Predictive Factors of Long-Term Survival after Neoadjuvant Radiotherapy and Chemotherapy in High-Risk Breast Cancer.

BACKGROUND: Neoadjuvant radiotherapy (naRT) in addition to neoadjuvant chemotherapy (naCT) has been used for locally advanced, inoperable breast cancer or to allow breast conserving surgery (BCS). Retrospective analyses suggest that naRT + naCT might result in an improvement in pathological complete response (pCR rate and disease-free survival). pCR is a surrogate parameter for improved event-free and overall survival (OS) and allows for the adaption of the post-neoadjuvant therapy regimens. However, it is not clear whether pCR achieved with the addition of naRT has the same prognostic value. PATIENTS AND METHODS: We performed a retrospective re-analysis of 356 patients (cT1-cT4/cN0-N+) treated with naRT and naCT with a long-term follow-up. Patients underwent naRT on the breast and regional lymph nodes combined with a boost to the primary tumor. Chemotherapy with different agents was given either sequentially or concomitantly to naRT. We used the Cox proportional hazard regression model to estimate the effect of pCR in our cohort in different subgroups as well as chemotherapy protocols. Clinical response markers correlating with OS were also analyzed. RESULTS: For patients with median follow-ups of 20 years, 10 years, 15 years, 20 years, and 25 years, OS rates were 69.7%, 60.6%, 53.1%, and 45.1%, respectively. pCR was achieved in 31.1% of patients and associated with a significant improvement in OS (HR = 0.58; CI-95%: 0.41-0.80; p = 0.001). The prognostic impact of pCR was evident across breast cancer subtypes and chemotherapy regimens. Multivariate analysis showed that age, clinical tumor and nodal stage, chemotherapy, and pCR were prognostic for OS. CONCLUSION: NaCT and naRT prior to surgical resection achieve good long-term survival in high-risk breast cancer. pCR after naRT maintains its prognostic value in breast cancer subtypes and across different subgroups. pCR driven by naRT and naCT independently influences long-term survival.

Should oncoplastic breast conserving surgery be used for the treatment of early stage breast cancer? Using the GRADE approach for development of clinical recommendations.

INTRODUCTION: The potential advantages of oncoplastic breast conserving surgery (BCS) have not been validated in robust studies that constitute high levels of evidence, despite oncoplastic techniques being widely adopted around the globe. There is hence the need to define the precise role of oncoplastic BCS in the treatment of early breast cancer, with consensual recommendations for clinical practice. METHODS: A panel of world-renowned breast specialists was convened to evaluate evidence, express personal viewpoints and establish recommendations for the use of oncoplastic BCS as primary treatment of unifocal early stage breast cancers using the GRADE approach. RESULTS: According to the results of the systematic review of literature, the panelists were asked to comment on the recommendation for use of oncoplastic BCS for treatment of operable breast cancer that is suitable for breast conserving surgery, with the GRADE approach. Based on the voting outcome, the following recommendation emerged as a consensus statement: Oncoplastic breast conserving surgery should be recommended versus standard breast conserving surgery for the treatment of operable breast cancer in adult women who are suitable candidates for breast conserving surgery (with very low certainty of evidence). DISCUSSION: This review has revealed a low level of evidence for most of the important outcomes in oncoplastic surgery with lack of any randomized data and absence of standard tools for evaluation of clinical outcomes and especially patients' values. Despite areas of controversy, about one-third (36%) of panel members expressed a strong recommendation in support of oncoplastic BCS. Presumably, this reflects a synthesis of views on the relative complexity of these techniques, associated complications, impact on quality of life and costs.

Long-term quality of life after preoperative radiochemotherapy in patients with localized and locally advanced breast cancer.

BACKGROUND: Preoperative radiotherapy (PRT) or radiochemotherapy (PRCT) is used in different tumor sites. The aim of the study was to examine the long-term quality of life (QoL) of localized / locally advanced breast cancer patients treated with PRT/PRCT followed by breast-conserving surgery (BCS) or mastectomy (ME). METHODS: Assessment of QoL was done using EORTC QLQ-C30 questionnaires for overall QoL and EORTC QLQ-BR23 for breast-specific QoL. The summary scores were categorized into 4 distinct groups to classify the results. Furthermore, a comparative analysis was performed between the study cohort and a previously published reference cohort of healthy adults. We assessed the impact of different clinical, prognostic, and treatment-related factors on selected items from C30 and BR23 using a dependence analysis. RESULTS: Out of 315 patients treated with PRT/PCRT in the years 1991 to 1999, 203 patients were alive at long-term follow-up after a mean of 17.7 years (range 14-21). 37 patients were lost to follow-up and 61 patients refused to be contacted, leading to 105 patients (64 patients after BCS and 41 after ME) being willing to undergo further clinical assessment regarding QoL outcome. Overall, QoL (QLQ-C30) was rated "excellent" or "good" in 85% (mean value) of all patients (BCS 83%, ME 88%). Comparative analysis between the study cohort and a published healthy control group revealed significantly better global health status and physical and role functioning scores in the PRT/PRCT group. The analysis demonstrates no differences in nausea/vomiting, dyspnea, insomnia, constipation, or financial difficulties. According to the dependence analysis, global QoL was associated with age, operation type and ME reconstruction. CONCLUSION: We did not detect any inferiority of PRT/PRCT compared to a healthy reference group with no hints of a detrimental long-term effect on general and breast-specific quality of life.

Long-term cosmetic outcome after preoperative radio-/chemotherapy in locally advanced breast cancer patients.

BACKGROUND: Preoperative radiotherapy and chemoradiotherapy (PRT/PCRT) represent an increasingly used clinical strategy in different tumor sites. We have previously reported on a PRT/PRCT protocol in patients with locally advanced non-inflammatory breast cancer (LABC) with promising clinical results. However, concerns regarding a possible unfavorable influence on cosmesis still exist. Thus, the aim of the current study was to examine long-term cosmetic outcome in our series of LABC patients treated with PRT/PCRT followed by breast-conserving surgery (BCS) or mastectomy (ME). PATIENTS AND METHODS: Of the 315 patients treated with PRT/PCRT in the years 1991 to 1999, 203 were still alive at long-term follow-up of mean 17.7 years (range 14-21). Thirty-seven patients were lost to follow-up and 58 patients refused to be contacted, which resulted in 107 patients (64 patients after BCS and 43 after mastectomy) being available and willing to undergo further cosmetic assessment. One patient had a complete response after PRT/PCRT and refused surgery. PRT/PCRT consisted of external beam radiation therapy (EBRT) with 50 Gy (5â€¯× 2 Gy/week) to the breast and the supra-/infraclavicular lymph nodes combined with a consecutive electron boost or (in case of BCS) a 10-Gy interstitial brachytherapy boost with Ir-192 prior to EBRT. Overall, chemotherapy was administered either prior to RT or concomitantly in the majority of patients. BCS and mastectomy were performed with and without reconstruction. The cosmetic outcome was assessed by patient questionnaire, panel evaluation, and breast retraction assessment (BRA) score. RESULTS: Eighty percent of all BCS patients rated their overall cosmetic result as "excellent" or "good" as compared to 55.8% after mastectomy. Patient and panel ratings on cosmetic outcomes were similar between the two groups. No grade III or IV fibrosis were detected in any of the groups. The median BRA score after breast conserving surgery was 2.9. CONCLUSION: PRT/PCRT is associated with low grades of fibrosis and a good to excellent long-term cosmetic outcome.

Skin-sparing mastectomy and immediate reconstruction with DIEP flap after breast-conserving therapy.

BACKGROUND: Currently about 70% of women who suffer from breast cancer undergo breast-conserving therapy (BCT) without removing the entire breast. Thus, this surgical approach is the standard therapy for primary breast cancer. If corrections are necessary, the breast surgeon is faced with irritated skin and higher risks of complications in wound healing. After radiation, an implant-based reconstruction is only recommended in selected cases. Correction of a poor BCT outcome is often only solved with an additional extended operation using autologous reconstruction. MATERIAL/METHODS: In our plastic surgery unit, which focuses on breast reconstruction, we offer a skin-sparing or subcutaneous mastectomy, followed by primary breast reconstruction based on free autologous tissue transfer to correct poor BCT outcomes. Between July 2004 and May 2011 we performed 1068 deep inferior epigastric artery perforator (DIEP) flaps for breast reconstruction, including 64 skin-sparing or subcutaneous mastectomies, followed by primary DIEP breast reconstruction procedures after BCT procedures. RESULTS: In all free flap-based breast reconstruction procedures, we had a total flap loss in 0.8% (9 cases). Within the group of patients after BCT, we performed 41 DIEP flaps and 23 ms-2 TRAM flaps after skin-sparing or subcutaneous mastectomies to reconstruct the breast. Among this group we had of a total flap loss in 1.6% (1 case). CONCLUSIONS: In cases of large tumour sizes and/or difficult tumour locations, the initial oncologic breast surgeon should inform the patients of a possibly poor cosmetic result after BCT and radiation. In our opinion a skin-sparing mastectomy with primary breast reconstruction should be discussed as a valid alternative.

Combination of two local flaps for large defects after breast conserving surgery.

PURPOSE: Oncoplastic surgery is a technique for wide excision of breast cancer without compromising the natural shape of the breast. We have combined two local flaps, referred to as a 'combined local flap', for large defects of the breast after a partial mastectomy. PATIENTS AND METHODS: Twenty-one patients with breast cancer underwent a partial mastectomy with immediate reconstruction when the surgical margin was positive and further excision was required or the tumor size was larger than the pre-operative evaluation. Reconstruction was consisted of a rotational local flap and a thoraco-epigastric flap (TEF), so-called a combined local flap. The cosmetic results were self-estimated after chemotherapy and radiotherapy according to a four-point scoring system. RESULTS: The mean age of patients was 53.3 years and the mean tumor size was 2.2 cm. The mean excised breast volume was 133.8 mm(3) and the percentage of excised volume was 20.4%. The cosmetic outcomes were judged as excellent, good, and fair in 11, 8, and 2 cases, respectively. CONCLUSION: The combined local flap, consisting of a rotational local flap and a TEF is a useful oncoplastic technique for large defects after breast-conserving surgery.

Retrospective study of neoadjuvant versus adjuvant radiochemotherapy in locally advanced noninflammatory breast cancer : survival advantage in cT2 category by neoadjuvant radiochemotherapy.

PURPOSE: This retrospective study compares patients treated between 1991 and 1998 with neoadjuvant radiotherapy +/- chemotherapy (RCT) or adjuvant RCT for locally advanced noninflammatory breast cancers (LABC) in terms of pathologic complete response (pCR), 10-year relapse-free (RFS), and overall survival (OS). PATIENTS AND METHODS: Preoperative RCT in 315 and adjuvant RCT in 329 cases consisted in 50 Gy (5 x 2 Gy/week) to the breast and the supra-/infraclavicular lymph nodes. 101 neoadjuvant patients received - in case of breast conservation - a 10-Gy interstitial boost with (192)Ir afterloading before and 214 neoadjuvant patients a preoperative electron boost after external-beam radiotherapy. In the neoadjuvant RCT group, chemotherapy was applied prior to radiotherapy in 192 patients, and simultaneously in 113; ten had no chemotherapy. In the adjuvant RCT group, chemotherapy was applied to 44 patients before surgery and to 166 after surgery; 119 had no chemotherapy. RESULTS: Breast conservation became possible in 50.8% after neoadjuvant RCT for LABC with a pCR rate at surgery of 29.2%. A complete nodal remission (pN0) after RCT was observed in 56% (89/159) of the cN+ (clinically node-positive) neoadjuvant patients. There were trends in favor of preoperative RCT for RFS and OS (hazard ratio [HR] = 0.85; p = 0.09 for RFS; HR = 0.8130; p = 0.1037 for OS). For patients with cT2 tumors the RFS and OS were statistically significantly better (HR = 0.5090; p = 0.0130 for RFS; HR = 0.4390; p = 0.0026 for OS) after neoadjuvant compared to adjuvant RCT. CONCLUSION: Neoadjuvant RCT achieved a pCR rate of 29.2% and a statistically significantly better RFS and OS in patients with cT2-category breast cancer.

Improved safety of autologous breast reconstruction surgery by stabilisation of microsurgical vessel anastomoses using fibrin sealant in 349 free DIEP or fascia-muscle-sparing (fms)-TRAM flaps: a two-centre study.

BACKGROUND: We routinely perform free DIEP flap and fascia-muscle-sparing (fms) TRAM flap procedures using fibrin sealant to stabilise anastomosed vessels, thus avoiding some of the difficulties associated with microsurgical anastomoses. METHODS: Women undergoing elective, autologous breast reconstruction with free DIEP flaps or fms-TRAM flaps between June 2004 and June 2007 in two Interdisciplinary Breast Centres were included in a retrospective chart review. RESULTS: A total of 349 breast reconstructions were performed in 325 women. Of these, 201 (57.6%) were free DIEP flap procedures and 148 (42.4%) were fms-TRAM flap procedures. Average hospital stay was 9.8 days. Complete flap loss was seen in 3 cases (0.9%). Low rates of post-operative complications were observed. CONCLUSIONS: Microsurgical breast reconstruction using free DIEP flaps and fms-TRAM flaps, with fibrin sealant for stabilisation of microvascular anastomoses, provides good post-operative outcome featuring a low incidence of flap loss or other common post-operative complications.

The management of lobular carcinoma in situ (LCIS). Is LCIS the same as ductal carcinoma in situ (DCIS)?

Lobular carcinoma in situ was first described over 60 years ago. Despite the long history, it continues to pose significant difficulties in screening, diagnosis, management and treatment. This is partly due its multi-focal and bilateral presentation, an incomplete understanding of its biology and natural history and perpetuation of misconceptions gathered over the last decades. In this review, the working group on behalf of EUSOMA has attempted to summarise the current thinking and management of this interesting lesion.

Predictive biological markers for response of invasive breast cancer to anthracycline/cyclophosphamide-based primary (radio-)chemotherapy.

BACKGROUND: The role of biological markers for the prediction of neoadjuvant chemotherapy and radio-chemotherapy may be evaluated using pathological complete response [pCR] in patients with invasive breast cancer. MATERIALS AND METHODS: To investigate this, pre-treatment biopsies from 517 patients with locally advanced breast cancer were analyzed for expression of estrogen receptor [ER], progesterone receptor [PgR], Her-2/neu, epidermal growth factor receptor [EGF-R], p53, Bcl-2 and MIB-1 by immunohistochemistry [IHC], and these data were compared to the pathological response after preoperative epirubicine/cyclophosphamide [EC] chemotherapy (+/- radiotherapy). RESULTS: pCR was more frequent (28.30%, 56/198) in tumors that received radio-chemotherapy compared to chemotherapy alone (11.9%, 38/319, p < 0.0001). Patients with high grading, lower ER, PgR, Bcl-2 or a higher proliferation had a significantly greater benefit from chemotherapy. The overexpressions of Her2/neu or EGF-R were weakly correlated to pCR, while p53 staining did not have any predictive value. Younger patients, with negative PgR and high proliferation index, had the highest benefit from EC therapy (56% pCR). The different multivariate indices of binary regression, PLS-DA and SIMCA, had similar predictive quality and were slightly superior to univariate factors. CONCLUSION: This study emphasizes the value of traditional biological markers and Bcl-2 for use in the individual selection of a primary therapy regimen.

Predictors of primary breast cancers responsiveness to preoperative epirubicin/cyclophosphamide-based chemotherapy: translation of microarray data into clinically useful predictive signatures.

BACKGROUND: Our goal was to identify gene signatures predictive of response to preoperative systemic chemotherapy (PST) with epirubicin/cyclophosphamide (EC) in patients with primary breast cancer. METHODS: Needle biopsies were obtained pre-treatment from 83 patients with breast cancer and mRNA was profiled on Affymetrix HG-U133A arrays. Response ranged from pathologically confirmed complete remission (pCR), to partial remission (PR), to stable or progressive disease, "No Change" (NC). A primary analysis was performed in breast tissue samples from 56 patients and 5 normal healthy individuals as a training cohort for predictive marker identification. Gene signatures identifying individuals most likely to respond completely to PST-EC were extracted by combining several statistical methods and filtering criteria. In order to optimize prediction of non responding tumors Student's t-test and Wilcoxon test were also applied. An independent cohort of 27 patients was used to challenge the predictive signatures. A k-Nearest neighbor algorithm as well as two independent linear partial least squares determinant analysis (PLS-DA) models based on the training cohort were selected for classification of the test samples. The average specificity of these predictions was greater than 74% for pCR, 100% for PR and greater than 62% for NC. All three classification models could identify all pCR cases. RESULTS: The differential expression of 59 genes in the training and the test cohort demonstrated capability to predict response to PST-EC treatment. Based on the training cohort a classifier was constructed following a decision tree. First, a transcriptional profile capable to distinguish cancerous from normal tissue was identified. Then, a "favorable outcome signature" (31 genes) and a "poor outcome signature" (26 genes) were extracted from the cancer specific signatures. This stepwise implementation could predict pCR and distinguish between NC and PR in a subsequent set of patients. Both PLS-DA models were implemented to discriminate all three response classes in one step. CONCLUSION: In this study signatures were identified capable to predict clinical outcome in an independent set of primary breast cancer patients undergoing PST-EC.

Immediate gene expression changes after the first course of neoadjuvant chemotherapy in patients with primary breast cancer disease.

PURPOSE: Our goal was to identify genes undergoing expressional changes shortly after the beginning of neoadjuvant chemotherapy for primary breast cancer. EXPERIMENTAL DESIGN: The biopsies were taken from patients with primary breast cancer prior to any treatment and 24 hours after the beginning of the neoadjuvant chemotherapy. Expression analyses from matched pair samples representing 25 patients were carried out with Clontech filter arrays. A subcohort of those 25 paired samples were additionally analyzed with the Affymetrix GeneChip platform. All of the transcripts from both platforms were queried for expressional changes. RESULTS: Performing hierarchical cluster analysis, we clustered pre- and posttreatment samples from individual patients more closely to each other than the samples taken from different patients. This reflects the rather low number of transcripts responding directly to the drugs used. Although transcriptional drug response occurring during therapy differed between individual patients, two genes (p21(WAF1/CIP1) and MIC-1) were up-regulated in posttreatment samples. This could be validated by semiquantitative and real-time reverse transcription-PCR. Partial least- discriminant analysis based on approximately 25 genes independently identified by either Clontech or Affymetrix platforms could clearly discriminate pre- and posttreatment samples. However, correlation of certain gene expression levels as well as of differential patterns and clusters as determined by a different platform was not always satisfying. CONCLUSIONS: This study has demonstrated the potential of monitoring posttreatment changes in gene expression as a measure of the pharmacodynamics of drugs. As a clinical laboratory model, it can be useful to identify patients with sensitive and reactive tumors and to help for optimized choice for sequential therapy and obviously improve relapse- free and overall survival.

Remission rates in breast cancer treated with preoperative chemotherapy and radiotherapy.

PURPOSE: Evaluation of remission rates after neoadjuvant chemotherapy alone or followed by preoperative radiotherapy. PATIENTS AND METHODS: 194 women with 198 biopsy-proven breast tumors were evaluated in this retrospective study. Of the 198 cases evaluated, 64 received neoadjuvant chemotherapy followed by surgery and adjuvant irradiation (CT group). In 134 cases, sequential preoperative chemo-/radiotherapy (CT-RT group) was given. In both groups, endocrine treatment was initiated in case of positive hormone receptor status after chemotherapy. The whole breast was homogeneously irradiated using 2-Gy fractions up to a total dose of 50 Gy, followed by a boost of 6-11 Gy to the tumor. RESULTS: A histologically proven complete remission (pCR) was achieved in 3% (2/64) in the CT and in 42% (56/134) in the CTRT group. The logistic regression analysis, including clinical tumor category (cT), lymph node (cN) and metastasis status (cM), grading (G), hormone receptor status (HRS), number of preoperative chemotherapy cycles, preoperative tumor volume, and preoperative radiotherapy, revealed that HRS (p = 0.0232) and radiotherapy (p < 0.0001) were significant factors for achieving pCR. CONCLUSION: Combination of neoadjuvant chemo-/radiotherapy results in significantly higher rates of complete remission than neoadjuvant chemotherapy alone. The significance for tumor-free and overall survival has to be evaluated.

The Estrogen Receptor Paradox in Breast Cancer: Association of High Receptor Concentrations with Reduced Overall Survival.

Occasional reports have suggested an unfavorable effect of high estrogen receptor (ER) concentrations in primary breast cancer. In a population-based study we identified a subgroup explicitly exhibiting this seemingly paradoxical effect. ER concentrations were prospectively measured in a single laboratory by multipoint DCC assay. The relative risk of death in relation to the concentration of the interval-scaled variables ER and PgR was continually estimated by serial Cox regression analyses. Thus we circumvented loss of information due to primary categorization and avoided assumptions about relations between factor and risk. Based on 2,735 consecutively accrued primary breast cancer cases (median follow-up 56 months) we identified node-negative patients up to 60 years of age as the relevant subpopulation. High (>/=300 fmol/mg protein) ER concentrations exhibited an even more unfavorable impact (p < 0.03) on overall survival than ER concentrations of less than 10 fmol/mg protein. The well-known association of age and ER concentration was definitely excluded as an underlying biological cause for the increased risk. Differences in the distribution of other prognostic factors (HER-2/neu, Ki-67, DNA ploidy) were also excluded. As we observed a preponderance of pT2 tumors in the high ER group, we repeated the analysis, selectively focusing on pT2 tumors in the relevant subgroup, but the effect remained unchanged. In contrast, node-positive patients adjusted for age significantly (p = 0.02) profited from high ER concentrations as compared to the ER-negative group. As the phenomenon did not occur in node-positive patients, receptor defects in the high-ER group seem unlikely. To the contrary, we suspect that ER overexpressing cells are hypersensitive even to low levels of estrogens. Once they have sneaked past local barriers prior to primary surgery, they may cause early death in the absence of appropriate adjuvant endocrine therapy.