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    Evaluation of Pathologic Complete Response (pCR) to Neoadjuvant Chemotherapy in Iranian Breast Cancer Patients with Estrogen Receptor Positive and HER2 Negative and impact of predicting variables on pCR. Omranipour Ramesh,Jalili Roghiyeh,Yazdankhahkenary Adel,Assarian Abdolali,Mirzania Mehrzad,Eslami Bita European journal of breast health Objective:The pathologic complete response (pCR) in the breast and axillary lymph node after neoadjuvant chemotherapy (NAC) would improve outcomes and it is used as a surrogate marker for survival. Our objective was to evaluate the breast and nodal pCR in breast cancer patients with estrogen receptor-positive (ER) and HER2 negative subtypes. Meanwhile, we sought to examine the impact of predicting factors on the rate of pCR. Materials and Methods:In this multicenter retrospective study, medical records data of 314 women with ER+/HER2- breast cancer subtype who received neoadjuvant chemotherapy was extracted from oncology centers' data between 2011 and 2018. Breast and axillary lymph node pCR were assessed. Meanwhile, receiver operating characteristic (ROC) curve analysis was performed to assess the predictive value for proliferative index (Ki-67%) expression. Results:Breast pCR was seen in 25.2% (n=79) of the 314 cancer patients and partial response was seen in 47.8% (n=150), too. Nodal pCR was reported in 30.9% (n=97) of the 249 node-positive patients. The overall pCR (both breast & node) was observed in 14.6 % (n=46) of the 272 patients in which the data of breast and nodal were available. We identified 22.5% as the best cut-off value for ki-67 expression in predicting complete response to NAC. Conclusion:The pCR rate after NAC in ER+/HER2- subtypes of breast cancer is low. Therefore, the optimal therapy for these patients should be further investigated. 10.5152/ejbh.2020.5487
    Efficacy of neoadjuvant endocrine therapy compared with neoadjuvant chemotherapy in pre-menopausal patients with oestrogen receptor-positive and HER2-negative, lymph node-positive breast cancer. Kim Hee Jeong,Noh Woo Chul,Lee Eun Sook,Jung Yong Sik,Kim Lee Su,Han Wonshik,Nam Seok Jin,Gong Gyung -Yub,Kim Hwa Jung,Ahn Sei Hyun Breast cancer research : BCR INTRODUCTION:Neoadjuvant endocrine therapy (NET) has demonstrated efficacy in post-menopausal patients with hormone-responsive breast cancer. This trial was designed to compare the efficacy of neoadjuvant chemotherapy (NCT) with NET in pre-menopausal breast cancer. PATIENTS AND METHODS:In this prospective, randomised, phase III study, oestrogen receptor (ER)-positive, HER2-negative, and lymph node-positive pre-menopausal breast cancer patients were recruited from 7 hospitals in South Korea. Enrolled patients were randomly assigned (1:1) to receive 24 weeks of either NCT or NET with goserelin and tamoxifen. The primary purpose was to evaluate the non-inferiority of NET compared to NCT using clinical response, assessed by MRI. Besides, pathological complete response rate (pCR), changes in Ki-67 expression, breast conservation surgery (BCS) rate, and quality of life were included as secondary endpoints. RESULTS:A total of 187 patients were assigned to receive NCT (n = 95) or NET (n = 92), and 87 patients in each group completed treatments. More NCT patients had complete response or partial response than NET patients using MRI (NCT 83.7% vs. NET 52.9%, 95% CI 17.6-44.0, p < 0.001) and callipers (NCT 83.9% vs. NET 71.3%, 95% CI 0.4-24.9, p = 0.046). Three NCT patients (3.4%) and one NET patient (1.2%) showed pCR (p < 0.005). No difference existed in the conversion rate of BCS (13.8% for NCT vs. 11.5% for NET, p = 0.531) and Ki-67 change (p = 0.114) between the two groups. Nineteen NCT patients had treatment-related grade 3 or worse events compared with none in the NET group. CONCLUSIONS:Better clinical responses were observed in pre-menopausal patients after 24 weeks of NCT compared to those observed after NET. TRIAL REGISTRATION:Clinicaltrials.gov, NCT01622361. Registration June 19, 2012. 10.1186/s13058-020-01288-5
    Effect of neoadjuvant anthracycline-taxane-based chemotherapy in different biological breast cancer phenotypes: overall results from the GeparTrio study. Huober Jens,von Minckwitz Gunter,Denkert Carsten,Tesch Hans,Weiss Erich,Zahm Dirk Michael,Belau Antje,Khandan Fariba,Hauschild Maik,Thomssen Christoph,Högel Bernhard,Darb-Esfahani Silvia,Mehta Keyur,Loibl Sibylle Breast cancer research and treatment In order to explore the effect of neoadjuvant chemotherapy (NACT) on clinical mid-course and pathological complete response (pCR) at surgery in different biological breast cancer subtypes. The GeparTrio study included 2,072 patients with operable or locally advanced breast cancer. After two cycles with docetaxel, doxorubicin and cyclophosphamide (TAC) patients were randomized according to their clinical response. Clinical and biological factors were assessed for predicting clinically mid-course response and pCR at surgery. The overall pCR rate, defined as no invasive residuals in breast and axilla, was 20.5%. The highest pCR rate of 57% was observed in patients below 40 years of age with triple negative or grade 3 tumors. Independent factors for mid-course response and pCR were: young age, non-T4 tumors, high grade, and hormone receptor status, the strongest single predictive factor. Within the biological subtypes, grading was an independent factor to predict pCR for luminal tumors, clinical tumor stage for the HER2 like tumors and age for the triple negative ones. Grading gave independent information for mid-course response within the triple negative group. No factor predicted mid-course response within the other groups. Grading and age can identify subgroups within the luminal and triple negative patients who have an increased benefit from NACT. 10.1007/s10549-010-1103-9
    Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. Denkert Carsten,Loibl Sibylle,Noske Aurelia,Roller Marc,Müller Berit Maria,Komor Martina,Budczies Jan,Darb-Esfahani Silvia,Kronenwett Ralf,Hanusch Claus,von Törne Christian,Weichert Wilko,Engels Knut,Solbach Christine,Schrader Iris,Dietel Manfred,von Minckwitz Gunter Journal of clinical oncology : official journal of the American Society of Clinical Oncology PURPOSE Preclinical data suggest a contribution of the immune system to chemotherapy response. In this study, we investigated the prespecified hypothesis that the presence of a lymphocytic infiltrate in cancer tissue predicts the response to neoadjuvant chemotherapy. METHODS We investigated intratumoral and stromal lymphocytes in a total of 1,058 pretherapeutic breast cancer core biopsies from two neoadjuvant anthracycline/taxane-based studies (GeparDuo, n = 218, training cohort; and GeparTrio, n = 840, validation cohort). Molecular parameters of lymphocyte recruitment and activation were evaluated by kinetic polymerase chain reaction in 134 formalin-fixed, paraffin-embedded tumor samples. Results In a multivariate regression analysis including all known predictive clinicopathologic factors, the percentage of intratumoral lymphocytes was a significant independent parameter for pathologic complete response (pCR) in both cohorts (training cohort: P = .012; validation cohort: P = .001). Lymphocyte-predominant breast cancer responded, with pCR rates of 42% (training cohort) and 40% (validation cohort). In contrast, those tumors without any infiltrating lymphocytes had pCR rates of 3% (training cohort) and 7% (validation cohort). The expression of inflammatory marker genes and proteins was linked to the histopathologic infiltrate, and logistic regression showed a significant association of the T-cell-related markers CD3D and CXCL9 with pCR. CONCLUSION The presence of tumor-associated lymphocytes in breast cancer is a new independent predictor of response to anthracycline/taxane neoadjuvant chemotherapy and provides useful information for oncologists to identify a subgroup of patients with a high benefit from this type of chemotherapy. 10.1200/JCO.2009.23.7370
    Androgen receptor expression in primary breast cancer and its predictive and prognostic value in patients treated with neoadjuvant chemotherapy. Loibl Sibylle,Müller Berit Maria,von Minckwitz Gunter,Schwabe Michael,Roller Marc,Darb-Esfahani Silvia,Ataseven Beyhan,du Bois Andreas,Fissler-Eckhoff Annette,Gerber Bernd,Kulmer Uwe,Alles Jens-Uwe,Mehta Keyur,Denkert Carsten Breast cancer research and treatment The androgen receptor (AR) has been shown to be of potential prognostic importance in retrospective cohorts. We evaluated immunohistochemical AR expression on a tissue microarray of 673 core biopsies from primary breast cancer patients treated with neoadjuvant docetaxel/doxorubicin/cyclophosphamide (TAC) chemotherapy in the prospective GeparTrio phase-III trial. AR was detected in 53.2% of tumours. Lowest AR expression was detected in triple-negative breast cancers (TNBC) with 21.2%. Highest AR expression was observed in Luminal A-like tumours with 67%. In AR-positive tumours, pathological complete response (pCR) rate was 12.8% compared to 25.4% in AR-negative tumours (P < 0.0001). In multivariate analysis, AR independently predicted pCR (OR 1.86; 95% CI [1.16-2.79] P = 0.0086). Overall patients with an AR-positive tumour had a significant better disease-free (DFS) (AR-positive 78.9% vs. AR-negative 72.5%; log-rank P = 0.0329) and overall survival (OS) (88.8% vs. 82.7%; log-rank P = 0.0234) than those with AR-negative tumours. Stratified analysis revealed that in the TNBC subgroup, but not in the other subgroups defined by ER, PgR and HER2, AR expression predicted a better DFS (AR-positive 85.7% vs. AR-negative 65.5% log-rank P = 0.0544) and OS (95.2% vs. 76.2%; log-rank P = 0.0355). Within the non-pCR subgroup, AR positivity selected a group with a significant better DFS (P = 0.045) and OS (0.021) but not within the pCR group. Patients with an AR-negative tumour have a higher chance of achieving a pCR than those with an AR-positive one. But, patients with AR-positive tumours have a better survival especially if they did not achieve a pCR. 10.1007/s10549-011-1715-8
    Ki67 measured after neoadjuvant chemotherapy for primary breast cancer. von Minckwitz Gunter,Schmitt Wolfgang D,Loibl Sibylle,Müller Berit M,Blohmer Jens U,Sinn Bruno V,Eidtmann Holger,Eiermann Wolfgang,Gerber Bernd,Tesch Hans,Hilfrich Jörn,Huober Jens,Fehm Tanja,Barinoff Jana,Rüdiger Thomas,Erbstoesser Erhard,Fasching Peter A,Karn Thomas,Müller Volkmar,Jackisch Christian,Denkert Carsten Clinical cancer research : an official journal of the American Association for Cancer Research PURPOSE:The value of Ki67 measured on residual disease after neoadjuvant chemotherapy is not sufficiently described. EXPERIMENTAL DESIGN:Participants of the GeparTrio study with primary breast cancer randomly received neoadjuvant response-guided [8 cycles TAC (docetaxel/doxorubicin/cyclophosphamide) in responding and TAC-NX (vinorelbine/capecitabine) in nonresponding patients] or conventional (6 cycles TAC) chemotherapy according to interim response assessment. Ki-67 levels were centrally measured immunohistochemically after neoadjuvant treatment if tumor tissue was available. Here, we analyze 1,151 patients having a pathologic complete response (pCR; n, 484), or residual disease with low (0-15%), intermediate (15.1-35%), or high (35.1-100%) posttreatment Ki67 levels in 488, 77, and 102 patients, respectively. RESULTS:Patients with high posttreatment Ki67 levels showed higher risk for disease relapse (P < 0.0001) and death (P < 0.0001) compared with patients with low or intermediate Ki67 levels. Patients with low Ki67 levels showed a comparable outcome to patients with a pCR (P = 0.211 for disease-free and P = 0.779 for overall survival). Posttreatment Ki67 levels provided more prognostic information than pretreatment Ki67 levels or changes of Ki67 from pre- to posttreatment. Information on pCR plus posttreatment Ki67 levels surmount the prognostic information of pCR alone in hormone-receptor-positive disease [hazard ratios (HR), 1.82-5.88] but not in hormone-receptor-negative disease (HR: 0.61-1.73). Patients with conventional and response-guided treatment did not show a different distribution of posttreatment Ki67 (P = 0.965). CONCLUSIONS:Posttreatment Ki67 levels provide prognostic information for patients with hormone-receptor-positive breast cancer and residual disease after neoadjuvant chemotherapy. Levels were not prognostic for outcome after response-guided chemotherapy. High posttreatment Ki67 indicates the need for innovative postneoadjuvant treatments. 10.1158/1078-0432.CCR-12-3628
    Impact of multifocal or multicentric disease on surgery and locoregional, distant and overall survival of 6,134 breast cancer patients treated with neoadjuvant chemotherapy. Ataseven Beyhan,Lederer Bianca,Blohmer Jens U,Denkert Carsten,Gerber Bernd,Heil Jörg,Kühn Thorsten,Kümmel Sherko,Rezai Mahdi,Loibl Sibylle,von Minckwitz Gunter Annals of surgical oncology BACKGROUND:The impact of tumor focality on type of surgery, local recurrence rate, and survival after neoadjuvant chemotherapy (NACT) for breast cancer is not fully understood. This study aimed to compare local recurrence-free survival (LRFS), disease-free survival (DFS), and overall survival (OS) according to focality stratified by type of surgery and pathologic complete response (pCR), with a focus on breast conservation. METHODS:Participants (n = 6,134) in the GeparTrio, GeparQuattro, and GeparQuinto trials with operable or locally advanced tumors receiving NACT were classified as having unifocal (1 lesion), multifocal (≥ 2 lesions in 1 quadrant), or multicentric (≥ 1 lesion in ≥ 2 quadrants) disease. The study investigated LRFS, DFS, and OS according to focality stratified by type of surgery and pathologic complete response. RESULTS:The patients were classified as having unifocal (n = 4,733, 77.1 %), multifocal (n = 820, 13.4 %), or multicentric (n = 581, 9.5 %) tumors. The respective pCR rates were 19.4, 16.5, and 14.4 %. Breast conservation was performed for 71.6, 58.5, and 30 % of these patients, respectively (P < 0.001). The LRFS rate was 92.9 % for the unifocal, 95.1 % for the multifocal, and 90.4 % for the multicentric tumors (P = 0.002). The patients with multicentric tumors but not the patients with multifocal tumors had worse DFS (P < 0.001) and OS (P = 0.009) than the patients with unifocal tumors. However, LRFS, DFS, and OS were not inferior for the patients with multicentric or multifocal tumors if pCR was achieved or breast conservation was performed after NACT. CONCLUSION:Breast conservation is feasible for clinically multifocal or multicentric breast cancer patients who undergo NACT without worsening LRFS if tumor-free margins can be attained or if patients achieve a pCR. 10.1245/s10434-014-4122-7
    Clinical usefulness and relevance of intermediate endpoints for cytotoxic neoadjuvant therapy. Fontanella Caterina,Loibl Sibylle,von Minckwitz Gunter Breast (Edinburgh, Scotland) Intermediate endpoints are surrogate markers of treatment efficacy assessed earlier than the true outcome of interest. Tumor response after systemic neoadjuvant therapy is considered a suitable intermediate endpoint, especially for specific breast cancer subtypes. Response can be evaluated either after only 1 cycle of treatment by clinical evaluation or at the end of the planned neoadjuvant treatment by histomorphologic examination of all surgically removed tissues from the breast and regional nodes. Although several meta-analyses showed a lower risk of death among patients who attain a pathologic complete response (pCR) compared with patients with residual tumor in breast and/or lymph nodes after neoadjuvant therapy, a statistically significant linkage between increased pCR rate by a specific treatment and improvement of survival by the same treatment has not been demonstrated yet. Therefore, formal surrogacy of pCR is not established. Moreover, the better definition of pCR is still an open issue: a large pooled analysis demonstrated that patients who attained ypT0 ypN0 (no invasive or non-invasive residual cancer in breast and nodes) experienced longer DFS (p < 0.001) compared with patients who attained ypTis ypN0 (no invasive residual in breast and nodes irrespective of residual non-invasive disease). Nevertheless, the Food and Drug Administration (FDA) recently allowed using pCR as a surrogate endpoint for accelerated approval process. Several meta-analyses demonstrated the greatest prognostic value of pCR in more aggressive breast cancer subtypes (i.e. triple-negative, HER2-positive, or high grade breast cancer). Usefulness of an earlier intermediate endpoints was prospectively demonstrated in the GeparTrio trial in which patients showing an early response achieved 4-times more frequently a pCR than those without early response. 10.1016/j.breast.2015.07.020