Is the CTS5 a helpful decision-making tool in the extended adjuvant therapy setting?

PURPOSE: The Clinical Treatment Score post-5 years (CTS5) is an easy-to-use tool estimating the late distant recurrence (LDR) risk in patients with hormone receptor-positive breast cancer after 5 years of endocrine therapy (ET). Apart from evaluating the prognostic value and calibration accuracy of CTS5, the aim of this study is to clarify if this score is able to identify patients at higher risk for LDR who will benefit from extended ET. METHODS: Prognostic power, calibration, and predictive value of the CTS5 was tested in patients of the prospective ABCSG-06 and -06a trials (n = 1254 and 860 patients, respectively). Time to LDR was analyzed with Cox regression models. RESULTS: Higher rates of LDR in the years five to ten were observed in high- and intermediate-risk patients compared to low-risk patients (HR 4.02, 95%CI 2.26-7.15, p < 0.001 and HR 1.93, 95%CI 1.05-3.56, p = 0.035). An increasing continuous CTS5 was associated with increasing LDR risk (HR 2.23, 95% CI 1.74-2.85, p < 0.001). Miscalibration of CTS5 in high-risk patients could be observed. Although not reaching significance, high-risk patients benefitted the most from prolonged ET with an absolute reduction of the estimated 5-year LDR of - 6.1% (95%CI - 14.4 to 2.3). CONCLUSION: The CTS5 is a reliable prognostic tool that is well calibrated in the lower and intermediate risk groups with a substantial difference of expected versus observed LDR rates in high-risk patients. While a numerical trend in favoring prolonged ET for patients with a higher CTS5 was found, a significantly predictive value for the score could not be confirmed. CLINICAL TRIAL REGISTRATION: ABCSG-06 trial (NCT00309491), ABCSG-06A7 1033AU/0001 (NCT00300508).

Estrogen Receptor Alpha Gene Amplification Is an Independent Predictor of Long-Term Outcome in Postmenopausal Patients with Endocrine-Responsive Early Breast Cancer.

PURPOSE: Estrogen receptor (ER) expression is a prognostic parameter in breast cancer, and a prerequisite for the use of endocrine therapy. In ER+ early breast cancer, however, no receptor-associated biomarker exists that identifies patients with a particularly favorable outcome. We have investigated the value of ESR1 amplification in predicting the long-term clinical outcome in tamoxifen-treated postmenopausal women with endocrine-responsive breast cancer. EXPERIMENTAL DESIGN: 394 patients who had been randomized into the tamoxifen-only arm of the prospective randomized ABCSG-06 trial of adjuvant endocrine therapy with available formalin-fixed, paraffin-embedded tumor tissue were included in this analysis. IHC ERα expression was evaluated both locally and in a central lab using the Allred score, while ESR1 gene amplification was evaluated by FISH analysis using the ESR1/CEP6 ratio indicating focal copy number alterations. RESULTS: Focal ESR1 copy-number elevations (amplifications) were detected in 187 of 394 (47%) tumor specimens, and were associated with a favorable outcome: After a median follow-up of 10 years, women with intratumoral focal ESR1 amplification had a significantly longer distant recurrence-free survival [adjusted HR, 0.48; 95% confidence interval (CI), 0.26-0.91; P = 0.02] and breast cancer-specific survival (adjusted HR 0.47; 95% CI, 0.27-0.80; P = 0.01) as compared with women without ESR1 amplification. IHC ERα protein expression, evaluated by Allred score, correlated significantly with focal ESR1 amplification (P < 0.0001; χ2 test), but was not prognostic by itself. CONCLUSIONS: Focal ESR1 amplification is an independent and powerful predictor for long-term distant recurrence-free and breast cancer-specific survival in postmenopausal women with endocrine-responsive early-stage breast cancer who received tamoxifen for 5 years.

The iTOP trial: Comparing immediate techniques of oncoplastic surgery with conventional breast surgery in women with breast cancer - A prospective, controlled, single-center study.

INTRODUCTION: Oncoplastic techniques allow resection of larger tumors, permitting breast conservation in cases otherwise requiring mastectomy. We sought to prospectively compare quality of life (QoL) in patients undergoing oncoplastic surgery as compared to conventional breast conservation (CBC) or mastectomy is lacking. METHODS: Patients diagnosed with BIRADS IV-VI lesion were eligible if resection of ≥10% of the breast volume was planned. Patients were allowed to decide whether they wanted to undergo CBC or oncoplastic breast conservation (OBC). Patients who underwent mastectomy and immediate breast reconstruction (IBR) were also included for comparison. The primary endpoint was breast self-esteem using the Breast Image Scale (BIS) at 12 months, secondary endpoints were perioperative morbidity and QoL using the BREAST-Q questionnaire. RESULTS: From 2011 to 2016, 205 patients were included in the study. 116 patients (56.6%) received CBC, 46 (22.4%) OBC and 43 (21%) MIBR. Women in the OBC group were more likely to have tumors ≥ 2 cm than those in the CBC group (34.7% vs. 17.5%, respectively). Women who underwent MIBR were more likely to have tumors > 5 cm than those in the CBC and OBC groups (23% vs 1% and 10%, respectively). The BIS and BREAST-Q improved in each group after 12 months but did not differ significantly between groups at any time point. Surgical complications (seroma, bleeding, infection, necrosis) were numerically more likely in the OBC and MIBR groups. CONCLUSION: OBC and the MIBR allow for resection of larger tumors with a similar quality of life as CBC.

Long-Term Outcomes of Adjuvant Denosumab in Breast Cancer.

BACKGROUND: Adjuvant aromatase inhibitors increase osteoporosis and fractures in patients with hormone receptor­positive breast cancer. We have previously reported outcomes of the ABCSG-18 (study 18 from the Austrian Breast & Colorectal Cancer Study Group) trial showing that adjuvant anti­receptor activator of nuclear factor-κB ligand denosumab treatment counteracts these adverse effects and may improve outcomes. We report here the final long-term outcomes. METHODS: ABCSG-18 is a prospective, double-blind, placebo-controlled, phase 3 trial in which 3425 postmenopausal patients with early hormone receptor­positive breast cancer receiving aromatase inhibitor therapy were randomly assigned in 58 trial centers to receive either denosumab 60 mg or placebo administered subcutaneously every 6 months. The primary end point was the time to first clinical fracture after randomization. Secondary disease outcome­related end points were disease-free survival (DFS), bone metastasis­free survival (BMFS), and overall survival (OS). RESULTS: For this final protocol-defined analysis, median follow-up is 8 years (interquartile range, 6 to 9.6 years). There were 309 versus 368 DFS events (hazard ratio, 0.83; 95% confidence interval [CI], 0.71 to 0.97) in the denosumab versus the placebo group, respectively, resulting in an absolute 9-year DFS benefit of 3.5 percentage points (79.4 vs. 75.9%). Adjuvant denosumab improved BMFS by 2.5 percentage points (88.9 vs. 86.4%; hazard ratio, 0.81; 95% CI, 0.65 to 1.00) and OS by 1.0 percentage point (90.9 vs. 89.9%; hazard ratio, 0.80; 95% CI, 0.64 to 1.01). No new toxicities for this dose of adjuvant denosumab were observed. CONCLUSIONS: DFS, BMFS, and OS continued to show benefit in this final long-term analysis of ABCSG-18. There were no new toxicities. (Funded by Amgen; ClinicalTrials.gov number, NCT00556374.)

Duration of Adjuvant Aromatase-Inhibitor Therapy in Postmenopausal Breast Cancer.

BACKGROUND: For postmenopausal women with hormone-receptor-positive breast cancer, the most effective duration for adjuvant therapy with an aromatase inhibitor remains unclear. METHODS: In this prospective, phase 3 trial, we randomly assigned postmenopausal women with hormone-receptor-positive breast cancer who had received 5 years of adjuvant endocrine therapy to receive the aromatase inhibitor anastrozole for an additional 2 years (2-year group, receiving a total of 7 years) or an additional 5 years (5-year group, receiving a total of 10 years). The primary end point was disease-free survival. The primary analysis included all the patients who were still participating in the trial and who had no recurrence 2 years after randomization (i.e., when treatment in the 2-year group had ended). Secondary end points were overall survival, contralateral breast cancer, second primary cancer, and clinical bone fracture. RESULTS: Among the 3484 women who were enrolled in the trial, 3208 remained in the trial without disease progression after the first 2 years of extended anastrozole treatment following randomization. Among these women, disease progression or death occurred in 335 women in each treatment group in the primary-analysis set at 8 years (hazard ratio, 0.99; 95% confidence interval [CI], 0.85 to 1.15; P = 0.90). No between-group differences occurred in most secondary end points, and subgroup analyses did not indicate differences in any particular subgroup. The risk of clinical bone fracture was higher in the 5-year group than in the 2-year group (hazard ratio, 1.35; 95% CI, 1.00 to 1.84). CONCLUSIONS: In postmenopausal women with hormone-receptor-positive breast cancer who had received 5 years of adjuvant endocrine therapy, extending hormone therapy by 5 years provided no benefit over a 2-year extension but was associated with a greater risk of bone fracture. (Funded by AstraZeneca and the Austrian Breast and Colorectal Cancer Study Group; ABCSG-16/SALSA ClinicalTrials.gov number, NCT00295620.).

Conventional versus reverse sequence of neoadjuvant epirubicin/cyclophosphamide and docetaxel: sequencing results from ABCSG-34.

BACKGROUND: Preoperative chemotherapy containing anthracyclines and taxanes is well established in early-stage breast cancer. Previous studies have suggested that the chemotherapy sequence may matter but definitive evidence is missing. ABCSG trial 34 evaluated the activity of the MUC1 vaccine tecemotide when added to neoadjuvant treatment; the study provided the opportunity for the second randomisation to compare two different anthracycline/taxane sequences. METHODS: HER2-negative early-stage breast cancer patients were recruited to this randomised multicentre Phase 2 study. Patients in the chemotherapy cohort (n = 311) were additionally randomised to a conventional or reversed sequence of epirubicin/cyclophosphamide and docetaxel. Residual cancer burden (RCB) with/without tecemotide was defined as primary study endpoint; RCB in the two chemotherapy groups was a key secondary endpoint. RESULTS: No significant differences in terms of RCB 0/I (40.1% vs. 37.2%; P = 0.61) or pathologic complete response (pCR) rates (24.3% vs. 25%, P = 0.89) were observed between conventional or reverse chemotherapy sequence. No new safety signals were reported, and upfront docetaxel did not result in decreased rates of treatment delay or discontinuation. CONCLUSION: Upfront docetaxel did not improve chemotherapy activity or tolerability; these results suggest that upfront neoadjuvant treatment with anthracyclines remains a valid option.

Efficacy and safety of the therapeutic cancer vaccine tecemotide (L-BLP25) in early breast cancer: Results from a prospective, randomised, neoadjuvant phase II study (ABCSG 34).

BACKGROUND: Immune-based strategies represent a promising approach in breast cancer (BC) treatment. The glycoprotein mucin-1 (MUC-1) is overexpressed in more than 90% of BC patients, and is targeted by the cancer vaccine tecemotide. We have investigated the efficacy and safety of tecemotide when added to neoadjuvant standard-of-care (SoC) treatment in early BC patients. PATIENTS AND METHODS: A total of 400 patients with HER2-early BC were recruited into this prospective, multicentre, randomised 2-arm academic phase II trial. Patients received preoperative SoC treatment (chemotherapy or endocrine therapy) with or without tecemotide. Postmenopausal women with oestrogen receptor (ER)+++, or ER++ and Ki67 < 14%, and G1,2 tumours ('luminal A' tumours) received 6 months of letrozole. Postmenopausal patients with triple-negative, ER-/+/++ and Ki67 ≥ 14%, and with G3 tumours, as well as premenopausal patients, received four cycles of epirubicin/cyclophosphamide plus four cycles of docetaxel. Primary end-point was residual cancer burden (RCB; 0/I versus II/III) at surgery. Secondary end-points included pathological complete response (pCR), safety, and quality of life. FINDINGS: We observed no significant difference in RCB 0/I rates between patients with (36.4%) and without (31.9%) tecemotide in the overall study population (p = 0.40) nor in endocrine and chemotherapy-treated subgroups (25.0% versus 13.3%, p = 0.17; 39.6% versus 37.8%, p = 0.75, respectively). The addition of tecemotide did not affect overall pCR rates (22.5% versus 17.4%, p = 0.23), MUC-1 expression, or tumour-infiltrating lymphocytes content. Tecemotide did not increase toxicity when compared to SoC therapy alone. INTERPRETATION: Neoadjuvant tecemotide is safe, but does not improve RCB or pCR rates in patients receiving standard neoadjuvant therapy.

Endocrine therapy with or without whole breast irradiation in low-risk breast cancer patients after breast-conserving surgery: 10-year results of the Austrian Breast and Colorectal Cancer Study Group 8A trial.

PURPOSE: To investigate long-term results of patients with hormonal receptor-positive breast cancer treated with breast-conserving surgery (BCS) and consecutive endocrine therapy (ET) with or without whole breast irradiation (WBI). METHODS AND MATERIALS: Within the 8 A trial of the Austrian Breast and Colorectal Cancer Study Group, a total of 869 patients received ET after BCS which was randomly followed by WBI (n = 439, group 1) or observation (n = 430, group 2). WBI was applied up to a mean total dosage of 50 Gy (+/- 10 Gy boost) in conventional fractionation. RESULTS: After a median follow-up of 9.89 years, 10 in-breast recurrences (IBRs) were observed in group 1 and 31 in group 2, resulting in a 10-year local recurrence-free survival (LRFS) of 97.5% and 92.4%, respectively (p = 0.004). This translated into significantly higher rates for disease-free survival (DFS): 94.5% group 1 vs 88.4% group 2, p = 0.0156. For distant metastases-free survival (DMFS) and overall survival (OS), respective 10-year rates amounted 96.7% and 86.6% for group 1 versus 96.4% and 87.6%, for group 2 (ns). WBI (hazard ratio [HR]: 0.27, p < 0.01) and tumour grading (HR: 3.76, p = 0.03) were found as significant predictors for IBR in multiple cox regression analysis. CONCLUSIONS: After a median follow-up of 10 years, WBI resulted in a better local control and DFS compared with ET alone. The omission of WBI and tumour grading, respectively, were the only negative predictors for LRFS.

Adjuvant denosumab in postmenopausal patients with hormone receptor-positive breast cancer (ABCSG-18): disease-free survival results from a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: In postmenopausal women with hormone receptor-positive, early-stage breast cancer, treatment with adjuvant aromatase inhibitors is the standard of care, but it increases risk for osteoporosis and fractures. Results from the ABCSG-18 trial showed that use of denosumab as an adjuvant to aromatase inhibitor therapy significantly reduced clinical fractures. Disease-free survival outcomes from ABCSG-18 have not yet been reported. METHODS: Postmenopausal patients with early, hormone receptor-positive, non-metastatic adenocarcinoma of the breast, who had completed their initial adjuvant treatment pathway (surgery, radiotherapy, or chemotherapy, or a combination) and were receiving adjuvant aromatase inhibitors, were enrolled at 58 trial centres in Austria and Sweden into this prospective, double-blind, placebo-controlled, phase 3 trial. With permuted block randomisation (block sizes 2 and 4, stratified by previous aromatase inhibitor use, total lumbar spine bone mineral density score at baseline, and type of centre), patients were assigned (1:1) to receive subcutaneous denosumab (60 mg) or matching placebo every 6 months during aromatase inhibitor therapy. The primary endpoint (previously reported) was the time to first clinical fracture after randomisation. The secondary endpoint reported here is disease-free survival (defined as time from randomisation to first evidence of local or distant metastasis, contralateral breast cancer, secondary carcinoma, or death from any cause) in the intention-to-treat population. This study is registered with EudraCT (number 2005-005275-15) and ClinicalTrials.gov (number NCT00556374), and is ongoing for long-term follow-up. FINDINGS: Between Dec 18, 2006, and July 22, 2013, 3425 eligible patients were enrolled and randomly assigned; 1711 to the denosumab group and 1709 to the placebo group (with five others withdrawing consent). After a median follow-up of 73 months (IQR 58-95), 240 (14·0%) patients in the denosumab and 287 (16·8%) in the placebo group had disease-free survival events. Disease-free survival was significantly improved in the denosumab group versus the placebo group (hazard ratio 0·82, 95% CI 0·69-0·98, Cox p=0·0260; descriptive analysis, without controlling for multiplicity). In the denosumab group, disease-free survival was 89·2% (95% CI 87·6-90·8) at 5 years and 80·6% (78·1-83·1) at 8 years of follow-up, compared with 87·3% (85·7-89·0) at 5 years and 77·5% (74·8-80·2) and 8 years in the placebo group. No independently adjudicated cases of osteonecrosis of the jaw or confirmed atypical femoral fractures were recorded. The total number of adverse events was similar in the denosumab group (1367 [including 521 serious] adverse events) and the placebo group (1339 [515 serious]). The most common serious adverse events were osteoarthritis (62 [3·6%] of 1709 in the denosumab group vs 58 [3·4%] of 1690 in the placebo group), meniscus injury (23 [1·3%] vs 24 [1·4%]), and cataract (16 [0·9%] vs 28 [1·7%]). One (<0·1%) treatment-related death (due to pneumonia, septic kidney failure, and cardiac decompensation) occurred in the denosumab group. INTERPRETATION: Denosumab constitutes an effective and safe adjuvant treatment for patients with postmenopausal hormone receptor-positive early breast cancer receiving aromatase inhibitor therapy. FUNDING: Amgen.

Objective breast symmetry analysis with the breast analyzing tool (BAT): improved tool for clinical trials.

PURPOSE: Objective cosmetic analysis is important to evaluate the cosmetic outcome after breast surgery or breast radiotherapy. For this purpose, we aimed to improve our recently developed objective scoring software, the Breast Analyzing Tool (BAT®). METHODS: A questionnaire about important factors for breast symmetry was handed out to ten experts (surgeons) and eight non-experts (students). Using these factors, the first-generation BAT® software formula has been modified and the breast symmetry index (BSI) from 129 women after breast surgery has been calculated by the first author with this new BAT® formula. The resulting BSI values of these 129 breast cancer patients were then correlated with subjective symmetry scores from the 18 observers using the Harris scale. The BSI of ten images was also calculated from five observers different from the first author to calculate inter-rater reliability. In a second phase, the new BAT® formula was validated and correlated with subjective scores of additional 50 women after breast surgery. RESULTS: The inter-rater reliability analysis of the objective evaluation by the BAT® from five individuals showed an ICC of 0.992 with almost no difference between different observers. All subjective scores of 50 patients correlated with the modified BSI score with a high Pearson correlation coefficient of 0.909 (p < .001) which was better compared to the old software (r = 0.769; p < .001). CONCLUSIONS: The modified BAT® software improves the correlation between subjective and objective BSI values, and may be a new standard for trials evaluating breast symmetry.

Adjuvant Bisphosphonates and Breast Cancer Survival.

Randomized trials have studied bisphosphonates in the adjuvant setting of early breast cancer to investigate their ability to prevent treatment-induced bone loss. Trial results have also suggested their potential to prevent disease recurrence and metastases. These trials are summarized in this review. A recent patient-level meta-analysis by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) finds convincing evidence that adjuvant antiresorptive treatments provide persistent benefits to breast cancer patients in low-estrogen situations and should be considered an important part of the treatment algorithm.

Postoperative CMF Does Not Ameliorate Poor Outcomes in Women With Residual Invasive Breast Cancer After Neoadjuvant Epirubicin/Docetaxel Chemotherapy.

BACKGROUND: Neoadjuvant chemotherapy (NACT) is an accepted treatment approach in early-stage breast cancer. In contrast, the potential role of postneoadjuvant chemotherapy after taxane-containing NACT remains unclear. The aim of this study was to evaluate postneoadjuvant chemotherapy and further prognostic factors that predict outcome in women without pathologic complete remission (pCR). PATIENTS AND METHODS: A total of 377 patients with breast cancer who received preoperative chemotherapy were included in this retrospective study. Patients without standard NACT (6 cycles of epirubicin with docetaxel) or primary metastatic breast cancer and locally advanced, inoperable cancer were excluded from further analysis (n = 186). This resulted in a study population of 191 women (30 [15.7%] with pCR; 161 [84.3%] without pCR). Major outcome parameters were event-free survival (EFS) and overall survival (OS). The following parameters were tested for their prognostic role: postneoadjuvant chemotherapy, patient age, breast cancer subtype (luminal/HER2-negative tumors, HER2-positive tumors, and triple-negative tumors), histological grade, pCR, residual lymph node invasion, and residual invasive tumor size. RESULTS: At a median follow-up of 54 months, 51 disease relapses (26.7%) and 21 deaths (11%) were observed. In a comparison of patients with pCR with those without, no significant differences in EFS or OS were observed. Postneoadjuvant chemotherapy was significantly associated with shorter OS in patients without pCR. CONCLUSION: In this population, which included a high percentage of patients with luminal cancers, pCR did not predict for improved OS. Postneoadjuvant chemotherapy showed no discernible benefit even in subgroups with aggressive tumor biology or significant remaining tumor burden. The use of such treatment should therefore be discouraged outside of clinical trials.

Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Adjuvant endocrine therapy compromises bone health in patients with breast cancer, causing osteopenia, osteoporosis, and fractures. Antiresorptive treatments such as bisphosphonates prevent and counteract these side-effects. In this trial, we aimed to investigate the effects of the anti-RANK ligand antibody denosumab in postmenopausal, aromatase inhibitor-treated patients with early-stage hormone receptor-positive breast cancer. METHODS: In this prospective, double-blind, placebo-controlled, phase 3 trial, postmenopausal patients with early hormone receptor-positive breast cancer receiving treatment with aromatase inhibitors were randomly assigned in a 1:1 ratio to receive either denosumab 60 mg or placebo administered subcutaneously every 6 months in 58 trial centres in Austria and Sweden. Patients were assigned by an interactive voice response system. The randomisation schedule used a randomly permuted block design with block sizes 2 and 4, stratified by type of hospital regarding Hologic device for DXA scans, previous aromatase inhibitor use, and baseline bone mineral density. Patients, treating physicians, investigators, data managers, and all study personnel were masked to treatment allocation. The primary endpoint was time from randomisation to first clinical fracture, analysed by intention to treat. As an additional sensitivity analysis, we also analysed the primary endpoint on the per-protocol population. Patients were treated until the prespecified number of 247 first clinical fractures was reached. This trial is ongoing (patients are in follow-up) and is registered with the European Clinical Trials Database, number 2005-005275-15, and with ClinicalTrials.gov, number NCT00556374. FINDINGS: Between Dec 18, 2006, and July 22, 2013, 3425 eligible patients were enrolled into the trial, of whom 3420 were randomly assigned to receive denosumab 60 mg (n=1711) or placebo (n=1709) subcutaneously every 6 months. Compared with the placebo group, patients in the denosumab group had a significantly delayed time to first clinical fracture (hazard ratio [HR] 0·50 [95% CI 0·39-0·65], p<0·0001). The overall lower number of fractures in the denosumab group (92) than in the placebo group (176) was similar in all patient subgroups, including in patients with a bone mineral density T-score of -1 or higher at baseline (n=1872, HR 0·44 [95% CI 0·31-0·64], p<0·0001) and in those with a bone mineral density T-score of less than -1 already at baseline (n=1548, HR 0·57 [95% CI 0·40-0·82], p=0·002). The patient incidence of adverse events in the safety analysis set (all patients who received at least one dose of study drug) did not differ between the denosumab group (1366 events, 80%) and the placebo group (1334 events, 79%), nor did the numbers of serious adverse events (521 vs 511 [30% in each group]). The main adverse events were arthralgia and other aromatase-inhibitor related symptoms; no additional toxicity from the study drug was reported. Despite proactive adjudication of every potential osteonecrosis of the jaw by an international expert panel, no cases of osteonecrosis of the jaw were reported. 93 patients (3% of the full analysis set) died during the study, of which one death (in the denosumab group) was thought to be related to the study drug. INTERPRETATION: Adjuvant denosumab 60 mg twice per year reduces the risk of clinical fractures in postmenopausal women with breast cancer receiving aromatase inhibitors, and can be administered without added toxicity. Since a main side-effect of adjuvant breast cancer treatment can be substantially reduced by the addition of denosumab, this treatment should be considered for clinical practice. FUNDING: Amgen.

TP53 germline mutation may affect response to anticancer treatments: analysis of an intensively treated Li-Fraumeni family.

Li-Fraumeni syndrome (LFS) is a rare autosomal dominant inherited disorder associated with the occurrence of a wide spectrum of early-onset malignancies, the most prevalent being breast cancer and sarcoma. The presence of TP53 germline mutations in the majority of LFS patients suggests a genetic basis for the cancer predisposition. No special recommendations for the treatment of LFS patients have been made to date, except that of minimizing radiation. We hypothesized that TP53 germline mutations may be associated not only with cancer predisposition, but also with lack of response to chemo- and radiotherapy. Here, we present an Austrian LFS family whose members were intensively treated with chemo- and radiotherapy due to cancers that occurred at a predominantly young age, including eight breast cancers in six patients. Material from seven family members was screened for p53 mutation by Sanger sequencing and immunohistochemistry. A rare missense mutation in the tetramerization domain of exon 10 of the TP53 gene was found to segregate with malignant disease in this family. Lack of response to various chemotherapies and radiotherapy could be ascertained by histopathology of surgical specimens after neoadjuvant treatment, by cancer relapse occurring while receiving adjuvant systemic treatment and by the occurrence of second primaries in areas of adjuvant radiation. Our observations suggest that current standards of cancer treatment may not be valid for patients with LFS. In patients with TP53 germline mutation, cytotoxic treatment may bear not only the risk of tumor induction but also the risk of treatment failure.

Quality of life after sympathetic surgery at the T4 ganglion for primary hyperhidrosis: clip application versus diathermic cut.

INTRODUCTION: Limited procedures at the T4 ganglion show low rates of compensatory sweating (CS). The aim of the study was to compare endoscopic sympathetic block (ESB) via clip application with endothoracic sympathicotomy (ETS) via diathermy with special regard on patients' quality of life (Qol). PATIENTS AND METHODS: Treatment success, side effects and patient satisfaction were evaluated in a prospectively gathered database of a tertiary-care referral hospital. Two disease-specific Qol questionnaires were used (Keller, Milanez de Campos). RESULTS: 406 operations were performed in 205 patients (ESB4 N = 114, ETS4 N = 91) with a median follow-up of 12 months. Both procedures improved Qol significantly (P < 0.001) and the degree of improvement was equal in both groups. Palmar and axillary HH were ameliorated after both procedures (P < 0.001). Accordingly, plantar HH decreased after ESB4 (P = 0.002), while remaining unaltered after ETS4. Nineteen patients (9.3%) reported CS and 10 patients (4.9%) judged it as "disturbing". Nine of the latter belonged to the ETS4 group compared to one ESB patient (P = 0.015). Patients developed higher rates of plantar CS after ETS4 compared to ESB4 (P = 0.006). Five patients (2.4%) from both cohorts reported persistence of axillary HH. Recurrence of axillary symptoms was found in 5 ESB4 patients. Satisfaction rates did not differ significantly. CONCLUSION: Patients' Qol and satisfaction rates are similar in both treatment groups for upper limb HH. Outcome and recurrence rates speak in the favor of ETS4, severity of CS and potential reversibility argue for ESB4.

The PAM50 risk-of-recurrence score predicts risk for late distant recurrence after endocrine therapy in postmenopausal women with endocrine-responsive early breast cancer.

PURPOSE: To assess the prognostic value of the PAM50 risk-of-recurrence (ROR) score on late distant recurrence (beyond 5 years after diagnosis and treatment) in a large cohort of postmenopausal, endocrine-responsive breast cancer patients. EXPERIMENTAL DESIGN: The PAM50 assay was performed on formalin-fixed paraffin-embedded whole-tumor sections of patients who had been enrolled in the Austrian Breast and Colorectal Cancer Study Group Trial 8 (ABCSG-8). RNA expression levels of the PAM50 genes were determined centrally using the nCounter Dx Analysis System. Late distant recurrence-free survival (DRFS) was analyzed using Cox models adjusted for clinical and pathologic parameters. RESULTS: PAM50 analysis was successfully performed in 1,246 ABCSG-8 patients. PAM50 ROR score and ROR-based risk groups provided significant additional prognostic information with respect to late DRFS compared with a combined score of clinical factors alone (ROR score: ΔLRχ(2) 15.32, P < 0.001; ROR-based risk groups: ΔLRχ(2) 14.83, P < 0.001). Between years 5 and 15, we observed an absolute risk of distant recurrence of 2.4% in the low ROR-based risk group, as compared with 17.5% in the high ROR-based risk group. The DRFS differences according to the PAM50 ROR score were observed for both node-positive and node-negative disease. CONCLUSION: PAM50 ROR score and ROR-based risk groups can differentiate patients with breast cancer with respect to their risk for late distant recurrence beyond what can be achieved with established clinicopathologic risk factors.

Standardization of morbidity assessment in breast cancer surgery using the Clavien Dindo Classification.

INTRODUCTION: There are no published data on standardized scoring systems for morbidity after breast cancer surgery. Aim of the study was to establish the Clavien Dindo Classification (CDC) as assessment tool and to identify risk factors for morbidity after breast surgery investigating new techniques including oncoplastic surgery and neoadjuvant chemotherapy. PATIENTS AND METHODS: Between 2008 and 2010, data were retrospectively evaluated from 485 women with breast cancer who underwent surgery at a university hospital. The CDC was used to assess the severity of postoperative complications. Multivariable analyses were adjusted by body-mass index, smoking, diabetes mellitus and tumour size. RESULTS: Overall complications (CDC 1-4) were reported in 28.7%. Second surgery related to major complications (CDC 3-4) was mandatory in 4.7%. Axillary dissection was an independent predictor for CDC 1-4 in all patients (P = 0.008, OR of 1.81, 95%CI 1.17-2.82). We found no independent predictor for CDC 3-4. Oncoplastic surgery increased the rate of wound infections (P = 0.010, OR: 2.94, 95%CI 1.30-6.67) and necroses (P < 0.001, OR: 8.38, 95%CI 3.28-21.4). Axillary dissection elevated wound infection (P = 0.040, OR: 2.07, 95%CI 1.03-4.14) and seroma rates (P < 0.001, OR: 2.46, 95%CI 1.51-4.01). Neoadjuvant chemotherapy had no impact on morbidity. CONCLUSION: The CDC is a valid assessment tool for future clinical trials and may be useful for hospital quality control. While axillary dissection and oncoplastic surgery raised morbidity, no single factor predicted for morbidity related second surgery.

Influence of resection extent on morbidity in surgery for squamous cell cancer at the pharyngoesophageal junction.

PURPOSE: Squamous cell cancer (SCC) of the pharyngoesophageal junction area has a poor prognosis mainly due to late symptom manifestation and diagnosis. Treatment of choice is still pharyngolaryngoesophagectomy, substantially affecting quality of life. Limited surgical procedures have been adopted as well. The aim of this retrospective study was to evaluate whether the extent of resection influences postoperative safety and mortality. METHODS: From 1984 to 2006, 66 patients were operated at a single tertiary referral center. Nineteen patients (28.8 %) had SCC of the hypopharynx and 47 patients (71.2 %) had SCC of the cervical and cervicothoracic esophagus. Thirty-five patients (53.0 %) underwent cervical esophageal resection (CE) and 31 underwent total esophagectomy (TE). In 39 patients (59.1 %), the larynx was preserved. Thirteen patients (19.7 %) underwent multimodal treatment. RESULTS: Overall postoperative morbidity was 69.7 % and reoperation rate reached 28.8 %. TE (P = 0.03) and larynx preservation (P = 0.02) were followed by a higher rate of non-lung infections compared with CE and pharyngolaryngectomy, respectively. Pulmonary complications have been observed more frequently after larynx preservation (P = 0.02). Hospital mortality was 9.1 %. Four patients died after TE (12.9 %) and two patients died after CE (5.7 %). In all of them, the larynx had been preserved (15.4 %). Overall, 53 patients (80.3 %) died until follow-up. One-year and 5-year survival in patients with the major tumor burden at the cervicothoracic site was 35.7 and 0 %. CONCLUSIONS: CE can be recommended as long as R0 resection is warranted. The advantage of larynx preservation is gained by higher morbidity and mortality rates and may not be recommended as standard procedure. Surgery may not be appropriate for advanced SCC in the cervicothoracic region.

CYP2D6 metabolism and patient outcome in the Austrian Breast and Colorectal Cancer Study Group trial (ABCSG) 8.

PURPOSE: Controversy exists about CYP2D6 genotype and tamoxifen efficacy. EXPERIMENTAL DESIGN: A matched case-control study was conducted using the Austrian Breast and Colorectal Cancer Study Group Trial 8 (ABCSG8) that randomized postmenopausal women with estrogen receptor (ER)-positive breast cancer to tamoxifen for 5 years (arm A) or tamoxifen for 2 years followed by anastrozole for 3 years (arm B). Cases had disease recurrence, contralateral breast cancer, second non-breast cancer, or died. For each case, controls were identified from the same treatment arm of similar age, surgery/radiation, and tumor-node-metastasis (TNM) stage. Genotyping was conducted for alleles associated with no (PM; *3, *4, *6), reduced (IM; *10, and *41), and extensive (EM: absence of these alleles) CYP2D6 metabolism. RESULTS: The common CYP2D6*4 allele was in Hardy-Weinberg equilibrium. In arm A during the first 5 years of therapy, women with two poor alleles [PM/PM: OR, 2.45; 95% confidence interval (CI), 1.05-5.73, P = 0.04] and women with one poor allele (PM/IM or PM/EM: OR, 1.67; 95% CI, 0.95-2.93; P = 0.07) had a higher likelihood of an event than women with two extensive alleles (EM/EM). In years 3 to 5 when patients remained on tamoxifen (arm A) or switched to anastrozole (arm B), PM/PM tended toward a higher likelihood of a disease event relative to EM/EM (OR, 2.40; 95% CI, 0.86-6.66; P = 0.09) among women on arm A but not among women on arm B (OR, 0.28; 95% CI, 0.03-2.30). CONCLUSION: In ABCSG8, the negative effects of reduced CYP2D6 metabolism were observed only during the period of tamoxifen administration and not after switching to anastrozole.