Andrea Sagona

Phase I-II study of hypofractionated simultaneous integrated boost using volumetric modulated arc therapy for adjuvant radiation therapy in breast cancer patients: a report of feasibility and early toxicity results in the first 50 treatments

BackgroundTo report results in terms of feasibility and early toxicity of hypofractionated simultaneous integrated boost (SIB) approach with Volumetric Modulated Arc Therapy (VMAT) as adjuvant treatment after breast-conserving surgery.MethodsBetween September 2010 and May 2011, 50 consecutive patients presenting early-stage breast cancer were submitted to adjuvant radiotherapy with SIB-VMAT approach using RapidArc in our Institution (Istituto Clinico Humanitas ICH). Three out of 50 patients were irradiated bilaterally (53 tumours in 50 patients). All patients were enrolled in a phase I-II trial approved by the ICH ethical committee. All 50 patients enrolled in the study underwent VMAT-SIB technique to irradiate the whole breast with concomitant boost irradiation of the tumor bed. Doses to whole breast and surgical bed were 40.5 Gy and 48 Gy respectively, delivered in 15 fractions over 3 weeks. Skin toxicities were recorded during and after treatment according to RTOG acute radiation morbidity scoring criteria with a median follow-up of 12 months (range 8–16). Cosmetic outcomes were assessed as excellent/good or fair/poor.ResultsThe median age of the population was 68 years (range 36–88). According to AJCC staging system, 38 breast lesions were classified as pT1, and 15 as pT2; 49 cases were assessed as N0 and 4 as N1. The maximum acute skin toxicity by the end of treatment was Grade 0 in 20/50 patients, Grade 1 in 32/50, Grade 2 in 0 and Grade 3 in 1/50 (one of the 3 cases of bilateral breast irradiation). No Grade 4 toxicities were observed. All Grade 1 toxicities had resolved within 3 weeks. No significant differences in cosmetic scores on baseline assessment vs. 3 months and 6 months after the treatment were observed: all patients were scored as excellent/good (50/50) compared with baseline; no fair/poor judgment was recorded. No other toxicities or local failures were recorded during follow-up.ConclusionsThe 3-week course of postoperative radiation using VMAT with SIB showed to be feasible and was associated with acceptable acute skin toxicity profile. Long-term follow-up data are needed to assess late toxicity and clinical outcomes.

When Sentinel Lymph Node is Intramammary

IntroductionSentinel lymph node biopsy is an accepted standard of care for staging the axilla in patients with early-stage breast cancer. Little attention has been placed to the presence of intramammary sentinel lymph nodes (intraMSLNs) on preoperative lymphoscintigraphy.MethodsBetween December 2001 and September 2006, in 9632 breast cancer patients with clinically uninvolved axillary nodes, lymphoscintigraphy was performed at the European Institute of Oncology (EIO). An axillary SLN (axSLN) was identified in 99.4% of cases. An intraMSLN was identified in association with the axillary sentinel lymph node in 22 patients (0.2%). In 15 cases both the axSLN and the intraMSLN were excised.ResultsThe intraMSLN was positive in six patients (micrometastatic in three cases). The axSLNs were negative in all 15 cases. Two patients with positive intraMSLNs and one patient with a negative intraMSLN underwent axillary dissection; all three cases had negative axillary nodes. At a median follow-up of 24 months, no locoregional or systemic recurrences were observed.ConclusionsPositive intraMSLNs can improve disease staging but do not necessarily portend axillary lymph node metastasis. When intraMSLNs and axSLNs are present, we advocate biopsy of both sites and that management of the axilla should rely on axSLN status. In cases with intraMSLNs as the only draining site on lymphoscintigraphy, decisions on axillary management should be made on individualized basis.

Unavoidable mastectomy for ipsilateral breast tumour recurrence after conservative surgery: patient outcome

BACKGROUND In the case of ipsilateral breast tumour recurrence (IBTR) after breast-conserving surgery (BCS), a second conservative surgical approach maybe considered in some motivated patients whereas in others mastectomy is unavoidable. PATIENTS AND METHODS From 1997 to 2004, 282 patients presented at the European Institute of Oncology with an operable invasive IBTR after BCS. One hundred and sixty-one (57%) underwent a second conservative surgery, whereas 121 patients (43%) were given a mastectomy and represent the study population. We investigated the prognosis and determined predictive factors of outcome. RESULTS Median time from primary breast cancer to IBTR was 41 months (range 5-213). Recurrences were T2-T4 and/or multifocal in 83 cases (68.6%). With a median follow-up of 5 years after mastectomy, 5-year overall survival (OS) and disease-free survival (DFS) were 73.3% [95% confidence interval (CI) 65.0% to 81.6%] and 50.4% (95% CI 40.9% to 59.8%), respectively. At the multivariate analysis, early onset of IBTR, presence of vascular invasion and Ki67 >or=20 of the recurrent tumour were found to significantly affect both DFS and OS. CONCLUSIONS In women who need mastectomy for IBTR, early onset of the relapse, high proliferation index and presence of vascular invasion represent the worst prognostic factors.

Potential impact of the 70-gene signature in the choice of adjuvant systemic treatment for ER positive, HER2 negative tumors: a single institution experience.

PURPOSE We investigated in a single institution series of 124 women with operable breast cancer whether tumor clinicopathological features could predict the 70-gene signature (Mammaprint, MP) results, and whether MP results could help to make decisions for the use of chemotherapy (CT) in patients (pts) with ER positive breast cancer beyond recommendations of international guidelines. RESULTS Among the 68 ER/PgR positive, HER2 negative tumors, Ki-67 ≥ 20% was the only significant predictor of a high risk-MP among standard clinicopathological features. In candidates for endocrine therapy with undetermined benefit from CT according to international guidelines, MP results would have led to different treatment decisions in 13/46 (28%) and in 20/68 (29%) pts according to NCCN and St. Gallen recommendations, respectively. CONCLUSIONS Ki-67 independently predicted high risk-MP in ER/PgR positive, HER2 negative tumors. MP results would have led to discordant treatment recommendations in about 30% of cases, generally increasing indication rate for CT. The results of large randomized trials are warranted in order to understand whether we should rely on multigene assays rather than on standard clinicopathological features for treatment decisions.

Can axillary and supraclavicular radiotherapy be avoided after breast-conserving surgery and axillary dissection in women with multiple involved axillary nodes? Experience at the European Institute of Oncology.

AIMS AND BACKGROUND Although some guidelines recommend adjuvant radiotherapy (RT) to the axilla and supraclavicular nodes if 4 or more axillary nodes are involved, the current practice at our Institute is not to irradiate the axilla but to perform complete axillary dissection in which all 3 Berg levels are removed. We performed a retrospective analysis of patients with 4 or more axillary nodes involved and sufficient follow-up to provide indications as to whether our current treatment is adequate. METHODS We retrospectively analyzed 287 T1-T3 patients with a median follow-up of 5 years and 4 or more involved nodes treated by quadrantectomy and breast RT but no axillary RT; supraclavicular RT was given only when prognostic factors were unfavorable. RESULTS A total of 170 (59.2%) patients did not receive supraclavicular RT, while 117 (40.8%) patients received supraclavicular irradiation. No patient received axillary RT. After a median follow-up of 5 years (range, 4-105 months), 4.7% had died and 13.5% had developed distant metastases in the no supraclavicular RT group, compared to 12.0% dead (P = 0.028 log rank) and 24.8% (P = 0.201 log rank) in the supraclavicular RT group. No patients with supraclavicular RT developed supraclavicular metastases compared to 4 in the no supraclavicular RT group. There were no axillary recurrences. CONCLUSIONS Complete axillary dissection appears adequate treatment in patients with 4 or more involved nodes. The low breast recurrence rate also suggests that breast conservation is adequate treatment in such patients. Supraclavicular RT appears to reduce the number of supraclavicular metastases but confers no survival advantage. Although a small number of cases were examined in this retrospective single-center series, all received highly uniform treatment.

[18F]FDG PET/CT features for the molecular characterization of primary breast tumors

PurposeThe aim of this study was to evaluate the role of imaging features derived from [18F]FDG-PET/CT to provide in vivo characterization of breast cancer (BC).MethodsImages from 43 patients with a first diagnosis of BC were reviewed. Images were acquired before any treatment. Histological data were derived from pretreatment biopsy or surgical histological specimen; these included tumor type, grade, ER and PgR receptor status, lymphovascular invasion, Ki67 index, HER2 status, and molecular subtype. Standard parameters (SUVmean, TLG, MTV) and advanced imaging features (histogram-based and shape and size features) were evaluated. Univariate analysis, hierarchical clustering analysis, and exact Fisher’s test were used for statistical analysis of data. Imaging-derived metrics were reduced evaluating the mutual correlation within group of features as well as the mutual correlation between groups of features to form a signature.ResultsA significant correlation was found between some advanced imaging features and the histological type. Different molecular subtypes were characterized by different values of two histogram-based features (median and energy). A significant association was observed between the imaging signature and luminal A and luminal B HER2 negative molecular subtype and also when considering luminal A, luminal B HER2-negative and HER2-positive groups. Similar results were found between the signature and all five molecular subtypes and also when considering the histological types of BC.ConclusionsOur results suggest a complementary role of standard PET imaging parameters and advanced imaging features for the in vivo biological characterization of BC lesions.

CXCR4/CXCL12 Signaling and Protumor Macrophages in Primary Tumors and Sentinel Lymph Nodes Are Involved in Luminal B Breast Cancer Progression

Luminal B breast cancers (BC) have a more aggressive behavior associated with a higher rate of tumor relapse and worse prognosis compared to luminal A tumors. In this study, we evaluated the involvement of specific epithelial-to-mesenchymal transition- (EMT-) and immune-related pathways in the dissemination of luminal B BC cells. The expression of 42 EMT- and immune-related genes was evaluated in matched sentinel lymph nodes (SLNs) analyzed by the one-step nucleic acid amplification assay (OSNA) and primary tumors of 40 luminal B BC patients by gene array and immunohistochemistry. The results were validated in an independent group of 150 luminal B tumors by immunohistochemistry and immunofluorescence and using gene expression data from 315 luminal B BC patients included in the Metabric dataset. We found that the expression of CXCR4 (p = 3.28E − 02) and CD163 (p = 6.92E − 03) was significantly upregulated in SLNs of recurrent luminal B BC patients. Luminal B primary tumors overexpressing CXCR4 were characterized by an increased expression of vimentin and a high content of CD163-positive macrophages. Bioinformatics analysis confirmed the correlation of CXCR4 with CXCL12, VIM, and CD163 expression and LN involvement. Our results suggest that the upregulation of the CXCR4/CXCL12 pathway and the presence of protumor macrophages in the primary tumor and SLNs sustain the aggressiveness of an important subgroup of luminal B BC.

P4-09-27: Can We Predict the Benefit of the 70-Gene Signature in the Choice of Adjuvant Systemic Treatment for ER Positive, HER2 Negative Tumors in Daily Practice? A Single Institution Experience.

Purpose : Studies have shown that the 70-gene signature (MammaPrint®) (MP) may outperform clinicopathological risk assessment and may predict the benefit from chemotherapy (CT) in patients (pts) with early-stage breast cancer. However, the need of fresh tissue and the high cost of the assay limit its use in daily clinical practice. We investigated whether 1) tumor clinicopathologic features can predict MP risk (high vs. low); 2) MP results could help to make decisions for the use of CT in pts with ER positive (ER+ve) breast cancer beyond recommendations of known international guidelines (NCCN, St. Gallen). Patients and methods : Women with operable invasive breast cancer without evidence of distant disease undergoing surgery at the Breast Surgery Department were enrolled into the study. A 3 mm punch biopsy of the tumor was obtained from the specimen within the first hour after surgery. Samples were shipped to the laboratory in an RNA-stabilizing solution and were studied to ensure the presence of at least 30% of tumor cells and a customized microarray containing 70 genes was analyzed as described by the manufacturer. Results : 124 consecutive pts were enrolled into the study; 106 tumor samples were adequate for the microarray. Median age was 53 yrs (range 28–83), mean tumor size was 2.3 cm (SD ±1.34), 52.4% pts had pN0, 55% of tumors had Ki-67 ≥20% and 36% were poorly differentiated. ER were detected in ≥50% of cells in 82% and As expected, poorly differentiated, ER and PgR negative, HER2 positive and highly proliferating tumors were more likely to be classified as high-MP. We then focused our analysis on ER and PgR +ve, HER2 negative tumors and assessed features correlated with MP results in this subgroup. Unexpectedly, 31/80 (39%) of these tumors were classified as high-MP vs. 49 (61%) low-MP. We found that tumor size (T1 vs. T2-T4), poor differentiation (G3 vs G1-2) and high proliferation (Ki-67 ≥20%) were significantly associated with a high-MP result. In an exploratory multivariate analysis tumor size and Ki-67 remained as independent predictors of high-MP result. At last, when we compared MP risk with recommendations for AT from international guidelines we found that in the subgroup of candidates for endocrine therapy (ET) in whom the benefit from the addition of CT is undetermined, 25/68 pts (37%) were high-MP and 43 pts (63%) low-MP. When we considered recommendations for AT proposed by our multidisciplinary team according to international guidelines, 11/25 pts (44%) with high-MP received ET only and 14 pts (56%) CT + ET, while among 43 pts with low-MP only 9 received both CT and ET. Conclusions : Our study shows that the 70-gene signature was feasible in the clinical setting, as 85% of tumor samples were adequate. A substantial proportion of ER/PgR+ve, HER2 negative tumors was classified as high-MP; within this subgroup, proliferation and tumor size independently predicted high-MP results. In 20 pts, MP risk would have resulted in discordant recommendations for AT compared to those based on standard clinicopathologic features. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-09-27.