Intraoperative irradiation for early breast cancer (ELIOT): long-term recurrence and survival outcomes from a single-centre, randomised, phase 3 equivalence trial.

BACKGROUND: In the randomised, phase 3 equivalence trial on electron intraoperative radiotherapy (ELIOT), accelerated partial breast irradiation (APBI) with the use of intraoperative radiotherapy was associated with a higher rate of ipsilateral breast tumour recurrence (IBTR) than whole-breast irradiation (WBI) in patients with early-stage breast cancer. Here, we aimed to examine the planned long-term recurrence and survival outcomes from the ELIOT trial. METHODS: This single-centre, randomised, phase 3 equivalence trial was done at the European Institute of Oncology (Milan, Italy). Eligible women, aged 48-75 years with a clinical diagnosis of a unicentric breast carcinoma with an ultrasound diameter not exceeding 25 mm, clinically negative axillary lymph nodes, and who were suitable for breast-conserving surgery, were randomly assigned (1:1) via a web-based system, with a random permuted block design (block size of 16) and stratified by clinical tumour size, to receive post-operative WBI with conventional fractionation (50 Gy given as 25 fractions of 2 Gy, plus a 10 Gy boost), or 21 Gy intraoperative radiotherapy with electrons (ELIOT) in a single dose to the tumour bed during surgery. The trial was open label and no-one was masked to treatment group assignment. The primary endpoint was the occurrence of IBTR. The trial was designed assuming a 5-year IBTR rate of 3% in the WBI group and equivalence of the two groups, if the 5-year IBTR rate in the ELIOT group did not exceed a 2·5 times excess, corresponding to 7·5%. Overall survival was the secondary endpoint. The main analysis was done by intention to treat. The cumulative incidence of IBTR events and overall survival were assessed at 5, 10, and 15 years of follow-up. This trial is registered with ClinicalTrials.gov, NCT01849133. FINDINGS: Between Nov 20, 2000, and Dec 27, 2007, 1305 women were enrolled and randomly assigned: 654 to the WBI group and 651 to the ELIOT group. After a median follow-up of 12·4 years (IQR 9·7-14·7), 86 (7%) patients developed IBTR, with 70 (11%) cases in the ELIOT group and 16 (2%) in the WBI group, corresponding to an absolute excess of 54 IBTRs in the ELIOT group (HR 4·62, 95% CI 2·68-7·95, p<0·0001). In the ELIOT group, the 5-year IBTR rate was 4·2% (95% CI 2·8-5·9), the 10-year rate was 8·1% (6·1-10·3), and the 15-year rate was 12·6% (9·8-15·9). In the WBI group, the 5-year IBTR rate was 0·5% (95% CI 0·1-1·3), the 10-year rate was 1·1% (0·5-2·2), and the 15-year rate was 2·4% (1·4-4·0). At final follow-up on March 11, 2019, 193 (15%) women had died from any cause, with no difference between the two groups (98 deaths in the ELIOT group vs 95 in the WBI group; HR 1·03, 95% CI 0·77-1·36, p=0·85). In the ELIOT group, the overall survival rate was 96·8% (95% CI 95·1-97·9) at 5 years, 90·7% (88·2-92·7) at 10 years, and 83·4% (79·7-86·4) at 15 years; and in the WBI group, the overall survival rate was 96·8% (95·1-97·9) at 5 years, 92·7% (90·4-94·4) at 10 years, and 82·4% (78·5-85·6) at 15 years. We did not collect long-term data on adverse events. INTERPRETATION: The long-term results of this trial confirmed the higher rate of IBTR in the ELIOT group than in the WBI group, without any differences in overall survival. ELIOT should be offered to selected patients at low-risk of IBTR. FUNDING: Italian Association for Cancer Research, Jacqueline Seroussi Memorial Foundation for Cancer Research, Umberto Veronesi Foundation, American Italian Cancer Foundation, The Lombardy Region, and Italian Ministry of Health.

Serum HER2 extracellular domain levels and HER2 circulating tumor cell status in patients with metastatic breast cancer.

AIM: To shed light on the clinical role of HER2 status in serum as extracellular domain (ECD) and corresponding circulating tumor cells (CTCs) in metastatic breast cancer patients. METHODS: 68 patients were analyzed. Serum HER2 was determined by ADVIA Centaur(®) Serum HER2 test. CellSearch System was performed for CTC quantification. RESULTS: HER2 was overexpressed in 21 primary tumors. In total, 19 patients had ECD >15 ng/ml (the cut-off used), 48 patients had at least one CTC. ECD positivity was associated with CTC number (p = 0.01), HER2-positive CTC (p = 0.01) and the ratio HER2-positive CTC/total CTC (p = 0.02). ECD was not associated with survival. CONCLUSION: ECD in combination with HER2 CTC status would deserve further investigation in larger series for addressing its putative prognostic relevance.

New frontiers in proton therapy: applications in breast cancer.

PURPOSE OF REVIEW: The aim of this article is to review published data on proton therapy in the multimodality treatment of breast cancer so as to provide an overview of the advantages and critical issues relating to this irradiation modality. RECENT FINDINGS: In-silico studies show a clear advantage in terms of dose homogeneity to the target and dose reduction to the non-target structures including heart, lungs, and healthy breast tissues. Clinical studies have shown the feasibility of proton therapy in breast cancer and allowed optimizing the technique by using multiple beams and intensity modulation. SUMMARY: Proton therapy is able to optimize the dose to the target and to reduce the irradiation of the healthy tissues. Clinical studies are expected to show a decreased risk of late side effects with potential improvement of the quality of life of breast cancer patients.

Milestones in breast cancer treatment.

Modern treatment started in the 1880s with Halsted's mastectomy. The next milestone-a century later-was breast-conserving surgery, with equivalent survival but better esthetic outcomes than mastectomy. Sentinel node biopsy, introduced in the 1990s, was a milestone that permitted avoidance of axillary dissection if the sentinel node was disease-free. Chemotherapy was established for early breast cancer in the 1980s and its efficacy continues to improve; however side effects remain a concern, particularly since chemotherapy does not benefit most patients. External whole breast irradiation was introduced with conservative surgery, as it reduces recurrences. By the 2000s, 3-week regimens had been shown equivalent to standard 6-week regimens-easing pressure on patients and radiation centers. Intraoperative partial breast irradiation is potentially more beneficial as it permits complete local treatment in a single session; however, trials show that patients must be very carefully selected. From the 1990s irradiation technology was combined with imaging and computer technologies to produce equipment that directs radiation to more precisely defined target volumes, allowing increased dose to the target and markedly reduced dose to nearby tissues. Irradiation systems are evolving rapidly but are being implemented without data on long-term morbidity or efficacy, while costs rise steeply. The first targeted treatment was tamoxifen, a selective estrogen receptor inhibitor. Since its widespread use starting in the 1980s, tamoxifen has saved the lives or prolonged the survival of millions with estrogen-positive disease; it is cheap and has limited (but not negligible) side effects. The same cannot be said of newer targeted treatments like trastuzumab and pertuzumab, which, although effective against human epidermal growth factor receptor 2-positive cancer, come with important side effects and huge costs. Breast cancer mortality is declining in rich countries, but treatments have become more demanding and more expensive, so the outlook for the increasing numbers of women worldwide who develop the disease is uncertain.

Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a randomised controlled equivalence trial.

BACKGROUND: Intraoperative radiotherapy with electrons allows the substitution of conventional postoperative whole breast irradiation with one session of radiotherapy with the same equivalent dose during surgery. However, its ability to control for recurrence of local disease required confirmation in a randomised controlled trial. METHODS: This study was done at the European Institute of Oncology (Milan, Italy). Women aged 48-75 years with early breast cancer, a maximum tumour diameter of up to 2·5 cm, and suitable for breast-conserving surgery were randomly assigned in a 1:1 ratio (using a random permuted block design, stratified for clinical tumour size [<1·0 cm vs 1·0-1·4 cm vs ≥1·5 cm]) to receive either whole-breast external radiotherapy or intraoperative radiotherapy with electrons. Study coordinators, clinicians, and patients were aware of the assignment. Patients in the intraoperative radiotherapy group received one dose of 21 Gy to the tumour bed during surgery. Those in the external radiotherapy group received 50 Gy in 25 fractions of 2 Gy, followed by a boost of 10 Gy in five fractions. This was an equivalence trial; the prespecified equivalence margin was local recurrence of 7·5% in the intraoperative radiotherapy group. The primary endpoint was occurrence of ipsilateral breast tumour recurrences (IBTR); overall survival was a secondary outcome. The main analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01849133. FINDINGS: 1305 patients were randomised (654 to external radiotherapy and 651 to intraoperative radiotherapy) between Nov 20, 2000, and Dec 27, 2007. After a medium follow-up of 5·8 years (IQR 4·1-7·7), 35 patients in the intraoperative radiotherapy group and four patients in the external radiotherapy group had had an IBTR (p<0·0001). The 5-year event rate for IBRT was 4·4% (95% CI 2·7-6·1) in the intraoperative radiotherapy group and 0·4% (0·0-1·0) in the external radiotherapy group (hazard ratio 9·3 [95% CI 3·3-26·3]). During the same period, 34 women allocated to intraoperative radiotherapy and 31 to external radiotherapy died (p=0·59). 5-year overall survival was 96·8% (95% CI 95·3-98·3) in the intraoperative radiotherapy group and 96·9% (95·5-98·3) in the external radiotherapy group. In patients with data available (n=464 for intraoperative radiotherapy; n=412 for external radiotherapy) we noted significantly fewer skin side-effects in women in the intraoperative radiotherapy group than in those in the external radiotherapy group (p=0·0002). INTERPRETATION: Although the rate of IBTR in the intraoperative radiotherapy group was within the prespecified equivalence margin, the rate was significantly greater than with external radiotherapy, and overall survival did not differ between groups. Improved selection of patients could reduce the rate of IBTR with intraoperative radiotherapy with electrons. FUNDING: Italian Association for Cancer Research, Jacqueline Seroussi Memorial Foundation for Cancer Research, and Umberto Veronesi Foundation.

Axillary dissection versus no axillary dissection in patients with sentinel-node micrometastases (IBCSG 23-01): a phase 3 randomised controlled trial.

BACKGROUND: For patients with breast cancer and metastases in the sentinel nodes, axillary dissection has been standard treatment. However, for patients with limited sentinel-node involvement, axillary dissection might be overtreatment. We designed IBCSG trial 23-01 to determine whether no axillary dissection was non-inferior to axillary dissection in patients with one or more micrometastatic (≤2 mm) sentinel nodes and tumour of maximum 5 cm. METHODS: In this multicentre, randomised, non-inferiority, phase 3 trial, patients were eligible if they had clinically non-palpable axillary lymph node(s) and a primary tumour of 5 cm or less and who, after sentinel-node biopsy, had one or more micrometastatic (≤2 mm) sentinel lymph nodes with no extracapsular extension. Patients were randomly assigned (in a 1:1 ratio) to either undergo axillary dissection or not to undergo axillary dissection. Randomisation was stratified by centre and menopausal status. Treatment assignment was not masked. The primary endpoint was disease-free survival. Non-inferiority was defined as a hazard ratio (HR) of less than 1·25 for no axillary dissection versus axillary dissection. The analysis was by intention to treat. Per protocol, disease and survival information continues to be collected yearly. This trial is registered with ClinicalTrials.gov, NCT00072293. FINDINGS: Between April 1, 2001, and Feb 28, 2010, 465 patients were randomly assigned to axillary dissection and 469 to no axillary dissection. After the exclusion of three patients, 464 patients were in the axillary dissection group and 467 patients were in the no axillary dissection group. After a median follow-up of 5·0 (IQR 3·6-7·3) years, we recorded 69 disease-free survival events in the axillary dissection group and 55 events in the no axillary dissection group. Breast-cancer-related events were recorded in 48 patients in the axillary dissection group and 47 in the no axillary dissection group (ten local recurrences in the axillary dissection group and eight in the no axillary dissection group; three and nine contralateral breast cancers; one and five [corrected] regional recurrences; and 34 and 25 distant relapses). Other non-breast cancer events were recorded in 21 patients in the axillary dissection group and eight in the no axillary dissection group (20 and six second non-breast malignancies; and one and two deaths not due to a cancer event). 5-year disease-free survival was 87·8% (95% CI 84·4-91·2) in the group without axillary dissection and 84·4% (80·7-88·1) in the group with axillary dissection (log-rank p=0·16; HR for no axillary dissection vs axillary dissection was 0·78, 95% CI 0·55-1·11, non-inferiority p=0·0042). Patients with reported long-term surgical events (grade 3-4) included one sensory neuropathy (grade 3), three lymphoedema (two grade 3 and one grade 4), and three motor neuropathy (grade 3), all in the group that underwent axillary dissection, and one grade 3 motor neuropathy in the group without axillary dissection. One serious adverse event was reported, a postoperative infection in the axilla in the group with axillary dissection. INTERPRETATION: Axillary dissection could be avoided in patients with early breast cancer and limited sentinel-node involvement, thus eliminating complications of axillary surgery with no adverse effect on survival. FUNDING: None.

Can we avoid axillary dissection in the micrometastatic sentinel node in breast cancer?

There is considerable interest in foregoing axillary dissection (AD) when the sentinel node (SN) is positive in early breast cancer, particularly when involvement is minimal (micrometastases or isolated tumor cells). To address this issue we analyzed outcomes in patients with a single micrometastatic SN who did not receive AD. We selected 377 consecutive patients treated at the European Institute of Oncology between 1999 and 2007 for invasive breast cancer. Classical and competing risks survival analyses were performed to estimate prognostic factors for axillary recurrence, first events and overall survival. Median age was 53 years (range 26-80); median follow-up was 5 years (range 1-9). Most (91.8%) patients received conservative surgery; 209 (55.4%) had only one SN (range 1-8). Five-year overall survival was 97.3%. There were 10 local events, 2 simultaneous local and axillary events, 6 axillary recurrences and 12 distant events. The cumulative incidence of axillary recurrence was 1.6% (95% CI 0.7-3.3). By multivariable analysis, tumor size and grade were significantly associated with axillary recurrence. The high five-year survival and low cumulative incidence of axillary recurrence in this cohort provide justification for the increasingly common practice of foregoing AD in women with minimal SN involvement, and suggest in particular that AD can safely be avoided in women with small, low-grade tumors. Nevertheless, a subset of patients might be at high risk of developing overt axillary disease and efforts should be made to identify such patients by ancillary analyses of the results of ongoing or recently published clinical trials.

Influence of margin status on outcomes in lobular carcinoma: experience of the European Institute of Oncology.

OBJECTIVE: We analyzed 382 patients with pure lobular carcinoma treated up to 2002 with sufficient follow-up to draw prognostic conclusions, all treated by conservative surgery. Our aim was to evaluate the influence of margin status on outcomes with a view assessing the appropriateness of conservative surgery in this breast cancer subtype. METHODS: We assessed locoregional relapse, distant metastasis, contralateral breast cancer, breast cancer-related event free survival, disease-free survival and overall survival according to margin status categorized as at least 10 mm versus less than 10 mm (usually considered negative). RESULTS: The proportions of patients with less than 10 mm margins varied significantly with age (P = 0.02), menopausal status (P = 0.006), and tumor size (P = 0.02) but no other characteristic was significantly related to margin status. As regards unfavorable events during follow-up, none differed significantly between at least 10 mm and less than 10 mm margin groups. In particular, there were 11 (3.7%) local relapses in the same quadrant in at least 10 mm margin group compared to 4 (4.6%) in the less than 10 mm margin group, and 7 (2.4%) ipsilateral breast cancers in the 10 mm or more margin group but none in the less than 10 mm group. These findings indicate that minimal residual disease as evidenced by margins less than 10 mm is eradicated by radiotherapy (backed up in selected cases by reexcision, which in this series was always conservative). The rate of contralateral breast cancer was low at 2.9% indicating that prophylactic contralateral mastectomy is not justified. CONCLUSIONS: We conclude that the surgical approach and criteria for adjuvant hormonal and systemic treatment in lobular carcinoma should be the same as for ductal carcinoma, provided that adequate preoperative investigations exclude extensive multifocal and contralateral disease.

The management of ductal intraepithelial neoplasia (DIN): open controversies and guidelines of the Istituto Europeo di Oncologia (IEO), Milan, Italy.

The management of ductal intraepithelial neoplasia (DIN) has substantially changed over the past 30 years, as its incidence has increased (from 2-3% to more than 20%), mainly due to the widespread use of mammography screening. This article describes not only the more widespread theoretical concepts on DIN but also the differences in the practical applications of the theory between different countries, different oncology specialists, and different cancer centers. Papers related to the international multicentre-randomized trials and retrospective studies were analyzed. We include articles and papers published between 1993 and 2010 related to patients with DIN, and abstracts and reports from MEDLINE and other sources were indentified. The standard of care for DIN consists of (a) breast conservative surgery (mastectomy is still indicated in large lesions--masses or microcalcifications--in about 30% of cases); (b) radiotherapy (RT) after conservative surgery, and (c) medical treatment in estrogen receptors-positive patients. However, most studies have shown significant differences between theory and practical application. Moreover, there are differences regarding (a) the indications of sentinel lymph node biopsy, (b) the definition and identification of low-risk DIN subgroups that can avoid RT and tamoxifen, and (c) the research into new alternative drugs in adjuvant medical therapy. A general agreement on the best management of DIN does not exist as yet. New large trials are needed in order to define the best management of DIN patients which is (in most respects) still complex and controversial.

Sentinel lymph node biopsy in breast cancer: ten-year results of a randomized controlled study.

OBJECTIVE: Sentinel node biopsy (SNB) is widely used to stage the axilla in breast cancer. We present 10-year follow-up of our single-institute trial designed to compare outcomes in patients who received no axillary dissection if the sentinel node was negative, with patients who received complete axillary dissection. METHODS: From March 1998 to December 1999, 516 patients with primary breast cancer up to 2 cm in pathologic diameter were randomized either to SNB plus complete axillary dissection (AD arm) or to SNB with axillary dissection only if the sentinel node contained metastases (SN arm). RESULTS: The 2 arms were well-balanced for number of sentinel nodes found, proportion of positive sentinel nodes, and all other tumor and patient characteristics. About 8 patients in the AD arm had false-negative SNs on histologic analysis: a similar number (8, 95% CI: 3-15) of patients with axillary involvement was expected in SN arm patients who did not receive axillary dissection; but only 2 cases of overt axillary metastasis occurred. There were 23 breast cancer-related events in the SN arm and 26 in the AD arm (log-rank, P = 0.52), while overall survival was greater in the SN arm (log-rank, P = 0.15). CONCLUSIONS: Preservation of healthy lymph nodes may have beneficial consequences. Axillary dissection should not be performed in breast cancer patients without first examining the sentinel node.

Nonpalpable breast carcinomas: long-term evaluation of 1,258 cases.

INTRODUCTION: In recent decades, a steady improvement in imaging diagnostics has been observed together with a rising adherence to regular clinical breast examinations. As a result, the detection of small clinically occult (nonpalpable) lesions has progressively increased. At present in our institution some 20% of the cases are treated when nonpalpable. The aim of the present study is to analyze the characteristics and prognosis of such tumors treated in a single institution. METHODS: The analysis focused on 1,258 women who presented at the European Institute of Oncology with a primary clinically occult carcinoma between 2000 and 2006. All patients underwent radioguided occult lesion localization (ROLL), axillary dissection when appropriate, whole breast radiotherapy, or partial breast intraoperative irradiation and received tailored adjuvant systemic treatment. RESULTS: Median age was 56 years. Imaging showed a breast nodule in half of the cases and a breast nodule accompanied by microcalcifications in 9%. Microcalcifications alone were present in 17.1% of the cases, whereas suspicious opacity, distortion, or thickening represented the remaining 24.6%. Most tumors were characterized by low proliferative rates (68.9%), positive estrogen receptors (92.3%), and non-overexpressed Her2/neu (91.3%). After a median follow-up of 60 months, we observed 19 local events (1.5%), 12 regional events (1%), and 20 distant metastases (1.6%). Five-year overall survival was 98.6%. CONCLUSIONS: Clinically occult (nonpalpable) carcinomas show very favorable prognostic features and high survival rates, showing the important role of modern imaging techniques.

Intraoperative radiotherapy during breast conserving surgery: a study on 1,822 cases treated with electrons.

Intraoperative radiotherapy with electrons (ELIOT) after conservative surgery for breast carcinoma was introduced at the IEO in 1999 as a research programme. The results on 1,822 patients treated from January 2000 to December 2008 are reported. Women with unicentric primary breast carcinoma of less than 2.5 cm in the largest diameter were assessed by imaging. All patients were treated with breast-conserving surgery (quadrantectomy). ELIOT was delivered by two mobile linear accelerators immediately after breast resection with a single dose of 21 Gy. Local side effects of ELIOT were mainly liponecrosis (4.2%) and fibrosis (1.8%). After a mean follow-up of 36.1 months, 42 women (2.3%) developed a local recurrence, 24 (1.3%) a new primary ipsilateral carcinomas and 26 (1.4%) distant metastases as first event. Forty-six women died (2.5%), 28 for breast carcinoma and 18 for other causes. Five- and ten-year survivals were, respectively, 97.4 and 89.7%. ELIOT appears a promising feature in early breast cancer treated with breast conserving surgery, reducing the exposure of normal tissues to radiations and shortening the radiation course from 6 weeks to one single session.

Pathological complete response after preoperative systemic therapy and outcome: relevance of clinical and biologic baseline features.

In order to evaluate the outcome of patients with breast cancer according to response after primary therapy and according to clinical and biologic baseline features, we identified patients who were treated with preoperative therapy and who underwent surgery at the European Institute of Oncology (IEO), Milan, Italy, between 1995 and 2006. The outcome of patients who achieved pathological complete remission (pCR) and patients with residual disease (RD) at final surgery was analyzed. Of the 687 patients treated with preoperative therapy, we identified 82 patients who achieved pCR (12%) and 605 patients with RD (88%). A statistically significant difference in disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) was observed for patients with pCR compared with those who had RD (5 year DFS 73% vs. 59% P = 0.029; 5 year DDFS 81% vs. 72% P = 0.085; 5 year OS 88% vs. 77% P = 0.033). At the multivariate analysis, for patients achieving pCR, large tumor size (> 5 cm) correlated with worse DFS (HR 3.18; 95% CI 1.34-7.51); clinical nodal involvement was associated with poorer DFS and DDFS (HR 6.94; 95% CI 1.62-29.73 and HR 9.87 95% CI 1.29-75.53, respectively). pCR after preoperative systemic therapy correlated with significant improved outcome. A substantial rate of relapse was observed for patients with large tumors and with clinical nodal involvement at baseline. Further improvement in adjuvant treatment might be warranted.

Intraoperative avidination for radionuclide treatment as a radiotherapy boost in breast cancer: results of a phase II study with (90)Y-labeled biotin.

PURPOSE: External beam radiotherapy (EBRT) after conservative surgery for early breast cancer requires 5-7 weeks. For elderly patients and those distant from an RT center, attending for EBRT may be difficult or impossible. We investigated local toxicity, cosmetic outcomes, and quality of life in a new breast irradiation technique-intraoperative avidination for radionuclide therapy (IART)-in which avidin is administered to the tumor bed and (90)Y-labelled biotin later administered intravenously to bind the avidin and provide irradiation. Reduced duration EBRT (40 Gy) is given subsequently. METHODS: After surgery, 50 (ten patients), 100 (15 patients) or 150 mg (ten patients) of avidin was injected into the tumor bed. After 12-24 h, 3.7 GBq (90)Y-biotin (beta source for therapeutic effect) plus 185 MBq (111)In-biotin (gamma source for imaging and dosimetry) was infused slowly. Whole-body scintigraphy and SPECT/CT images were taken for up to 30 h. Shortened EBRT started 4 weeks later. Local toxicity was assessed by RTOG scale; quality of life was assessed by EORTC QOL-30. RESULTS: Of 35 patients recruited (mean age 63 years; range 42-74) 32 received IART plus EBRT. 100 mg avidin provided 19.5 +/- 4.0 Gy to the tumor bed and was considered the optimum dose. No side-effects of avidin or (90)Y-biotin occurred, with no hematological or local toxicity. Local G3 toxicity occurred in 3/32 patients during EBRT. IART plus EBRT was well accepted, with good cosmetic outcomes and maintained quality of life. CONCLUSIONS: IART plus reduced EBRT can accelerate irradiation after conservative breast surgery.

Male breast cancer.

Diagnosis and treatment modalities for female breast cancer have developed spectacularly in recent years. Unfortunately, this is not the case for male breast cancer. Because the disease is so rare, controlled clinical trials have almost never been performed and treatment is based on findings in women or small series of men. Similarly, while breast cancer in women is diagnosed at an increasingly early stage, male breast cancer is usually diagnosed late, when the chances of cure are diminished. This article reviews what is currently known about male breast cancer, with an emphasis on areas where evidence-based data are scarce. While it is possible that some recent developments in female breast cancer treatment could be applicable to men, but the way forward is to increase awareness of the disease, and for treatment centers to pool patients for inclusion in randomized clinical trials.

A psychosocial cancer phone center staffed by professional psychologists as an integral part of the standard process of care: Its utility during the course of illness.

OBJECTIVE: Major cancer centers cannot ignore psychosocial patient needs that have a significant impact on the process of adjustment to cancer and on compliance to treatments. We introduced a new service, the Gigi Ghirotti Psychosocial Cancer Phone Center (GGPCPC), staffed by professional psychologists, for use by our patients and their relatives. This article investigates its feasibility as a support delivery vehicle for patients in their follow-up phase, and also investigates patients' sense of abandonment related to their care setting. METHOD: A close collaboration was set up between GGPCPC psychologists and European Institute of Oncology (IEO) psychologists. Education and awareness sessions regarding the importance of such a source of psychological support were conducted by IEO psychologists with nurses, secretaries, and receptionists. IEO psychologists input monthly data, recorded on specific paper-tabs by GGPCPC psychologists for each call received by the phone center between March 2007 and March 2009, into a SPSS database. RESULTS: Four hundred and thirty individuals contacted the center mainly to receive psychological support during their treatment phase, when they visited IEO for treatment sessions. Multiple indicators suggest that this telephone support program was feasible and provided support to a broad range of cancer patients. Patients seemed to prefer it to face-to-face psychological support during their treatment-phase. SIGNIFICANCE OF RESULTS: The GGPCPC was demonstrated to be an efficacious support and information delivery vehicle for patients and relatives during the illness course.

A Prospective Pilot Study on Use of Liquid Crystal Thermography to Detect Early Breast Cancer.

Background: Breast cancer is the most common cancer in women. While mammography is the standard for early detection in women older than 50 years of age, there is no standard for younger women. The aim of this prospective pilot study was to assess liquid crystal contact thermography, using the Braster device, as a means for the early detection of breast cancer. The device is intended to be used as a complementary tool to standard of care (sonography, mammography, etc). Patients and Methods: A total of 274 consecutive women presenting at Polish breast centers for prophylactic breast examination were enrolled to receive thermography; 19 were excluded for errors in thermographic image acquisition. The women were divided according to age (n = 135, <50 years; n = 120, ≥50 years). A control population was included (n = 40, <50 years; n = 23, ≥50 years). The primary endpoint, stratified by age group, was the C-statistic for discrimination between breast cancer and noncancer. Results: In women with abnormal breast ultrasound (n = 95, <50 years; n = 87, ≥50 years), the C-statistic was 0.85 and 0.75, respectively (P = .20), for discrimination between breast cancer and noncancer. Sensitivity did not differ (P = .79) between the younger (82%) and older women (78%), while specificity was lower in the older women (60% vs 87%, P = .025). The false-positive rate was similar in women with normal and abnormal breast ultrasound. Positive thermographic result in women with Breast Imaging Reporting and Data System (BIRADS) 4A on ultrasound increased the probability of breast cancer by over 2-fold. Conversely, a negative thermographic result decreased the probability of cancer more than 3-fold. Breast size and structure did not affect the thermography performance. No adverse events were observed. Conclusions: Thermography performed well in women <50 years of age, while its specificity in women ≥50 years was inadequate. These promising findings suggest that the Braster device deserves further investigation as a supporting tool for the early detection of breast cancer in women younger than 50 years of age.

The surgical margin status after breast-conserving surgery: discussion of an open issue.

Hypothesis The best therapeutic approach to the involved or proximal surgical margins has not been defined yet; surgical margins status can influence the local relapse of disease in breast carcinoma, but the impact on overall survival has not been clearly demonstrated. Purpose of this work is to find in the available literature further evidence to guide the therapeutic behaviour in patients with close margins by invasive carcinoma. Design Review of the currently available literature on the evaluation of surgical margins in breast conserving surgery; influence of margin involvement by invasive component or intraductal component. Patients or other participants Literature research by PubMed on the topics of breast carcinoma, conservative surgery and margin definition and status; therapeutic approach to involved margins. Main outcome measure We reviewed the available literature focusing our attention to the definition of clear surgical margins and to the value of the close proximity of margins in relation to the local control of disease and the best therapeutic management of different situations. Results Further evidence is needed on large numbers of patients to understand how to evaluate surgical margins in invasive breast carcinoma. Conclusions There is no consensus on the definition of "clear surgical margins", and the ideal approach to the close proximity of margins has not been defined. It is not sure whether a new surgical procedure is really needed in every case of close proximity of tumor cells to the margins. Radiation therapy could be a good option in the management of these cases, but further evidence is needed to establish the real impact of clear surgical margins on local control of disease and, furthermore, on survival.

Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis.

The biological antagonism between Notch and Numb controls the proliferative/differentiative balance in development and homeostasis. Although altered Notch signaling has been linked to human diseases, including cancer, evidence for a substantial involvement of Notch in human tumors has remained elusive. Here, we show that Numb-mediated control on Notch signaling is lost in approximately 50% of human mammary carcinomas, due to specific Numb ubiquitination and proteasomal degradation. Mechanistically, Numb operates as an oncosuppressor, as its ectopic expression in Numb-negative, but not in Numb-positive, tumor cells inhibits proliferation. Increased Notch signaling is observed in Numb-negative tumors, but reverts to basal levels after enforced expression of Numb. Conversely, Numb silencing increases Notch signaling in normal breast cells and in Numb-positive breast tumors. Finally, growth suppression of Numb-negative, but not Numb-positive, breast tumors can be achieved by pharmacological inhibition of Notch. Thus, the Numb/Notch biological antagonism is relevant to the homeostasis of the normal mammary parenchyma and its subversion contributes to human mammary carcinogenesis.