Stereotactic Radiotherapy in Early-Stage Breast Cancer in Neoadjuvant and Exclusive Settings: A Systematic Review.

INTRODUCTION: Breast cancer (BC) is one of the most common tumors; better screening policies and multidisciplinary approach allow personalized treatment. Radiotherapy (RT) plays a central role in the multimodal approach in BC, and recent evidence has shown the non-inferiority of hypofractionated treatments. The aim of this study was to describe the feasibility and validity of stereotactic RT (SBRT) in BC in a neoadjuvant and exclusive setting. METHODS: A PubMed/MEDLINE and Embase systematic review was conducted to assess the role of radiomics in BC. The search strategy was "breast [All Fields] AND "stereotactic" [All Fields] AND "radiotherapy" [All Fields]" and only original articles referred to BC in humans in the English language were considered. RESULTS: A total of 2,149 studies were obtained using the mentioned search strategy on PubMed and Embase. After the complete selection process, a total of 12 papers were considered eligible for the analysis of the results. SBRT in BC was described in 8 studies regarding neoadjuvant approach and 4 papers regarding exclusive approach. CONCLUSIONS: Relative low toxicity rates, the reduced treatment volumes in the neoadjuvant setting, and the possibility to replace surgery when not feasible in exclusive setting resulted to be main advantages for SBRT in BC. Current evidence shows that both the neoadjuvant and the definitive settings seem to be promising clinical scenarios for SBRT, especially for EBC.

Surgical removal of the breast primary for patients presenting with metastases - where to go?

One of the leading causes of cancer mortality in women worldwide is breast malignancy. In western countries 3.5-10% of newly diagnosed patients are found to have metastases at diagnosis (MBC). Despite the epidemiological burden of this condition, there are no guidelines on how to manage breast cancer patients presenting with systemic spread; for these patients treatment planning is essentially based on personal preferences rather than reliable clinical data. Through this review we outline the currently available evidence and discuss the role of surgical resection of the primary breast cancer in MBC.

Breast cancer in elderly women. Optimizing the treatment.

The elderly population is on the rise. Breast cancer is the most common cancer in western women and its incidence increases with age. Despite the epidemiological burden of this condition, there is a lack of knowledge regarding the management of older patients, as treatment planning is mainly based on personal preferences rather than hard data. Older women are often offered sub-optimal treatment when compared to their younger counterpart at any particular stage. This is due to various reasons, including the lack of scientific evidence from well-conducted clinical trials. Reluctance to prescribe systemic treatments may be explained by the complexity of cost-benefit evaluations in such patients. It is also an ethical dilemma to decide how aggressive one should be when it comes to treat cancer in the elderly in view of the higher rate of cognitive impairment and specific patients' expectations. This paper reviews the currently available evidence and attempts presenting and discussing chemoprevention of breast cancer, risk and benefit of hormone replacement therapy and the various treatment options for older women with breast cancer.

Elements related to heterogeneity of antibody-dependent cell cytotoxicity in patients under trastuzumab therapy for primary operable breast cancer overexpressing Her2.

Preliminary results from a pilot trial on trastuzumab's mechanism of action against operable breast tumors overexpressing Her2 suggested a role for antibody-dependent cell cytotoxicity (ADCC). To examine factors affecting ADCC intensity and variability, we extended this study to the phenotypic and functional analysis of circulating mononuclear cells in 18 patients. ADCC was induced by trastuzumab therapy in 15 of 18 patients (83%). Inability to develop ADCC in three patients did not depend on inadequate levels of trastuzumab because further increase in its concentration in vitro was ineffective. Rather, susceptibility to develop ADCC was fairly predicted by test with trastuzumab before therapy and was correlated to the number of lymphocytes coexpressing CD16 and CD56. Phenotypic analysis at the end of ADCC evaluating down-regulation of CD16, and up-regulation of CD69 and CD107a, confirmed that natural killer (NK) cells and CD56(+) T cells were involved in productive engagement of trastuzumab. Also, the killing efficiency of CD16(+) lymphocytes was influenced by 158 V/F polymorphism of Fc gamma RIII (CD16), whereas variations of CD247 on NK cells were consistent with trends between ADCC before and after therapy. Complete pathologic response was observed in one patient showing ADCC of outstanding intensity, whereas four cases of partial response showed intermediate ADCC; none of the three patients unable to mount ADCC had significant tumor regression. These data indicate that quantity and lytic efficiency of CD16(+) lymphocytes are major factors for ADCC induction by trastuzumab, and confirm that breast cancer responses to short-term trastuzumab monotherapy may depend on involvement of the ADCC mechanism.

Full-dose intraoperative radiotherapy with electrons in breast surgery: broadening the indications.

HYPOTHESIS: Although postoperative fractionated radiotherapy (PFR) remains the standard method for conservative treatment of breast carcinomas, widespread experience in the use of full-dose intraoperative radiotherapy with electrons (ELIOT) merits its application in novel clinical situations, although long-term results of ongoing clinical trials have not been fully reported. DESIGN: Retrospective case series. SETTING: Division of breast surgery in a comprehensive cancer center. PATIENTS: From June 1999 to September 2003 ELIOT was used as the sole radiotherapy in 355 patients with unifocal invasive carcinoma who were candidates for breast-conserving surgery and most of whom were participating in an ongoing institutional trial. In a group of patients in whom PFR was not considered safe or feasible (because of previous mantle field irradiation for Hodgkin disease, cosmetic breast augmentation, severe cardiopathy, large hypertrophic scarring from skin burns, vitiligo, and geographic or social obstacles), ELIOT was performed outside of the ongoing trial. RESULTS: No particular adverse effects, unusual acute reactions, late sequelae, and local or systemic events were noted in these patients after a mean follow-up of 27.3 months. CONCLUSIONS: In appropriated selected patients, when it is critical to perform PFR after breast-conserving therapy, a single dose of ELIOT may be considered to avoid mastectomy, reduce potential treatment toxicity, improve quality of life, and resolve logistic problems. The long-term results of ongoing clinical trials will further delineate patients in whom ELIOT may replace PFR.

Optimising surgical management of elderly cancer patients.

BACKGROUND: Elderly population is on rise. It is an ethical dilemma how aggressive one should be when it comes to treat cancer in elderly. Presumed fear of increased postoperative morbidity and mortality has resulted in delivery of sub-optimal cancer surgery. METHODS: In this review article we visit physiology of the aged, tools available to assess surgical risks in oncogeriatric patients, and current practice in the management of common cancers encountered in surgical oncology, with the view of increasing awareness on optimising surgical management of senior patients with cancer. A pubmed search for cancer, surgery, elderly, was carried out. RESULTS: Cancer is on rise with increasing age predominantly affecting breast, gastrointestinal tract and lung. Increasingly more surgeons are offering surgery to elderly cancer patient but selection bias is prevalent. Available data reflect short and long-term outcome of cancer surgery in elderly is not greatly different to that of younger patient. Declining physiological reserve along with inability to respond adequately to physiological stress are salient age related changes. Comprehensive Geriatric Assessment (CGA) is not tested in surgical patient. There is need for a tool to define individualised operative risk. Preoperative assessment of cancer in elderly is designed to offer this information based on functional status of an individual utilising currently available tools of risk assessment. CONCLUSION: All elderly cancer patients should be offered optimal treatment depending on their functional status not on chronological age. Oncogeriatric patient would benefit from dedicated multidisciplinary approach. Recruitment of elderly cancer patients to more clinical trials is needed to enhance our knowledge and to offer optimum treatment to this unique subgroup.

Sentinel node biopsy in breast cancer: early results in 953 patients with negative sentinel node biopsy and no axillary dissection.

Sentinel node biopsy in patients with breast carcinoma accurately predicts the axillary nodal status. However, in some 6% of patients with negative sentinel nodes the remaining axillary nodes harbour metastases. Our purpose was to observe a large number of patients who did not undergo an axillary dissection after a negative sentinel node biopsy for the appearance of overt axillary metastases. 953 patients treated from 1996 to 2000, with negative sentinel nodes not submitted to axillary dissection, were followed-up to 7 years, with a median follow-up of 38 months. Fifty-five unfavourable events occurred among the 953 patients, 37 (4%) related to the primary breast carcinoma. Three cases of overt axillary metastases were found: they received total axillary dissection and are presently alive and well. The 5 year overall survival rate of the whole series was 98%. Patients with negative sentinel node biopsies not submitted to axillary dissection show during follow-up a rate of overt axillary metastases that is lower than that expected.

Sentinel node biopsy in elderly breast cancer patients.

INTRODUCTION: Even if an increasing body of data suggests that sentinel node biopsy is a safe and accurate method of screening the axillary nodes for metastasis, there is a tendency to perform less extensive or no axillary surgery in older breast cancer women. The aim of this study therefore was to assess the safety of the procedure as well as the rate of axillary recurrences after sentinel node biopsy in this older population. METHODS: Between May 1997 and March 2003, 241 consecutive elderly patients (>or=70 years) with operable breast cancer up to 3 cm and clinically negative axillary lymph nodes were entered into this study. Sentinel node was identified using 5-10 MBq of 99 mTc-labeled colloidal particles and examined with immediate complete intraoperative frozen-section. RESULTS: The sentinel node identification rate was 100%. Ninety-seven percent of the patients underwent breast-conserving surgery. In 90 out of 241 patients (37.3%) the sentinel node was positive for metastasis and complete axillary dissection was immediately performed. In 56.7% of these patients the sentinel node was the only lymph node involved. Micrometastasis in the sentinel node was detected in 30 of the 90 (33.3%) patients. A total of 151 patients (62.7%) were sentinel node negative and no further surgical treatment was done. There were no axillary recurrences at a median followup of 29.7 months (range 3-87 months). The overall survival of this group of patients was 97.9%. CONCLUSIONS: Sentinel node biopsy is a safe and accurate method of screening the axillary nodes for elderly women with operable breast cancer less than 3 cm. The absence of axillary recurrences after sentinel node biopsy without complete axillary dissection supports the hypothesis.

Pilot study of the mechanism of action of preoperative trastuzumab in patients with primary operable breast tumors overexpressing HER2.

PURPOSE: To elucidate the mechanism by which trastuzumab, a humanized monoclonal antibody against HER2 with proven survival benefit in women with HER2-positive metastatic breast cancer, mediates its antitumor activity. EXPERIMENTAL DESIGN: A pilot study including 11 patients with HER2-positive tumors treated in a neo-adjuvant setting with trastuzumab was performed. Trastuzumab was administered i.v. at a dose of 4 mg/kg followed by three weekly i.v. doses of 2 mg/kg. The primary tumor was surgically removed 7 days after the last treatment. Surgical samples, tumor biopsies, and lymphocytes from these patients were collected for biological studies. RESULT: Clinical data indicated one complete pathological remission and four partial remissions using RECIST (Response Evaluation Criteria in Solid Tumors). Trastuzumab was well tolerated and neither serious adverse events nor changes in cardiac function were observed during this short-term treatment and after surgery. The biological data showed that, independent of response, (a) all patients showed high levels of circulating trastuzumab; (b) saturating level of trastuzumab was present in all of the tumors; (c) no down-modulation of HER2 was observed in any tumors; (d) no changes in vessel diameter was observed in any tumors; (e) no changes in proliferation was observed in any tumors; and (f) a strong infiltration by lymphoid cells was observed in all cases. Patients with complete remission or partial remission were found to have a higher in situ infiltration of leukocytes and a higher capability to mediate in vitro antibody-dependent cellular cytotoxicity activity. CONCLUSIONS: The results of this pilot study argue against trastuzumab activity in patients through down-modulation of HER2 but in favor of antibody-dependent cellular cytotoxicity guiding efforts to optimize the use of trastuzumab in breast cancer patients.

Clinicopathologic characteristics of 143 patients with synchronous bilateral invasive breast carcinomas treated in a single institution.

BACKGROUND: Synchronous bilateral invasive breast carcinoma (SBIBC) ranged in incidence from 0.3% to as high as 12%. METHODS: Between April 1997 and February 2003, 143 consecutive patients with SBIBC were treated at the European Institute of Oncology (Milan, Italy). Their information was collected prospectively in a database. The bilateral tumors were divded into left and right tumors. Tumor size, histology, grade, lymph node status, estrogen (ER) and progesterone receptor (PgR) status, HER-2 expression, peritumoral vascular invasion (PVI), Ki-67 expression, extensive in situ component (EIC), and multifocality between the two groups were analyzed. During the same time period, 6218 patients with unilateral invasive breast carcinoma (UIBC) were analyzed in the same manner for comparison with the patients with SBIBC. RESULTS: There were no significant differences between left and right tumors, and the observed histopathologic agreement within the same patient was significantly superior than statistically expected for all characteristics except size, lymph node status, and multifocality. When compared with patients with UIBC, patients with SBIBC were more likely to present with smaller tumors and showed a higher frequency of invasive lobular carcinoma, lower histologic grade, higher rate of ER and PgR positivity, and lower PVI and Ki-67 expression. CONCLUSIONS: The high concordance of histopathologic characteristics between SBIBC within the same patient could reflect a particular hormonal environment that influenced either the initiation and development of these lesions simultaneously and independently from the single or multi-clonal origin, either a less aggressive biological behavior compared with UIBC. In particular, the strong agreement of the observed EIC in SBIBC within the same patient seemed to definitively exclude the metastatic origin of these tumors.

Breast carcinoma in elderly women: features of disease presentation, choice of local and systemic treatments compared with younger postmenopasual patients.

BACKGROUND: Aging remains one of the single greatest risk factors for the development of new breast carcinoma. The aim of the study was to evaluate the relation between biologic features at first diagnosis of breast carcinoma and treatment choice for postmenopausal women > or = 50 years to optimize treatment in the elderly. METHODS: The sample included 2999 consecutive postmenopausal patients referred for surgery at the European Institute of Oncology (Milan, Italy) from April 1997 to February 2002. The patients were grouped according to age: young postmenopausal (YPM; 50-64 years, n = 2052), older postmenopausal (OPM; 65-74, n = 801), and elderly postmenopausal (EPM; > or = 75, n = 146). RESULTS: EPM patients referred to surgery had larger tumors compared with YPM patients (pT4: 6.7% vs. 2.4%) as well as greater lymph node involvement (lymph node positive: 62.5% vs. 51.3%). EPM patients showed a higher degree of estrogen and progesterone receptor expression (P < 0.01), less peritumoral vascular invasion (P < 0.01), and less HER-2/neu expression (P < 0.01) than YPM patients. Comorbidities were more often recorded for elderly patients (72% EPM vs. 45% YPM; P < 0.001), did not influence surgical choices, and were similar across groups (breast conservation: 73.9%, 76.9%, and 72.9%, respectively). No systemic therapy (either chemotherapy or endocrine therapy) was recommended for 19.1% of the EPM compared with 5.4% and 4.7% of the two other groups. CONCLUSIONS: In spite of larger tumor size at presentation, older patients had tumors with more favorable biologic characteristics, when compared with younger postmenopausal patients. Reluctance to prescribe systemic treatments was due to the complexity of evaluation for these patients. Taking into account the data from the current study and given the climate of uncertainty regarding optimal treatment, the authors decided to individualize care on the basis of biologic characteristics, comorbidity, social support, functional status, and patient preferences. Trials of tailored adjuvant therapy should be a health care priority.

Male breast cancer: a special therapeutic problem. Anything new? (Review).

Carcinoma of the male breast (MBC) is an uncommon phenomenon, accounting for <1% of all malignancies in man. It represents a biologically heterogeneous disorder, and its clinical course may vary from indolent and slowly progressive to rapidly metastatic disease. Most of our current knowledge regarding its biology, natural history, and treatment strategies has been extrapolated from its female counterpart. Information regarding prognostic relevance of new molecular markers is limited. At the European Institute of Oncology we performed a study showing data in which p21Waf1 and p27Kip1 proteins were evaluated in a series of male breast cancer patients. Our data suggest that the immunohistochemical evaluation of p21Waf1 and p27Kip1 expression in male breast carcinomas may be a further useful marker for selecting patients who express functional proteins that can be predictive for the most efficient endocrine response. Moreover, searching for more conservative treatment, we introduced in our clinical practice sentinel node biopsy, and if present, sentinel node biopsy of the internal mammary chain. The potential clinical implications of complete nodal staging are far-reaching, and give us a major new opportunity to stratify male patients with breast cancer for appropriate surgery as well as giving valuable prognostic information. Male breast cancer has biological differences compared with female breast cancer. It responds to hormonal manipulation and chemotherapy, but optimal treatment regimens in males are unknown. By analogy to the female breast cancer, post-mastectomy radiotherapy should be proposed in case of advanced T stage and/or lymph node positivity (considering the small volume of the male mammary gland, we suggest post-mastectomy irradiation in case of T >1 cm and/or presence of >1 metastatic axillary lymph node). Breast conserving surgery, performed in selected cases of male breast cancer, should be always followed by radiotherapy. Despite a wealth of small retrospective studies on MBC, its rarity means there is a lack of prospective randomized controlled treatment trials, which needs to be addressed if significant advances are to be made in the treatment of this unusual challenging disease.

Sentinel lymph node metastasis in microinvasive breast cancer.

BACKGROUND: Ductal carcinoma in situ with microinvasion (DCISM) is a separate pathological entity, distinct from pure ductal carcinoma in situ (DCIS). DCISM is a true invasive breast carcinoma with a well-known metastatic potential. Currently, there is controversy regarding the indication for complete axillary dissection (CAD) to stage the axilla in patients with DCISM. The role of CAD is questioned given its morbidity and reported low incidence of axillary involvement. Sentinel lymph node biopsy (SLNB) may obviate the need for CAD in these patients without compromising the staging of the axilla and the important prognostic information. METHODS: From March 1996 to December 2002, 4602 consecutive patients with invasive breast carcinoma underwent SLN biopsy. Of these, 41 patients with DCISM were selected. RESULTS: Metastasis in the SLN were detected in 4 of 41 (9.7%) patients. Two of the 4 patients had only micrometastasis in the SLN. In three patients, the SLN was the only positive node after CAD. CONCLUSIONS: SLN biopsy should be considered as a standard procedure in DCISM patients. SLNB can detect nodal micrometastasis and accurately stage the axilla avoiding the morbidity of a CAD. Complete AD may not be mandatory if only the SLN contains micrometastatic disease. Informed consent is very important in the decision not to undergo CAD.

A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer.

BACKGROUND: Although numerous studies have shown that the status of the sentinel node is an accurate predictor of the status of the axillary nodes in breast cancer, the efficacy and safety of sentinel-node biopsy require validation. METHODS: From March 1998 to December 1999, we randomly assigned 516 patients with primary breast cancer in whom the tumor was less than or equal to 2 cm in diameter either to sentinel-node biopsy and total axillary dissection (the axillary-dissection group) or to sentinel-node biopsy followed by axillary dissection only if the sentinel node contained metastases (the sentinel-node group). RESULTS: The number of sentinel nodes found was the same in the two groups. A sentinel node was positive in 83 of the 257 patients in the axillary-dissection group (32.3 percent), and in 92 of the 259 patients in the sentinel-node group (35.5 percent). In the axillary-dissection group, the overall accuracy of the sentinel-node status was 96.9 percent, the sensitivity 91.2 percent, and the specificity 100 percent. There was less pain and better arm mobility in the patients who underwent sentinel-node biopsy only than in those who also underwent axillary dissection. There were 15 events associated with breast cancer in the axillary-dissection group and 10 such events in the sentinel-node group. Among the 167 patients who did not undergo axillary dissection, there were no cases of overt axillary metastasis during follow-up. CONCLUSIONS: Sentinel-node biopsy is a safe and accurate method of screening the axillary nodes for metastasis in women with a small breast cancer.

Preoperative assessment of cancer in elderly patients: a pilot study.

The aim of this study was to assess the face validity and practical utility of the Preoperative Assessment of Cancer in the Elderly (PACE) tool in a sample of elderly patients with cancer. A prospective series of such patients with breast, colorectal, upper gastrointestinal, and other cancers were interviewed using the PACE; patients were scored for presurgical assessment using standard measures, including American Society of Anesthesiologists physical status, the Physiological and Operative Severity Score for Enumeration of Mortality and Morbidity (POSSUM), the Portsmouth POSSUM, and World Health Organization performance status before undergoing standard surgical management. Short-term surgical outcome (in terms of mortality and morbidity) and cancer site-specific data were collected to identify the risk groups. Seventy-two patients took part in the study (participation rate of 97%). The interview in which the questionnaire was given was found to take 20 minutes on average. Face validity was demonstrated, with clear comprehension of the requirements of the PACE being shown by all patients. The 2 groups identified according to the presence (n = 24) or absence (n = 48) of postoperative mortality/morbidity were compared according to components of the PACE. The study identified possible associations between these components and postoperative morbidity. No postoperative mortality was recorded; however, 24 patients (33%) had surgical complications. Performance status and Activities of Daily Living classification were found to be significantly related to postoperative short-term morbidity, whereas a lower score on the Mini Mental State Examination and a higher score on the Geriatric Depression Scale were found to be related to postoperative morbidity, although they did not achieve statistical significance because of the small numbers involved. The authors have demonstrated the practicality and face validity of PACE and identified some associations with postoperative morbidity. Based on the findings of this pilot study, a large, international multicenter trial is planned.

Stage migration after biopsy of internal mammary chain lymph nodes in breast cancer patients.

BACKGROUND: Involvement of the internal mammary chain lymph nodes (IMNs) is associated with worsened prognosis in breast cancer. Use of lymphoscintigraphy to visualize sentinel nodes reveals that IMNs often receive lymph from the area containing the tumor. METHODS: We biopsied IMNs in 182 patients because there was radiouptake to the IMNs or because the tumor was located in the medial portion of the breast. After tumor removal, pectoralis major fibers were divided to expose intercostal muscle. A portion of intercostal muscle adjacent to the sternum was removed. Lymph nodes and surrounding fatty tissue in the intercostal space were freed, removed, and analyzed histologically. The pleural cavity was breached in four cases (2.2%), with spontaneous resolution. RESULTS: IMNs were found in 160 (88%) of 182 patients; 146 (94.4%) were negative and 14 (8.8%) were positive. The latter received internal mammary chain radiotherapy. The axilla was negative in 4 of 14 cases and positive in 10. CONCLUSIONS: IMNs can be quickly and easily removed via the breast incision with insignificant risk and no increase in postoperative hospitalization. The patients with a positive IMN migrated from N0 (4 cases) or N1 (10 cases) to N3, prompting modification of both local (radiotherapy to internal mammary chain) and systemic treatment; without IMN sampling, they would have been understaged.

Dominant TCR-alpha requirements for a self antigen recognition in humans.

TCR-alpha and -beta chains are composed of somatically rearranged V, D, and J germline-encoded gene segments that confer Ag specificity. Recent crystallographic analyses revealed that TCR-alpha has more contacts with peptide than TCR-beta, suggesting the possibility that peptide recognition predominantly relies on TCR-alpha. T cells specific for the self Ag Melan-A/MART-1 possess an exceptionally high precursor frequency in human histocompatibility leukocyte Ag-A2 individuals. This provided a unique situation for assessment of the structural relationship between TCR and peptide/MHC ligand at both the pre- and postimmune levels. Molecular and phenotypic analysis of many different Melan-A-specific T cell populations revealed that a structural constraint is imposed on the TCR for engagement with Melan-A peptides presented by HLA-A2, namely the highly preferential use of a particular TCRAV segment, AV2. Examination of CD8 single-positive thymocytes indicated that this preferential use in forming the Melan-A-specific TCR is mainly imposed by intrathymic positive selection. Our data demonstrate a dominant function of TCRAV2 segment in forming the TCR repertoire specific for the human self Ag Melan-A/MART-1 and support the view that Ag recognition is mediated predominantly by TCR-alpha.