terms of LDFS using 2 different matching criteria, with the tumor size before and after neoadjuvant chemotherapy as the balancing covariate. In the first of the 2 comparisons, the hazards of local relapse were comparable between the 2 matched groups (HR, 1.23; 95% CI, 0.37-4.04; P = .739). In the second comparison, the NSM-PC patients showed a significant greater hazard of local relapse than did the NSM patients (HR, 3.60; 95% CI, 1.10-11.80; P = .035). CONCLUSION: NSM might be a valuable option for large breast cancer treated by primary chemotherapy. The rate of local relapse seemed to be related to the disease stage, and no significant association with the type of surgery was detected.

Neoadjuvant Chemotherapy Exerts Selection Pressure Towards Luminal Phenotype Breast Cancer.

BACKGROUND: Breast cancer (BC) phenotype after neoadjuvant chemotherapy (NAC) has not been extensively described and few data exist on whether expression of the primary tumor hormone receptors, HER2 and Ki-67 changes as a result of chemotherapy. MATERIALS AND METHODS: We analyzed specimens from all BC patients treated with anthracycline/taxane-based NAC at our Institution between January 2010 and March 2015 (n = 325). The expression of estrogen receptor (ER), progesterone receptor (PR), HER2 and Ki-67 was determined in pre- and post-NAC specimens. McNemar's test was used to compare paired proportions. RESULTS: Among patients with residual disease after NAC, basal phenotype was luminal A, luminal B, HER2 positive and triple negative in 44, 111, 74 and 27 cases, respectively. PR-positive tumors decreased from 68.0% in the initial biopsy sample to 61.7% in the surgical specimen (p = 0.024). A Ki-67 of < 20% increased from 23.6% to 45% (p < 0.001). ER expression changed from positive to negative in 5% and from negative to positive in 16.7% of cases. Overall, 30% of cases underwent subtype changes, 79% of them towards luminal differentiation. CONCLUSIONS: The switch towards luminal phenotype suggests some kind of endocrine effect of NAC. Our findings raise renewed interest in combinatorial cytotoxic chemotherapy with concomitant or rather sequential endocrine therapy, either alone or with targeted agents.

CDCP1 is a novel marker of the most aggressive human triple-negative breast cancers.

CDCP1, a transmembrane noncatalytic receptor, the expression of which has been associated with a poor prognosis in certain epithelial cancers, was found to be expressed in highly aggressive triple-negative breast cancer (TNBC) cell models, in which it promoted aggressive activities-ie, migration, invasion, anchorage-independent tumor growth, and the formation of vascular-like structures in vitro. By immunohistochemical (IHC) analysis of 100 human TNBC specimens, CDCP1 was overexpressed in 57% of samples, 38% of which exhibited a gain in CDCP1 copy number by fluorescence in situ hybridization (FISH). CDCP1 positivity was significantly associated between FISH and IHC. CDCP1 expression and gains in CDCP1 copy number synergized with nodal (N) status in determining disease-free and distant disease-free survival. The hazard ratios (HRs) of the synergies between CDCP1 positivity by IHC and FISH and lymph node positivity in predicting relapse did not differ significantly, indicating that CDCP1 overexpression in human primary TNBCs, regardless of being driven by gains in CDCP1, is for a critical factor in the progression of N-positive TNBCs. Thus, CDCP1 is a novel marker of the most aggressive N-positive TNBCs and a potential therapeutic target.

Association of adiposity, dysmetabolisms, and inflammation with aggressive breast cancer subtypes: a cross-sectional study.

Obesity and metabolic syndrome are risk and prognostic factors for breast cancer (BC) and are associated with chronic inflammation. We investigated the association between distinct BC subtypes and markers of adiposity, dysmetabolisms, and inflammation. We analyzed 1779 patients with primary invasive BC treated at a single institution, for whom anthropometric and clinical-pathological data were archived. BC subtypes were classified by immunohistochemical staining of ER, PR, HER2, and Ki67, and their relations with the study markers were assessed by multinomial logistic regression. Adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated taking luminal A as reference. All subtypes more aggressive than luminal A were significantly more frequent in younger (<45 years) than older women. Before menopause, luminal B HER2-negative tumors were positively associated with large waist (OR 2.55, 95 % CI 1.53-4.24) and insulin resistance (OR 1.90, 95 % CI 1.05-3.41); luminal B HER2-positive tumors with large waist (OR 2.11, 95 % CI 1.03-4.35) and triple-negative tumors with overweight (OR 3.04, 95 % CI 1.43-6.43) and high C-reactive protein (p trend = 0.026). In postmenopausal women aged <65, luminal B HER2-negative (OR 1.94, 95 % CI 1.16-3.24) and luminal B HER2-positive tumors (OR 2.48, 95 % CI 1.16-5.27) were positively related with metabolic syndrome. Dysmetabolisms and inflammation may be related to different BC subtypes. Before menopause, triple-negative cancers were related to obesity and chronic inflammation, and aggressive luminal subtypes to abdominal adiposity. After menopause, in women aged <65 these latter subtypes were related to metabolic syndrome. Control of adiposity and dysmetabolism can reduce the risk of aggressive BC subtypes, improving the prognosis.

Time trends in axilla management among early breast cancer patients: Persisting major variation in clinical practice across European centers.

Background We examined time trends in axilla management among patients with early breast cancer in European clinical settings. Material and methods EUROCANPlatform partners, including population-based and cancer center-specific registries, provided routinely available clinical cancer registry data for a comparative study of axillary management trends among patients with first non-metastatic breast cancer who were not selected for neoadjuvant therapy during the last decade. We used an additional short questionnaire to compare clinical care patterns in 2014. Results Patients treated in cancer centers were younger than population-based registry populations. Tumor size and lymph node status distributions varied little between settings or over time. In 2003, sentinel lymph node biopsy (SLNB) use varied between 26% and 81% for pT1 tumors, and between 2% and 68% for pT2 tumors. By 2010, SLNB use increased to 79-96% and 49-92% for pT1 and pT2 tumors, respectively. Axillary lymph node dissection (ALND) use for pT1 tumors decreased from between 75% and 27% in 2003 to 47% and 12% in 2010, and from between 90% and 55% to 79% and 19% for pT2 tumors, respectively. In 2014, important differences in axillary management existed for patients with micrometastases only, and for patients fulfilling the ACOSOG Z0011 criteria for omitting ALND. Conclusion This study demonstrates persisting differences in important aspects of axillary management throughout the recent decade. The results highlight the need for international comparative patterns of care studies in oncology, which may help to identify areas where further studies and consensus building may be necessary.

Out-of-pocket costs for cancer survivors between 5 and 10 years from diagnosis: an Italian population-based study.

PURPOSE: To illustrate the out-of-pocket (OOP) costs incurred by a population-based group of patients from 5 to 10 years since their cancer diagnosis in a country with a nationwide public health system. METHODS: Interviews on OOP costs to a sample of 5-10 year prevalent cases randomly extracted from four population-based cancer registries (CRs), two in the north and two in the south of Italy. The patients' general practitioners (GPs) gave assurance about the patient's physical and psychological condition for the interview. A zero-inflated negative binomial model was used to analyze OOP cost determinants. RESULTS: Two hundred six cancer patients were interviewed (48 % of the original sample). On average, a patient in the north spent €69 monthly, against €244 in the south. The main differences are for transport, room, and board (TRB) to reach the hospital and/or the cancer specialist (north €0; south €119). Everywhere, OOP costs without TRB costs were higher for patients with a low quality of life. CONCLUSIONS: Despite the limited participation, our study sample's characteristics are similar to those of the Italian cancer prevalence population, allowing us to generalize the results. The higher OOP costs in the south may be due to the scarcity of oncologic structures, obliging patients to seek assistance far from their residence. Implications for cancer survivors Cancer survivors need descriptive studies to show realistic data about their status. Future Italian and European descriptive studies on cancer survivorship should be based on population CRs and involve GPs in order to approach the patient at best.

Androgen receptor CAG repeat length and estrogen receptor status in postmenopausal breast cancer prognosis.

PURPOSE: The influence of the androgen receptor (AR) CAG repeat polymorphism on breast cancer is controversial. We investigated the combined effects of CAG repeat length and estrogen receptor (ER) status on prognosis in 355 postmenopausal women with primary breast cancer. METHODS: CAG repeat length was determined by the HUMARA test. Relapse-free survival (RFS) and overall survival (OS) according to the X-weighted CAG repeat biallelic mean (XWBM) were investigated by univariate and multivariate analysis. RESULTS: XWBM was not associated with RFS or OS, but a significant interaction between XWBM and ER status (p = 0.002) was found for OS. ER-negative patients with median XWBM <20 showed lower OS than ER-negative/XWBM ≥20 patients (HR = 0.270; 95% Cl: 0.073-0.999). ER-negative/XWBM <20 patients also had significantly lower OS than ER-positive women, irrespective of CAG repeat length (p<0.001). Accordingly, estimated OS was lowest in ER-negative patients with XWBM <20 (OS: 0.63, 95% CI: 0.41-0.79) and highest in ER-positive patients with XWBM <20 (OS: 0.95, 95% CI: 0.90-0.97). CONCLUSIONS: Our data suggest that short CAG repeat length is associated with increased risk of death in ER-negative disease but is related to better survival when ER is expressed. These findings are in agreement with the hypothesis that AR may stimulate or inhibit breast cancer growth depending on ER status, AR transactivation, and the endocrine-metabolic environment of breast tumors. Evaluation of CAG repeat length together with ER status could help improve the estimation of the risk of death, with possible implications for the optimization of standard breast cancer treatment and implementation of prevention strategies.

Survival of women with cancers of breast and genital organs in Europe 1999-2007: Results of the EUROCARE-5 study.

BACKGROUND: Survival differences across Europe for patients with cancers of breast, uterus, cervix, ovary, vagina and vulva have been documented by previous EUROCARE studies. In the present EUROCARE-5 study we update survival estimates and investigate changes in country-specific and over time survival, discussing their relationship with incidence and mortality dynamics for cancers for which organised screening programs are ongoing. METHODS: We analysed cases archived in over 80 population-based cancer registries in 29 countries grouped into five European regions. We used the cohort approach to estimate 5-year relative survival (RS) for adult (⩾15years) women diagnosed 2000-2007, by age, country and region; and the period approach to estimate time trends (1999-2007) in RS for breast and cervical cancers. RESULTS: In 2000-2007, 5-year RS was 57% overall, 82% for women diagnosed with breast, 76% with corpus uteri, 62% with cervical, 38% with ovarian, 40% with vaginal and 62% with vulvar cancer. Survival was low for patients resident in Eastern Europe (34% ovary-74% breast) and Ireland and the United Kingdom [Ireland/UK] (31-79%) and high for those resident in Northern Europe (41-85%) except Denmark. Survival decreased with advancing age: markedly for women with ovarian (71% 15-44years; 20% ⩾75years) and breast (86%; 72%) cancers. Survival for patients with breast and cervical cancers increased from 1999-2001 to 2005-2007, remarkably for those resident in countries with initially low survival. CONCLUSIONS: Despite increases over time, survival for women's cancers remained poor in Eastern Europe, likely due to advanced stage at diagnosis and/or suboptimum access to adequate care. Low survival for women living in Ireland/UK and Denmark could indicate late detection, possibly related also to referral delay. Poor survival for ovarian cancer across the continent and over time suggests the need for a major research effort to improve prognosis for this common cancer.

Secondary electrospray ionization-mass spectrometry and a novel statistical bioinformatic approach identifies a cancer-related profile in exhaled breath of breast cancer patients: a pilot study.

Breath analysis represents a new frontier in medical diagnosis and a powerful tool for cancer biomarker discovery due to the recent development of analytical platforms for the detection and identification of human exhaled volatile compounds. Statistical and bioinformatic tools may represent an effective complement to the technical and instrumental enhancements needed to fully exploit clinical applications of breath analysis. Our exploratory study in a cohort of 14 breast cancer patients and 11 healthy volunteers used secondary electrospray ionization-mass spectrometry (SESI-MS) to detect a cancer-related volatile profile. SESI-MS full-scan spectra were acquired in a range of 40-350 mass-to-charge ratio (m/z), converted to matrix data and analyzed using a procedure integrating data pre-processing for quality control, and a two-step class prediction based on machine-learning techniques, including a robust feature selection, and a classifier development with internal validation. MS spectra from exhaled breath showed an individual-specific breath profile and high reciprocal homogeneity among samples, with strong agreement among technical replicates, suggesting a robust responsiveness of SESI-MS. Supervised analysis of breath data identified a support vector machine (SVM) model including 8 features corresponding to m/z 106, 126, 147, 78, 148, 52, 128, 315 and able to discriminate exhaled breath from breast cancer patients from that of healthy individuals, with sensitivity and specificity above 0.9.Our data highlight the significance of SESI-MS as an analytical technique for clinical studies of breath analysis and provide evidence that our noninvasive strategy detects volatile signatures that may support existing technologies to diagnose breast cancer.