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.

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.

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.

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.

Sentinel lymph node biopsy and axillary dissection in breast cancer: results in a large series.

BACKGROUND: Axillary lymph node dissection is an established component of the surgical treatment of breast cancer, and is an important procedure in cancer staging; however, it is associated with unpleasant side effects. We have investigated a radioactive tracer-guided procedure that facilitates identification, removal, and pathologic examination of the sentinel lymph node (i.e., the lymph node first receiving lymphatic fluid from the area of the breast containing the tumor) to predict the status of the axilla and to assess the safety of foregoing axillary dissection if the sentinel lymph node shows no involvement. METHODS: We injected 5-10 MBq of 99mTc-labeled colloidal particles of human albumin peritumorally in 376 consecutive patients with breast cancer who were enrolled at the European Institute of Oncology during the period from March 1996 through March 1998. The sentinel lymph node in each case was visualized by lymphoscintigraphy, and its general location was marked on the overlying skin. During breast surgery, the sentinel lymph node was identified for removal by monitoring the acoustic signal from a hand-held gamma ray-detecting probe. Total axillary dissection was then carried out. The pathologic status of the sentinel lymph node was compared with that of the whole axilla. RESULTS: The sentinel lymph node was identified in 371 (98.7%) of the 376 patients and accurately predicted the state of the axilla in 359 (95.5%) of the patients, with 12 false-negative findings (6.7%; 95% confidence interval = 3.5%-11.4%) among a total of 180 patients with positive axillary lymph nodes. CONCLUSIONS: Sentinel lymph node biopsy using a gamma ray-detecting probe allows staging of the axilla with high accuracy in patients with primary breast cancer. A randomized trial is necessary to determine whether axillary dissection may be avoided in those patients with an uninvolved sentinel lymph node.

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.

Timing of breast cancer surgery in relation to the menstrual cycle: an update of developments.

It is well-established that hormones have multiple effects on breast cancer. Some, but not all studies indicate that the phase of the menstrual cycle (and hence hormonal status) at the time of breast surgery may influence survival. In this paper we review the literature in this area, explore how it is possible that such an association may occur, and note that randomised studies which unambiguously determined the phase of the cycle at the time of the operation are lacking. We go on to describe an ongoing self-randomised trial designed to address this problem and present preliminary results which show that only about 75% of the women ovulated during the cycle in which the operation took place, and that the established prognostic factor Ki-67 varied with the phase of the cycle in women who ovulated. It is too early to assess the significance of this finding.

Optimal Surgical Treatment of Breast Cancer.

Large-scale, controlled trials in the 1970s and 1980s demonstrated that wide resection (for example, quadrantectomy) was as effective as mastectomy for the treatment of breast cancer up to 3 cm in maximum diameter. Conservative treatment may also be extended to larger cancers following pre-operative chemotherapy to reduce tumor mass and leave sufficiently wide resection margins to ensure oncological radicality. Quadrantectomy is an operation of curative intent, distinct from "lumpectomy" or "tumorectomy," whose main aim is to debulk the tumor mass; nevertheless, wide resection should, in most cases, be flanked by radiotherapy to sterilize the tumor bed and by complete axillary dissection to remove any metastatic nodes and provide full prognostic information. This triple approach provides a high cure rate and low relapse rate for breast cancer, while providing an acceptable cosmetic outcome; we believe it is the optimal treatment for breast cancer at the present time. Modifications include simultaneous remodeling of the affected breast if, because of tumor position, the result of conservative surgery is less than satisfactory; and use of radioguided surgery to detect the sentinel node which, if not involved, may indicate that full axillary dissection is unnecessary.

Laser surgery for small perianal neoplasms.

Excisional laser surgery was used to treat 62 patients suffering from perianal, perineal, and anal canal neoplasms. 48 patients had benign epithelial or pigmented tumours, 12 had carcinoma in situ and 2 had invasive squamous cell carcinoma. Laser surgery was performed under local anaesthesia, in association with the operating microscope on an outpatient basis. 59 out of 62 patients (95%) had clear margins of resection after primary laser surgery, and 3 patients required a second excision for uncleared margins. 3 patients of the group of carcinoma in situ recurred, and 2 had new disease in an untreated area. These patients underwent re-section with the same technique. No significant local complications were observed for single or multiple operations at the perianal and anal canal level. All patients are disease-free in a follow-up ranging from 4 to 113 months, with a median of 25 months. Laser excisional surgery appears to be a suitable method for treating superficial tumours.

Risk of invasive cancer in women with lobular carcinoma in situ of the breast.

100 women underwent wide resection for palpable or mammographically detected breast lesions (1 woman had bilateral lesions). Histology excluded invasive cancer, but one or more foci of lobular carcinoma in situ (LCIS) were observed. There have been no recurrences in the 20 women who underwent total mastectomy. In the 12 patients who had a subsequent wide excision and the 68 who received no other treatment 5 presented with an invasive cancer in the same breast at some distance from the LCIS site (median follow-up 58 months). The (observed/expected) rate per 1000 per year is 10.3 for an untreated LCIS. LCIS is therefore a risk factor for invasive carcinoma. Nevertheless this risk does not indicate the use of mutilating procedures and a wait-and-see policy is appropriate.

Particle beam therapy (hadrontherapy): basis for interest and clinical experience.

The particle or hadron beams deployed in radiotherapy (protons, neutrons and helium, carbon, oxygen and neon ions) have physical and radiobiological characteristics which differ from those of conventional radiotherapy beams (photons) and which offer a number of theoretical advantages over conventional radiotherapy. After briefly describing the properties of hadron beams in comparison to photons, this review discusses the indications for hadrontherapy and analyses accumulated experience on the use of this modality to treat mainly neoplastic lesions, as published by the relatively few hadrontherapy centres operating around the world. The analysis indicates that for selected patients and tumours (particularly uveal melanomas and base of skull/spinal chordomas and chondrosarcomas), hadrontherapy produces greater disease-free survival. The advantages of hadrontherapy are most promisingly realised when used in conjunction with modern patient positioning, radiation delivery and focusing techniques (e.g. on-line imaging, three-dimensional conformal radiotherapy) developed to improve the efficacy of photon therapy. Although the construction and running costs of hadrontherapy units are considerably greater than those of conventional facilities, a comprehensive analysis that considers all the costs, particularly those resulting from the failure of less effective conventional radiotherapy, might indicate that hadrontherapy could be cost effective. In conclusion, the growing interest in this form of treatment seems to be fully justified by the results obtained to date, although more efficacy and dosing studies are required.

CA 15.3 determination in patients with breast cancer: clinical utility for the detection of distant metastases.

In 81 healthy women, 26 pregnant women, 25 patients with fibrocystic disease and 144 breast cancer patients, the overall diagnostic sensitivity and specificity of the CA 15.3 test was 27 and 97%, respectively. The positive and negative predictive values were 93 and 43%. In 150 node-negative patients taking part in a chemoprevention trial CA 15.3 was assayed at baseline and every 4 months for a median follow-up of 24 months (range 4-48). In these patients, 5 had local recurrences, 1 had a regional recurrence, 9 had distant metastases and 3 developed cancer in the contralateral breast. Among the patients with recurrences, those with distant metastases showed the highest ratio of CA 15.3 increase (8/9); in local and regional recurrences, this ratio was lower (2/6). The patients with contralateral breast cancer had no significant increase in CA 15.3. Patients in whom metastases were detected showed an increase in CA 15.3 4-48 months before clinical or instrumental detection of the metastases.

Breast conservation is a safe method in patients with small cancer of the breast. Long-term results of three randomised trials on 1,973 patients.

Breast conservation has become well-established in the treatment of early mammary carcinoma. However, a standardised treatment modality has not emerged. We have analysed the data from 1,973 patients treated in three consecutive randomised trials by four different radiosurgical procedures: Halsted mastectomy, quadrantectomy plus radiotherapy, lumpectomy plus radiotherapy, and quadrantectomy without radiotherapy, to compare the outcomes of these procedures in terms of local recurrence rate and overall survival. Eligibility criteria were similar in the three trials, and comparability between the four subgroups was excellent. Median follow-up for all patients was 82 months. The annual rates of local recurrence varied markedly according to the treatment. Patients treated with Halsted mastectomy and quadrantectomy plus radiotherapy had low annual rates of local recurrence (0.20 and 0.46, respectively) while both lumpectomy plus radiotherapy and quadrantectomy without radiotherapy had significantly higher rates (2.45 and 3.28, respectively). Patients under 45 years of age had a much higher incidence of local recurrences, while in women over 55 years local recurrences were much less frequent. Overall survival curves were identical in the four groups of patients, so that the three breast conserving radiosurgical procedures had the same survival rates as Halsted mastectomy. However, local recurrence rates were markedly influenced by the treatment method, patient age and specific histological features.

Palliative surgery of metastatic bone disease: a review of 83 cases.

Of a total of 83 patients with metastatic bone disease, surgery was performed in 17 cases at the prefracture stage, in 54 cases after complete fracture and in 10 cases to decompress the spinal cord. Positive short-term results were obtained in 75% of cases. 7 patients presented mild complications. In 2 cases, the patients had to be reoperated. 55% of the patients were still alive after 6 months, 31% after 12 months and 10% after 2 years.

Pre-operative chemotherapy and radiotherapy in breast cancer.

Primary systemic treatment of breast cancer with cytotoxics yields a high response rate and allows conservative surgical procedures in bulky tumours. In order to maximise local control of disease, two innovations were introduced in a pilot study. The first was to identify the good responders after three cycles of chemotherapy and to treat them with three additional cycles. The second was to also give this group of patients a full dose of radiotherapy before surgery with the aim of verifying the rate of pathological complete remissions in view of a possible treatment of breast primary with chemoradiotherapy only. Patients were treated with doxorubicin 60 mg/m2 and cyclophosphamide, 600 mg/m2 both intravenously on day 1, every 21 days for three courses. Partial or complete responders received three more courses followed by radiotherapy (50 Gy plus a 10 Gy boost). The others underwent immediate surgery. A total of 32 patients (median age, 50 years; range 28-69 years); performance status, 0-1; T2 22, T3 8, T4 2) were enrolled and were evaluable for response and side-effects. 9 patients had only three cycles of chemotherapy due to absence of response and 23 patients had six cycles of chemotherapy. Overall, 7 patients had a complete remission, 16 a partial remission and 9 had stable disease, for an overall response rate of 72% (95% confidence interval 53-86%). In the group of patients that completed the programme, two complete pathological remissions were observed and 5 patients had only microfoci of tumour. No toxic death or grade III-IV toxicities were observed. Mild or moderate side-effects included mucositis, nausea/vomiting and leucopenia. In conclusion, our results indicate that the addition of radiotherapy to pre-operative chemotherapy did not significantly enhance the incidence of pathological complete remissions. New primary treatment approaches should be explored in this subset of patients in order to improve outcome.

Sentinel lymph node biopsy as an indicator for axillary dissection in early breast cancer.

Sentinel node biopsy (SNB) is a new component of the surgical treatment of breast cancer that accurately predicts axillary status. Although the procedure is still mainly investigational, many patients are requesting SNB to avoid axillary dissection if the sentinel node (SN) is negative. From March 1996 to December 1999, 373 patients with breast carcinoma and clinically negative axillary nodes underwent breast surgery, mainly conservative, and SNB. If the SN was histologically uninvolved no further surgical treatment was given. All patients were informed in detail and signed a consent form. SNB involved injection of labelled albumin particles close to the primary tumour, lymphoscintigraphy and location of the sentinel node with a gamma probe during surgery. 379 SNBs were performed on 373 patients (6 were bilateral). In 94, the SN was positive and complete axillary dissection was performed. In 285 cases (280 patients) the SN was negative and no dissection was performed: these were carefully followed with quarterly clinical examination of the axilla. A total of 343 years at risk were available for evaluation from which seven cases of axillary metastases were expected. No cases of clinically evident axillary node metastasis have occurred. These findings provide further confirmation of the validity of SNB and prompt us to suggest that it should become the method of choice for axillary staging in small-sized breast cancer.

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.