The prevalence and clinical relevance of tumor-infiltrating lymphocytes (TILs) in ductal carcinoma in situ of the breast.

Background: Tumor-infiltrating lymphocytes (TILs) are a robust prognostic adjunct in invasive breast cancer, but their clinical role in ductal carcinoma in situ (DCIS) has not been ascertained. Patients and methods: We evaluated the prevalence and clinical relevance of TILs in a well annotated series of 1488 consecutive DCIS women with a median follow-up of 8.2 years. Detailed criteria for TILs evaluation were pre-defined involving the International Immuno-Oncology Biomarker Working Group. TILs percentage was considered both as a continuous and categorical variable. Levels of TILs were examined for their associations with ipsilateral breast event (IBE), whether in situ or invasive. Results: Of the 1488 patients with DCIS under study, 35.1% had <1%, 58.3% 1-49% and 6.5% ≥50% peri-ductal stromal lymphocytes. The interobserver agreement in TILs evaluation, measured by the intraclass correlation coefficient (ICC) was 0.96 (95% CI 0.95-0.97). At univariable analysis, clinical factors significantly associated with TILs (P ≤0.001) were intrinsic subtype, grade, necrosis, type of surgery. Her-2 positive DCIS were more frequently associated with TILs (24% of patients with TILs ≥50%), followed by the triple negative (11%), Luminal B/Her-2 positive (9%) and Luminal A/B subtypes (1%) (P < 0.0001). We did not find any association between TILs as a continuous variable and the risk of IBEs. Likewise, when patients were stratified by TILs percentage (<1%, between 1% and 49.9%, and ≥50%), no statistically significant association was observed (10-year cumulative incidence of IBEs: 19%, 17.3%, and 18.7% respectively, P = 0.767). Conclusion: TILs occur more frequently in the Her-2 positive DCIS. Although we did not find a significant association between TILs and the 10-year risk of IBE, our data suggest that immunotherapies might be considered in subsets of DCIS patients.

High Ki67 predicts unfavourable outcomes in early breast cancer patients with a clinically clear axilla who do not receive axillary dissection or axillary radiotherapy.

AIM: Axillary dissection is increasingly forgone in early breast cancer patients with a clinically negative axilla. The GRISO 053 randomised trial recruited 435 patients of age over 45 years, tumour ≤1.4 cm and clinically negative axilla, to assess the importance of axillary radiotherapy versus no axillary radiotherapy in patients not given axillary dissection. In the present study on a subgroup GRISO cases our aim was to assess the prognostic importance of tumour biological factors after more than 10 years of follow-up. METHODS: We retrospectively assessed biological factors in a subgroup of 285 GRISO cases (145 given axillary radiotherapy; 140 not given axillary radiotherapy) with complete biologic, therapeutic and follow-up information, using multivariable Cox proportional hazards regression modelling. RESULTS: Only 10-year cumulative incidence of distant metastasis was lower in the axillary radiotherapy (1%) than no axillary radiotherapy arm (7%) (p=0.037). Irrespective of study arm, hormone receptor positivity had significantly favourable effects on 10-year disease-free survival (DFS) and overall survival. human epidermal growth factor receptor 2 (HER2)-positive and triple-negative subtypes were associated with lower 10-year DFS (60% and 76%, respectively) than luminal A (96%) and B (91%) (p=0.001). Ten-year DFS for high (≥14%) Ki67 cancers was lower than for low Ki67 cancers (p=0.027); however, this effect was mainly confined to the no axillary radiotherapy arm. CONCLUDING STATEMENT: For patients with clinically node-negative small breast cancer not given axillary dissection, 10-year DFS is worsened by HER2 positivity, triple-negative phenotype and high Ki67. Axillary radiotherapy counteracts the negative prognostic effect of high Ki67 in patients not receiving axillary dissection.

Electronic portal imaging registration in breast cancer radiotherapy verification: analysis of inter-observer agreement among different categories of health practitioners.

Electronic portal imaging (EPI) is commonly used to identify and correct for inter-fraction variability in tangential breast irradiation. Based on the institutional policy, EPI registration is performed by either radiation oncologist or therapist. Little data is available on the inter-observer agreement in EPI registration among different health practitioners. The aim of our study was to analyze inter-observer agreement among radiation oncologists and therapists in the evaluation of EPI for breast cancer radiotherapy verification. EPI data of 40 patients treated with tangential fields were independently reviewed by a radiation oncologist (on-line, just before treatment) and off-line by junior and senior therapists. Displacement of each EPI image with respect to the digital reconstructed radiographs (DRRs) was quantified using manual EPI registration based on bony marks with the corresponding DRRs. Agreement between observers was evaluated using weighted Cohen's Kappa statistics. In 95% out of 720 EPI-DRR comparisons, the EPI-DRR misalignment was < 5 mm. The difference between observers was < 2 mm in 666 (92.5%) out of all 720 delta values. High inter-observer agreement was found, with weighted Cohen's Kappa values attesting evaluation overlaps ranging from moderate (among therapists) to almost perfect (among radiation oncologist and therapists). The high agreement among the observers demonstrated the precision of breast localization using EPI. These findings suggest that routine EPI-based patient set-up verification in breast cancer radiotherapy can be safely entrusted to trained therapists (supervision should be assured based on the local tasks definition). Our study might be useful in quality assurance and in the optimization of workload in the radiotherapy departments. They might allow for wider implementation of complex and evolving radiotherapy technologies.

Breast cancer subtypes and outcome after local and regional relapse.

BACKGROUND: To evaluate the outcome of breast cancer patients after locoregional recurrence (LRR) according to tumor biological features evaluated at first diagnosis and at the time of recurrence. PATIENTS AND METHODS: We collected information on all consecutive breast cancer patients operated at the European Institute of Oncology between 1994 and 2005. The tumor characteristics and subsequent outcome of patients who experienced LRR were analyzed. RESULTS: Two hundred and seventy nine patients with LRR were identified, 197 and 82 patients with local and regional recurrence respectively. The overall discordance rate between primary cancer and LRR was 9% for estrogen receptor expression, 22% for progesterone receptor and 4% for human epidermal growth factor receptor 2. For patients with regional recurrence, the risk of distant metastasis was significantly higher compared with local relapse in case of late recurrence (hazard ratio [HR] = 2.76; 95% CI 1.31-5.85). Patients with triple-negative breast cancer at LRR experienced a higher risk of subsequent relapse (HR 2.87 [1.67-4.91]) and death (HR 2.00 [1.25-3.19]). CONCLUSION: LRR correlates with a high risk of subsequent events and death in particular in patients with triple-negative subtype.

Nuevo TNM: clasificación del cáncer de mama propuesta por el Istituto Europeo di Oncologia de Milan, Italia / No disponible

La clasificación TNM de la Unión Internacional Contra elCáncer (TNMUICC) tiene más de 60 años desde su primera versióny por tanto, necesita un replanteamiento y una actualización.El Istituto Europeo di Oncologia (IEO) de Milán ha desarrolladouna nueva clasificación denominada TNMIEO, surgidade la aplicación en más de 6.000 casos con cáncer de mamadurante 3 años. Cirujanos, oncólogos médicos, radioterapeutas,anatomopatólogos, radiólogos y otros especialistas delIEO han contribuido a la elaboración de esta nueva clasificación,cuyas modificaciones principales en relación a la actualTNMUICC se sintetizan en cinco aspectos principales: a) uso deun lenguaje más riguroso y menos ambiguo, comprensible inclusopara los pacientes; b) descripción del tamaño exacto deltumor en lugar de categorías, lo cual lleva a un pronóstico máspreciso; c) especificación del estadio ganglionar del tumor; d)del número de ganglios linfáticos examinados; y e) de la localizaciónde las metástasis a distancia(AU)

Over 60 years after the first edition, the TNM classificationby the International Union Against Cancer (UICCTNM) needs tobe updated. The European Institute of Oncology (EIO) in Milan,Italy, developed a new classification called “EIOTNM” thatwas used on more than 6,000 cases of breast cancer over aperiod of 3 years. IEO surgeons, medical oncologists, radiationoncologists, pathologists, radiologists and other specialistscontributed to this new classification. Its main novelties comparedto the present UICCTNM can be summarized in five mainpoints: a) use of a more precise, less ambiguous vocabulary,that can be understood even by patients; b) description of theexact tumor size instead of cathegories, which leads to a moreprecise prognosis; c) specification of tumor nodal status; d)number of examined lymph nodes; and e) site of distant metastases(AU)

Long-term oncological results of breast conservative treatment with oncoplastic surgery.

Oncoplastic surgery combining breast conservative treatment (BCT) and plastic surgery techniques may allow more extensive breast resections and improve aesthetic outcomes, but no long-term oncological results have been published. Long-term oncologic results of 148 consecutive BCT with concomitant bilateral plastic surgery have been analysed and were compared to historical data of BCT trials. Median follow-up was 74 months. Complete excision was obtained in 135 patients (91%); focally involved margins in 8 (5%); and close (<2 mm) margins in 5 (3%). Five patients developed ipsilateral recurrence (3%), 19 (13%) developed distant metastasis and 11 patients died (7.53%). Patients with tumours larger than 2 cm were at greater risk of local recurrences and distant metastasis. Long-term oncologic results of BCT with oncoplastic surgery are comparable with the results of BCT randomized trials.

Early detection of cancer: ideas for a debate.

Even if the overall number of cancer is increasing, the mortality has started to decrease in the Western World. The role of early detection in this decrease is a matter of debate. To assess its impact on mortality it is important to distinguish between diagnosis of cancer in symptomatic patients, and early detection in asymptomatic individuals who may self-refer or who may be offered ad hoc or systematic screening. The policies for early detection and screening vary greatly between European countries, despite many similarities in their cancer burden, and this partly reflects the uncertainties surrounding asymptomatic testing for cancer. A Task Force of European expert, held in Azzate (VA), Italy, established to address these issues, acknowledged the need for more research in the field of individual risk assessment since general statistics are more and more perceived as inadequate to design personal early detection plans. The group also recognised that combinations of early detection and screening will enforce the effectiveness of new treatments in curbing mortality curves, although policies will vary with different cancers.

Breast cancer diagnosed during pregnancy and lactation: biological features and treatment options.

AIM OF THE STUDY: Assessment of biological features and treatment of patients with breast cancer presenting during pregnancy or lactation. PATIENTS AND METHODS: Immunohistochemical analysis of estrogen receptor (ER) and progesterone receptor (PgR), Ki-67, HER2/neu, prognostic markers, treatment and follow-up of 21 patients with breast cancer during pregnancy (BCdP) and 17 with breast cancer during lactation (BCdL) are presented. RESULTS: Median age was 36 and 33 years, median tumour size was 2.4 and 2.5 cm, axillary lymph nodes were positive in 10 of 21 pregnant patients and 11 of 17 lactating patients, respectively. Both ER and PgR were not expressed in six of 21 pregnant women and nine of 17 lactating patients. All the six women who had concurrent diagnosis of breast cancer and pregnancy (first trimester) preferred termination of pregnancy although an alternative option was discussed. Five patients received anthracycline containing chemotherapy during the second and third trimester with no complications for patient and child. Conservative surgery was performed in 15 of 21 patients during pregnancy with no local reappearance after a median follow-up of 24 months. Three pregnant women underwent lymphoscintigraphy and sentinel lymph node biopsy. CONCLUSIONS: Patients who had concurrent diagnosis of breast cancer and pregnancy (early first trimester) preferred termination of pregnancy to allow easier completion of treatment. Conservative surgery was safe also in women with BCdP. Sentinel node biopsy might be considered for pregnant patients with a clinically negative axilla.

Irradiation with standard tangential breast fields in patients treated with conservative surgery and sentinel node biopsy: using a three-dimensional tool to evaluate the first level coverage of the axillary nodes.

Recent data show that axillary coverage can be obtained, but only through a selective CT-based treatment planning, as standard tangential fields are inadequate to deliver therapeutic doses. Currently, the replacement of axillary dissection with new techniques, such as sentinel node (SN) biopsy, makes it necessary to re-address the question about the real role of axillary irradiation, complicated by the differences in the anatomy of dissected and undissected axillary regions. The purpose of this paper is the dosimetric analysis of first axillary level coverage in standard irradiation of 15 breast-cancer patients treated with quadrantectomy and SN biopsy (negative finding). During surgery a clip on the site of the SN was positioned, marking the caudal margin of first axillary level. After the breast treatment plan was completed, the first axillary level was contoured on CT scans, from the site of the surgical clip up to the sternal manubrium, for coverage analysis with dose-volume histograms (DVHs) and three-dimensional isodose visualization. The maximum dose mean ranged from 5% to 80% of the prescribed dose (mean value 48.7%). The mean total dose received by the volume of interest was lower than 40 Gy in all but one patient. No patient had total irradiation of first nodal level; only one patient had 35% of the volume enclosed in the 100% isodose. Our analysis lead to the conclusion that therapeutic doses are not really delivered to first level axillary level nodes by a standard tangential field technique, and that specific treatment planning and beam arrangement are required when adequate coverage is necessary.

Avoiding axillary dissection in breast cancer surgery: a randomized trial to assess the role of axillary radiotherapy.

BACKGROUND: The need to dissect axillary nodes in patients with early breast cancer and clinically negative axilla remains controversial. The aim of the study was to assess the role of axillary radiotherapy (RT) in reducing axillary metastases in patients with early breast cancer who did not receive axillary dissection. PATIENTS AND METHODS: From 1995 to 1998, 435 patients over 45 years old with breast cancer up to 1.2 cm and no palpable axillary nodes were randomized 214 to breast conservation without axillary treatment and 221 to breast conservation plus axillary RT. RESULTS: After a median follow-up of 63 months, overt axillary metastases were fewer than expected: three cases in the no axillary treatment group (1.5%) and one in the RT group (0.5%). Expected cases were 43 in the no axillary treatment group and 10 in the RT group. Rates of distant metastases and local failures were low, and 5-year disease free survival was 96.0% (95% confidence interval, 94.1%-97.9%) without significant differences between the two arms. CONCLUSIONS: This study suggests that occult axillary metastases might never become clinically overt and axillary dissection might be avoided in patients with small carcinomas and a clinically negative axilla. Axillary RT seems to protect the patients from axillary recurrence almost completely.

Development of axillary surgery in breast cancer.

Axillary surgery is a critical part of the treatment of breast carcinoma: its importance is related to the staging of disease, prescription of adjuvant therapy and prognosis. For years, complete axillary dissection has remained the standard approach to breast cancer lymphatic staging; its value is still high, but the development of sentinel-node biopsy has significantly changed the indication of the procedure. We discuss the evolution of axillary surgery in breast cancer.

Thyroid disease in northern Italian children born around the time of the Chernobyl nuclear accident.

BACKGROUND: The Chernobyl nuclear accident of 1986 caused a dramatic increase in the incidence of thyroid cancers in exposed children in Belarus. Airborne radioactivity from the reactor spread over northern Italy, where rainout gave rise to low levels of radioactivity at ground level. PATIENTS AND METHODS: As the latency between exposure to ionising radiation and development of thyroid cancer is thought to be about 10 years, in 1996/1997 all children born in 1985 and 1986 and attending school in an area of Milan, Italy were examined for thyroid nodules. A total of 3949 children were examined by two physicians blinded to the examination and diagnosis of the other. The children were to be reassessed in 2001/2002. RESULTS: In total, 1% had palpable nodules. The nodule diagnoses were: Hurtle cell adenoma (one), thyroglossal duct cyst (one), thyroid cyst (four) and thyroiditis (four). The prevalence of thyroid disease in the cohort was indistinguishable from that of populations not exposed to radioactive pollution. Only 10 children re-presented for examination 5 years later; all were negative. The direct costs of the study were estimated at 21,200 Euros. CONCLUSION: The high cost of the study in relation to reassuring lack of increase in thyroid nodule prevalence suggests that further studies are not justified.

Possible role of nitric oxide in the biology of breast carcinoma: review of the available literature.

Nitric oxide was studied to investigate its possible involvement in the promotion of breast carcinoma: both the development of the primary tumour and the process of metastasis seem to be influenced by the presence and the amount of nitric oxide. We review the available literature on this topic, which seems to suggest an influence of nitric oxide on the cancer cell biology in breast carcinoma, but the argument is still controversial. More studies are needed to clarify the sequence of events and the real impact of nitric oxide on the behaviour of the disease.

Paraneoplastic neurological disorders in breast cancer.

Paraneoplastic syndromes are the rarest neurological complications in patients with cancer. The neurological paraneoplastic syndromes that are mainly associated with breast cancer are subacute cerebellar degeneration, paraneoplastic retinopathy, opsoclonus-myoclonus syndrome, lower motor neuron diseases and Stiff-man syndrome. The aim of this paper is to briefly outline these paraneoplastic neurological syndromes and consider their relation to breast carcinoma.

Histologic detection and clinical implications of micrometastases in axillary sentinel lymph nodes for patients with breast carcinoma.

BACKGROUND: Sentinel lymph node (SLN) biopsy is used increasingly in patients with clinically lymph node negative, early-stage breast carcinoma, because it can spare axillary dissection when the sentinel lymph nodes are negative. The question arises, however, whether complete axillary lymph node dissection (ALND) also is necessary in patients with only micrometastases (< or = 2 mm in greatest dimension) in axillary SLNs. The authors carried out the current study to ascertain the risk of non-SLN axillary metastases in such patients and to assess the detection rate of SLN micrometastases in relation to the sectioning interval and the number of sections examined. METHODS: The authors examined 109 patients with micrometastatic SLNs from a series of 634 patients with carcinoma of the breast who underwent SLN biopsy and complete ALND as part of the surgical treatment for their disease. The SLNs were sectioned completely at 50-microm intervals, and the sections were examined intraoperatively. RESULTS: The overall frequency of metastases in axillary non-SLNs was 21.8%. The frequency was correlated significantly with the size of the SLN micrometastatic focus (P = 0.02): 36.4% of patients with foci > 1 mm had metastases in axillary lymph nodes--a percentage approaching 44.7% of patients with macrometastatic SLNs--whereas only 15.6% of patients with micrometastases < or = 1 mm had other involved axillary lymph nodes. CONCLUSIONS: Outside of clinical trials, patients with T1 and small T2 breast carcinoma and micrometastatic SLNs should undergo complete ALND for adequate staging. However, patients with SLN micrometastases up to 1 mm in greatest dimension have a significantly lower risk of additional axillary metastases, raising the question of whether ALND may be avoided in this subgroup of patients.

A preliminary report of intraoperative radiotherapy (IORT) in limited-stage breast cancers that are conservatively treated.

Local recurrences after breast conserving surgery occur mostly in the quadrant harbouring the primary carcinoma. The main objective of postoperative radiotherapy should be the sterilisation of residual cancer cells in the operative area, while irradiation of the whole breast may be avoided. We have developed a new technique of intra-operative radiotherapy (IORT) of a breast quadrant after the removal of the primary carcinoma. A mobile linear accelerator (linac) with a robotic arm is utilised delivering electron beams able to produce energies from 3 to 9 MeV. Through a perspex applicator, the radiation is delivered directly to the mammary gland and to spare the skin from the radiation, the skin margins are stretched out of the radiation field. To protect the thoracic wall, an aluminium-lead disc is placed between the gland and the pectoralis muscle. Different dose levels were tested from 10 to 21 Gy without important side-effects. We estimated that a single fraction of 21 Gy is equivalent to 60 Gy delivered in 30 fractions at 2 Gy/fraction. Seventeen patients received a dose of IORT of 10 to 15 Gy as an anticipated boost to external radiotherapy, while 86 patients received a dose of 17-19-21 Gy intra-operatively as their whole treatment. The follow-up time of the 101 patients varied from 1 to 17 months (mean follow-up time was 8 months). The IORT treatment was very well accepted by all of our patients, either due to the rapidity of the radiation course in cases where IORT was given as the whole treatment or to the shortening of the subsequent external radiotherapy in cases where IORT was given as an anticipated boost. We believe that single dose IORT after breast resection for small mammary carcinomas may be an excellent alternative to the traditional postoperative radiotherapy. However, a longer follow-up is needed for a better evaluation of the possible late side-effects.

Reverse transcription-polymerase chain reaction assay for multiple mRNA markers in the detection of breast cancer metastases in sentinel lymph nodes.

The identification of specific tumor mRNA markers by reverse transcription-polymerase chain reaction might be a valuable diagnostic adjunct for the detection of breast cancer metastases in axillary sentinel lymph nodes (SLNs). In this study we have compared the diagnostic accuracy of an extensive histopathologic examination of 146 SLNs from 123 breast carcinoma patients with that of the evaluation of 5 mRNA markers. When analyzed individually, none of the different markers attained a sensitivity higher than 77.8%, and the general concordance with the histopathologic findings ranged from 78.8 to 83.6%. In a multiple-marker assay, taking into account the expression of at least 1 of the 5 tumor markers, the sensitivity of the test rose to 95.6%, with a specificity of 66.3% and a general concordance with the histopathologic status of 75.3%. Finally, when at least 2 of 3 markers (maspin, cytokeratin 19 and mammaglobin 1) were expressed, the concordance with either SLN or axillary lymph node status was highest (88.4% and 84.6%, respectively). The high prevalence of positive reverse transcription-polymerase chain reaction assays in histologically uninvolved SLNs, however, may hamper extensive application of these techniques in the clinical setting.