Wolfgang Gatzemeier

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.

Clinicopathological and Immunohistochemical Characteristics in Male Breast Cancer: A Retrospective Case Series

BACKGROUND Due to its rarity, male breast cancer (mBC) remains an inadequately characterized disease, and current evidence for treatment derives from female breast cancer (FBC). METHODS We retrospectively analyzed the clinicopathological characteristics, treatment patterns, and outcomes of mBCs treated from 2000 to 2013. RESULTS From a total of 97 patients with mBC, 6 (6.2%) with ductal in situ carcinoma were excluded, and 91 patients with invasive carcinoma were analyzed. Median age was 65 years (range: 25-87 years). Estrogen receptors were positive in 88 patients (96.7%), and progesterone receptors were positive in 84 patients (92.3%). HER-2 was overexpressed in 13 of 85 patients (16%). Median follow-up was 51.5 months (range: 0.5-219.3 months). Five-year progression-free survival (PFS) was 50%, whereas overall survival (OS) was 68.1%. Patients with grades 1 and 2 presented 5-year PFS of 71% versus 22.5% for patients with grade 3 disease; 5-year OS was 85.7% for patients with grades 1 and 2 versus 53.3% of patients with grade 3. Ki-67 score >20% and adjuvant chemotherapy were also statistically significant for OS on univariate analyses. Twenty-six of 87 patients (29.8%) experienced recurrent disease and 16 of 91 patients (17.6%) developed a second neoplasia. CONCLUSION Male breast cancer shows different biological patterns compared with FBC, with higher positive hormone-receptor status and lower HER-2 overexpression. Grade 3 and Ki-67 >20% were associated with shorter OS. IMPLICATIONS FOR PRACTICE There is little evidence that prognostic features established in female breast cancer, such as grading and Ki-67 labeling index, could be applied to male breast cancer as well. This study found that grade 3 was associated with shorter overall survival and a trend for Ki-67 >20%; this could help in choosing the best treatment option in the adjuvant setting. Many questions remain regarding the impact of HER-2 positivity on survival and treatment with adjuvant anti-HER-2 therapy. Regarding metastatic male breast cancer, the results suggest that common regimens of chemo-, endocrine and immunotherapy used in female breast cancer are safe and effective for men. Male breast cancer patients show a higher incidence of second primary tumors, especially prostate and colon cancers and should therefore be carefully monitored.

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.

Controversies in clinicopathological characteristics and treatment strategies of male breast cancer: A review of the literature

Male breast cancer (MaBC) is a rare disease, accounting for less than 1% of malignancies in men. For this reason, literature data on its clinicopathological characteristics are very heterogeneous and treatment strategies have mostly been extrapolated from the female counterpart. However, immunohistochemical peculiarities of MaBC have recently emerged, defining it as a distinct entity from female breast cancer (FBC), thus requiring a tailored clinical approach. MaBC appears to be more often hormone receptor positive than FBC, while data on HER2 status still remain inconclusive, indicating a possible higher incidence of HER2 alterations. Treatment strategies for MaBC have evolved and less invasive local treatments such as lumpectomy and sentinel lymph node biopsy have become part of everyday clinical practice, while there are still controversies on the indication of radiotherapy, especially after mastectomy. Similarly, differences between male and female hormonal status have raised some concerns in the use of aromatase inhibitors in male patients and the choice of best endocrine therapy is still controversial.

One-Step Nucleic Acid Amplification in Breast Cancer Sentinel Lymph Node: A Single Institutional Experience and a Short Review

Sentinel lymph node (SLN) examination is a standard in breast cancer patients, with several methods employed along its 20 years history, the last one represented by one-step nucleic acid amplification (OSNA). The latter is a intra-operative molecular assay searching for CK19 mRNA as a surrogate of metastatic cells. Our 3 years experience with OSNA (1122 patients) showed results overlapping those recorded in the same institution with a morphological evaluation (930 patients) of SLN. In detail, the data of OSNA were almost identical to those observed with standard post-operative procedure in terms of patients with positive SLN (30%) and micrometastatic/macrometastatic involvement of SLN (respectively, 38–45 and 62–55%). By contrast, when OSNA was compared to the standard intraoperatory procedure, it was superior in terms of accuracy, prompting the use of this molecular assay as a very valid, and reproducible for intra-operative evaluation of SLN. Further possibilities prompting the use of OSNA range from adhesion to quality control programs, saving of medical time, ability to predict, during surgery, additional nodal metastasis, and molecular bio-banking.

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.