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.

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.

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.

¹8F-FLT PET/CT as an imaging tool for early prediction of pathological response in patients with locally advanced breast cancer treated with neoadjuvant chemotherapy: a pilot study.

PURPOSE: We evaluated whether (18)F-3'-deoxy-3'-fluorothymidine positron emission tomography (FLT PET) can predict the final postoperative histopathological response in primary breast cancer after the first cycle of neoadjuvant chemotherapy (NCT). METHODS: In this prospective cohort study of 15 patients with locally advanced operable breast cancer, FLT PET evaluations were performed before NCT, after the first cycle of NCT, and at the end of NCT. All patients subsequently underwent surgery. Variables from FLT PET examinations were correlated with postoperative histopathological results. RESULTS: At baseline, median of maximum standardized uptake values (SUVmax) in the groups showing a complete pathological response (pCR) + residual cancer burden (RCB) I, RCB II or RCB III did not differ significantly for the primary tumour (5.0 vs. 2.9 vs. 8.9, p = 0.293) or for axillary nodes (7.9 vs. 1.6 vs. 7.0, p = 0.363), whereas the Spearman correlation between SUVmax and Ki67 proliferation rate index was significant (r = 0.69, p < 0.001). Analysis of the relative percentage change of SUVmaxin the primary tumour (∆SUVTmax(t1)) and axillary nodes (∆SUVNmax(t1)) after the first NCT cycle showed that the power of ∆SUVTmax(t 1) to predict pCR + RCB I responses (AUC = 0.91, p < 0.001) was statistically significant, whereas ∆SUVNmax(t1) had a moderate ability (AUC = 0.77, p = 0.119) to separate subjects with ΔSUVTmax(t1) > -52.9 % into two groups: RCB III patients and a heterogeneous group that included RCB I and RCB II patients. A predictive score µ based on ΔSUVTmax(t1) and ΔSUVNmax(t1) parameters is proposed. CONCLUSION: The preliminary findings of the present study suggest the potential utility of FLT PET scans for early monitoring of response to NCT and to formulate a therapeutic strategy consistent with the estimated efficacy of NCT. However, these results in a small patient population need to be validated in a larger independent cohort.

Axillary lymph node dissection versus no dissection in patients with T1N0 breast cancer: a randomized clinical trial (INT09/98).

BACKGROUND: Although axillary surgery is still considered to be a fundamental part of the management of early breast cancer, it may no longer be necessary either as treatment or as a guide to adjuvant treatment. The authors conducted a single-center randomized trial (INT09/98) to determine the impact of avoiding axillary surgery in patients with T1N0 breast cancer and planning chemotherapy based on biological factors of the primary tumor on long-term disease control. METHODS: From June 1998 to June 2003, 565 patients aged 30 years to 65 years with T1N0 breast cancer were randomized to either quadrantectomy with (QUAD) or without (QU) axillary lymph node dissection; a total of 517 patients finally were evaluated. All patients received radiotherapy to the residual breast only. Chemotherapy for patients in the QUAD treatment arm was determined based on lymph node status, estrogen receptor status, and tumor grade. Chemotherapy for patients in the QU treatment arm was based on estrogen receptor status, tumor grade, and human epidermal growth factor receptor 2 and laminin receptor status. Overall survival (OS) was the primary endpoint. Disease-free survival (DFS) and rate and time of axillary lymph node recurrence in the QU treatment arm were the secondary endpoints. RESULTS: After a median follow-up of >10 years, the estimated adjusted hazards ratio of the QUAD versus QU treatment arms for OS was 1.09 (95% confidence interval, 0.59-2.00; P = .783) and was 1.04 (95% confidence interval, 0.56-1.94; P = .898) for DFS. Of the 245 patients in the QU treatment arm, 22 (9.0%) experienced axillary lymph node recurrence. The median time to axillary lymph node recurrence from breast surgery was 30.0 months (interquartile range, 24.2 months-73.4 months). CONCLUSIONS: Patients with T1N0 breast cancer did not appear to benefit in terms of DFS and OS from immediate axillary lymph node dissection in the current randomized trial. The biological characteristics of the primary tumor appear adequate for guiding adjuvant treatment.

Ex vivo MRI evaluation of breast tumors: a novel tool for verifying resection of nonpalpable only MRI detected lesions.

A fundamental question in surgery of only magnetic resonance imaging (MRI)-detected breast lesions is to ensure their removal when they are not palpable by clinical examination and surgical exploration. This is especially relevant in the case of small tumors, carcinoma in situ or lobular carcinoma. Thirty-nine patients were enrolled in the study, 21 patients with breast lesions detected by both conventional imaging and breast MRI (bMRI) and 18 patients with bMRI findings only. Preoperative bMRI allowed staging the disease and localizing the lesion. In the operating theater, contrast medium was injected 1 minute before skin incision. After removal, surgical specimens were submitted to ex vivo MRI, performed using a dedicated surface coil and Spair inversion recovery sequences for suppression of fat signal intensity. All MRI enhancing lesions were completely included within the surgical specimen and visualized by ex vivo MRI. In the first 21 patients, bMRI was able to visualize branching margins or satellite nodules around the core lesion, and allowed for better staging of the surrounding in situ carcinoma; in the last 18 patients, eight of whom were breast cancer type 1 susceptibility protein (BRCA) mutation carriers, bMRI identified 12 malignant tumors, otherwise undetectable, that were all visualized by ex vivo MRI. This is the first description of a procedure that re-enhances breast lesions within a surgical specimen, demonstrating the surgical removal of nonpalpable breast lesions diagnosed only with bMRI. This new strategy reproduces the morphology and the entire extension of the primary lesion on the specimen, with potentially better local surgical control, reducing additional unplanned surgery.

Significance of ipsilateral breast tumor recurrence after breast conserving treatment: role of surgical removal.

OBJECTIVE: To analyze the pattern over time (dynamics) of further recurrence and death after ipsilateral breast tumor recurrence (IBTR) in breast cancer patients undergoing breast conserving treatment (BCT). METHODS: A total of 338 evaluable patients experiencing IBTR were extracted from a database of 3,293 patients undergoing BCT. The hazard rates for recurrence and mortality throughout 10 years of follow-up after IBTR were assessed and were compared to the analogous estimates associated to the primary treatment. RESULTS: In a time frame with the time origin at the surgical treatment for IBTR, the hazard rate for further recurrence displays a bimodal pattern (peaks at the second and at the sixth year). Patients receiving mastectomy for IBTR reveal recurrence and mortality dynamics similar to that of node positive (N+) patients receiving mastectomy as primary surgery, apart from the first two-three years, when IBTR patients do worse. If the patients with time to IBTR longer than 2.5 years are considered, differences disappear. CONCLUSIONS: The recurrence and mortality dynamics following IBTR surgical removal is similar to the corresponding dynamics following primary tumor removal. In particular, patients with time to IBTR in excess of 2.5 years behave like N+ patients following primary tumor removal. Findings may be suitably explained by assuming that the surgical manoeuvre required by IBTR treatment is able to activate a sudden growing phase for tumor foci most of which, as suggested by the systemic model of breast cancer, would have reached the clinical level according to their own dynamics.

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.

Axillary dissection versus no axillary dissection in older patients with T1N0 breast cancer: 15-year results of a randomized controlled trial.

OBJECTIVE: To assess the role of axillary dissection in older breast cancer patients with a clinically clear axilla. BACKGROUND: Axillary dissection, once standard treatment for breast cancer, is associated with considerable morbidity. It has been substituted by sentinel node biopsy with dissection only if the sentinel node is positive. We aimed to determine whether axillary surgery can be omitted in older women, thereby sparing them morbidity, without compromising long-term disease control. METHODS: We carried out a randomized clinical trial on 238 older (65-80 years) breast cancer patients, with clinically N0 disease of radiographic diameter 2 cm or less. Patients were randomized to quadrantectomy with or without axillary dissection. All received radiotherapy to the residual breast but not the axilla; all were prescribed tamoxifen for 5 years. Main outcome measures were overall survival and breast cancer mortality. We also assessed overt axillary disease in those who did not receive axillary dissection. RESULTS: After 15 years of follow-up, distant metastasis rate, overall survival, and breast cancer mortality in the axillary dissection and no axillary dissection arms were indistinguishable. The 15-year cumulative incidence of overt axillary disease in the no axillary dissection arm was only 6%. CONCLUSIONS: Older patients with early breast cancer and a clinically clear axilla treated by conservative surgery, postoperative radiotherapy, and adjuvant tamoxifen do not benefit from axillary dissection. This study was registered at clinicaltrials.gov (ID NCT00002720).

Androgen receptors and serum testosterone levels identify different subsets of postmenopausal breast cancers.

BACKGROUND: Androgen receptors (AR) are frequently expressed in breast cancers, but their implication in cancer growth is still controversial. In the present study, we further investigated the role of the androgen/AR pathway in breast cancer development. METHODS: AR expression was evaluated by immunochemistry in a cohort of 528 postmenopausal breast cancer patients previously examined for the association of serum testosterone levels with patient and tumor characteristics. AR expression was classified according to the percentage of stained cells: AR-absent (0%) and AR-poorly (1%-30%), AR-moderately (>30%-60%), and AR-highly (>60%) positive. RESULTS: Statistical analysis was performed in 451 patients who experienced natural menopause. AR-high expression was significantly related with low histologic grade and estrogen receptor (ER)- and progesterone receptor (PR)-positive status (P trend<0.001). Mean testosterone levels were significantly higher in the AR-high category than in the other categories combined (P=0.022), although a trend across the AR expression categories was not present. When women defined by ER status were analyzed separately, regression analysis in the ER-positive group showed a significant association of high testosterone levels with AR-highly-positive expression (OR 1.86; 95% CI, 1.10-3.16), but the association was essentially due to patients greater than or equal to 65 years (OR 2.42; 95% CI, 1.22-4.82). In ER-positive group, elevated testosterone levels appeared also associated with AR-absent expression, although the small number of patients in this category limited the appearance of significant effects (OR 1.92; 95% CI, 0.73-5.02): the association was present in both age groups (<65 and ≥65 years). In the ER-negative group, elevated testosterone levels were found associated (borderline significance) with AR-absent expression (OR 2.82, 95% CI, 0.98-8.06). In this ER-negative/AR-absent subset of tumors, elevated testosterone levels cannot stimulate cancer growth either directly or after conversion into estrogens, but they probably induce increased synthesis of some other substance that is responsible for cancer growth through binding to its specific receptor. CONCLUSIONS: The findings in the present study confirm that testosterone levels are a marker of hormone-dependent breast cancer and suggest that the contemporary evaluation of ER status, AR expression, and circulating testosterone levels may identify different subsets of cancers whose growth may be influenced by androgens.

Axillary dissection versus no axillary dissection in elderly patients with breast cancer and no palpable axillary nodes: results after 15 years of follow-up.

OBJECTIVE: To assess the long-term safety of no axillary clearance in elderly patients with breast cancer and nonpalpable axillary nodes. BACKGROUND: Lymph node evaluation in elderly patients with early breast cancer and clinically negative axillary nodes is controversial. Our randomized trial with 5-year follow-up showed no breast cancer mortality advantage for axillary clearance compared with observation in older patients with T1N0 disease. METHODS: We further investigated axillary treatment in a retrospective analysis of 671 consecutive patients, aged ≥ 70 years, with operable breast cancer and a clinically clear axilla, treated between 1987 and 1992; 172 received and 499 did not receive axillary dissection; 20 mg/day tamoxifen was prescribed for at least 2 years. We used multivariable analysis to take account of the lack of randomization. RESULTS: After median follow-up of 15 years (interquartile range 14-17 years) there was no significant difference in breast cancer mortality between the axillary and no axillary clearance groups. Crude cumulative 15-year incidence of axillary disease in the no axillary dissection group was low: 5.8% overall and 3.7% for pT1 patients. CONCLUSIONS: Elderly patients with early breast cancer and clinically negative nodes did not benefit in terms of breast cancer mortality from immediate axillary dissection in this nonrandomized study. Sentinel node biopsy could also be foregone due to the very low cumulative incidence of axillary disease in this age group. Axillary dissection should be restricted to the small number of patients who later develop overt axillary disease.

Recurrence and mortality according to estrogen receptor status for breast cancer patients undergoing conservative surgery. Ipsilateral breast tumour recurrence dynamics provides clues for tumour biology within the residual breast.

BACKGROUND: The study was designed to determine how tumour hormone receptor status affects the subsequent pattern over time (dynamics) of breast cancer recurrence and death following conservative primary breast cancer resection. METHODS: Time span from primary resection until both first recurrence and death were considered among 2825 patients undergoing conservative surgery with or without breast radiotherapy. The hazard rates for ipsilateral breast tumour recurrence (IBTR), distant metastasis (DM) and mortality throughout 10 years of follow-up were assessed. RESULTS: DM dynamics displays the same bimodal pattern (first early peak at about 24 months, second late peak at the sixth-seventh year) for both estrogen receptor (ER) positive (P) and negative (N) tumours and for all local treatments and metastatic sites. The hazard rates for IBTR maintain the bimodal pattern for ERP and ERN tumours; however, each IBTR recurrence peak for ERP tumours is delayed in comparison to the corresponding timing of recurrence peaks for ERN tumours. Mortality dynamics is markedly different for ERP and ERN tumours with more early deaths among patients with ERN than among patients with ERP primary tumours. CONCLUSION: DM dynamics is not influenced by the extent of conservative primary tumour resection and is similar for both ER phenotypes across different metastatic sites, suggesting similar mechanisms for tumour development at distant sites despite apparently different microenvironments. The IBTR risk peak delay observed in ERP tumours is an exception to the common recurrence risk rhythm. This suggests that the microenvironment within the residual breast tissue may enforce more stringent constraints upon ERP breast tumour cell growth than other tissues, prolonging the latency of IBTR. This local environment is, however, apparently less constraining to ERN cells, as IBTR dynamics is similar to the corresponding recurrence dynamics among other distant tissues.

Angiosarcoma of the breast and vascular endothelial growth factor receptor.

BACKGROUND: Breast angiosarcoma is rare and often associated with previous breast cancer treatment. The present study aimed to define long-term outcomes in relation to common prognostic factors. The expression of vascular endothelial growth factor receptor was also evaluated, as it may be a potential target for anti-angiogenic therapy. PATIENTS AND METHODS: We retrospectively assessed outcomes in relation to age, association with previous breast-conserving treatment for breast cancer, tumor size, and grade in 19 patients without metastases at diagnosis. Vascular endothelial growth factor receptor was also assessed. RESULTS: Median follow-up was 33 months (range, 1-121). There were 6 local recurrences and 6 deaths for disease progression. Five-year disease-free survival and overall survival were 53% (95% CI, 20-86%) and 49% (95% CI, 14-84%), respectively. No factor significantly affected survival. Vascular endothelial growth factor receptor was positive in 50% of cases and was more frequent in better differentiated cancer. CONCLUSIONS: The association of vascular endothelial growth factor receptor with G1/G2 tumors requires further investigations. Our findings suggest that anti-angiogenic treatment in vascular endothelial growth factor receptor-positive cases be considered as a novel therapeutic modality in this rare and aggressive disease. Although information is still incomplete, we propose a multimodal therapeutic approach including surgery, radiotherapy and chemotherapy.

Is there a specific magnetic resonance phenotype characteristic of hereditary breast cancer?

AIMS AND BACKGROUND: The aim of the study was to investigate the growth rate of inherited breast cancer, to analyze its T2 signal intensity besides kinetic and morphologic aspects, and to verify whether there is any correlation between magnetic resonance imaging phenotype and BRCA status. METHODS: Between June 2000 and September 2009, we enrolled 227 women at high genetic risk for breast cancer in a surveillance program, within a multicenter project of the Istituto Superiore di Sanità (Rome). RESULTS: Thirty-four cancers were detected among 31 subjects. One patient refused magnetic resonance imaging because of claustrophobia. Compared with sporadic disease, hereditary cancer showed some differences, in terms of biologic attitude and semeiotic patterns. These differences were mainly registered for magnetic resonance imaging, where the most frequent radiological variant was represented by the very high T2 signal intensity (73%). Moreover, the size of 8 of the neoplasms showed a significant increase in less than one year, 5 of them in less than 6 months. Six lesions were in BRCA1 patients and the remaining in BRCA2. Furthermore, cancers with a high growth rate also demonstrated a significant increment in T2 signal intensity. CONCLUSIONS: Our results confirmed the high growth rate within BRCA-related breast cancers, especially for BRCA1 mutation carriers. In our experience, we found a specific imaging phenotype, represented by the high T2 signal intensity of hereditary breast cancer. To our knowledge, this is the first report that points out this new semeiotic parameter, which is usually typical of benign lesions. Considering the correlation between high growth rate and high T2 signal intensity, the former seems to be related to the absence of induction of a desmoplastic reaction that could somehow restrict cancer growth.

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.