Publications by authors named "Gunter von Minckwitz"

237 Publications

Palbociclib for Residual High-Risk Invasive HR-Positive and HER2-Negative Early Breast Cancer-The Penelope-B Trial.

J Clin Oncol 2021 Apr 1:JCO2003639. Epub 2021 Apr 1.

German Breast Group, Neu-Isenburg, Germany.

Purpose: About one third of patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer who have residual invasive disease after neoadjuvant chemotherapy (NACT) will relapse. Thus, additional therapy is needed. Palbociclib is a cyclin-dependent kinase 4 and 6 inhibitor demonstrating efficacy in the metastatic setting.

Patients And Methods: PENELOPE-B (NCT01864746) is a double-blind, placebo-controlled, phase III study in women with hormone receptor-positive, human epidermal growth factor receptor 2-negative primary breast cancer without a pathological complete response after taxane-containing NACT and at high risk of relapse (clinical pathological staging-estrogen receptor grading score ≥ 3 or 2 and ypN+). Patients were randomly assigned (1:1) to receive 13 cycles of palbociclib 125 mg once daily or placebo on days 1-21 in a 28-day cycle in addition to endocrine therapy (ET). Primary end point is invasive disease-free survival (iDFS). Final analysis was planned after 290 iDFS events with a two-sided efficacy boundary < .0463 because of two interim analyses.

Results: One thousand two hundred fifty patients were randomly assigned. The median age was 49.0 years (range, 19-79), and the majority were ypN+ with Ki-67 ≤ 15%; 59.4% of patients had a clinical pathological staging-estrogen receptor grading score ≥ 3. 50.1% received aromatase inhibitor, and 33% of premenopausal women received a luteinizing hormone releasing hormone analog in addition to either tamoxifen or an aromatase inhibitor. After a median follow-up of 42.8 months (92% complete), 308 events were confirmed. Palbociclib did not improve iDFS versus placebo added to ET-stratified hazard ratio, 0.93 (95% repeated CI, 0.74 to 1.17) and two-sided weighted log-rank test (Cui, Hung, and Wang) = .525. There was no difference among the subgroups. Most common related serious adverse events were infections and vascular disorders in 113 (9.1%) patients with no difference between the treatment arms. Eight fatal serious adverse events (two palbociclib and six placebo) were reported.

Conclusion: Palbociclib for 1 year in addition to ET did not improve iDFS in women with residual invasive disease after NACT.
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http://dx.doi.org/10.1200/JCO.20.03639DOI Listing
April 2021

Association of Immunophenotype With Pathologic Complete Response to Neoadjuvant Chemotherapy for Triple-Negative Breast Cancer: A Secondary Analysis of the BrighTNess Phase 3 Randomized Clinical Trial.

JAMA Oncol 2021 Feb 18. Epub 2021 Feb 18.

The University of Texas MD Anderson Cancer Center, Houston.

Importance: Adding carboplatin to standard neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) likely benefits a subset of patients; however, determinants of benefit are poorly understood.

Objective: To define the association of molecular subtype, tumor proliferation, and immunophenotype with benefit of carboplatin added to NAC for patients with stages II to III TNBC.

Design, Setting, And Participants: This was a prespecified secondary analysis of a phase 3, double-blind, randomized clinical trial (BrighTNess) that enrolled 634 women across 145 centers in 15 countries. Women with clinical stages II to III TNBC who had undergone pretreatment biopsy were eligible to participate. Whole transcriptome RNA sequencing was performed on the biopsy specimens. The prespecified end point was association of pathologic complete response (pCR) with gene expression-based molecular subtype, with secondary end points investigating established signatures (proliferation, immune) and exploratory analyses of immunophenotype. Data were collected from April 2014 to March 2016. The study analyses were performed from January 2018 to March 2019.

Interventions: Neoadjuvant chemotherapy with paclitaxel followed by doxorubicin and cyclophosphamide, or this same regimen with carboplatin or carboplatin plus veliparib.

Main Outcomes And Measures: Association of gene expression-based molecular subtype (PAM50 and TNBC subtypes) with pCR.

Results: Of the 634 women (median age, 51 [range, 22-78] years) enrolled in BrighTNess, 482 (76%) patients had evaluable RNA sequencing data, with similar baseline characteristics relative to the overall intention-to-treat population. Pathologic complete response was significantly more frequent in PAM50 basal-like vs nonbasal-like cancers overall (202 of 386 [52.3%] vs 34 of 96 [35.4%]; P = .003). Carboplatin benefit was not significantly different in basal-like vs nonbasal-like subgroups (P = .80 for interaction). In multivariable analysis, proliferation (hazard ratio, 0.36; 95% CI, 0.21-0.61; P < .001) and immune (hazard ratio, 0.62; 95% CI, 0.49-0.79; P < .001) signatures were independently associated with pCR. Tumors above the median for proliferation and immune signatures had the highest pCR rate (84 of 125; 67%), while those below the median for both signatures had the lowest pCR rate (42 of 125; 34%). Exploratory gene expression immune analyses suggested that tumors with higher inferred CD8+ T-cell infiltration may receive greater benefit with addition of carboplatin.

Conclusions And Relevance: In this secondary analysis of a randomized clinical trial, triple-negative breast cancer subtyping revealed high pCR rates in basal-like and immunomodulatory subsets. Analysis of biological processes related to basal-like and immunomodulatory phenotypes identified tumor cell proliferation and immune scores as independent factors associated with achieving pCR; the benefit of carboplatin on pCR was seen across all molecular subtypes. Further validation of immunophenotype with existing biomarkers may help to escalate or de-escalate therapy for patients with TNBC.

Trial Registration: ClinicalTrials.gov Identifier: NCT02032277.
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http://dx.doi.org/10.1001/jamaoncol.2020.7310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893540PMC
February 2021

Patient-reported outcomes from KATHERINE: A phase 3 study of adjuvant trastuzumab emtansine versus trastuzumab in patients with residual invasive disease after neoadjuvant therapy for human epidermal growth factor receptor 2-positive breast cancer.

Cancer 2020 Jul 14;126(13):3132-3139. Epub 2020 Apr 14.

NSABP Foundation and Houston Methodist Cancer Center, Houston, Texas.

Background: The phase 3 KATHERINE trial demonstrated significantly improved invasive disease-free survival with adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab in patients with HER2-positive early breast cancer and residual invasive disease after neoadjuvant chemotherapy plus HER2-targeted therapy.

Methods: Patients who received taxane- and trastuzumab-containing neoadjuvant therapy (with/without anthracyclines) and had residual invasive disease (breast and/or axillary nodes) at surgery were randomly assigned to 14 cycles of adjuvant T-DM1 (3.6 mg/kg intravenously every 3 weeks) or trastuzumab (6 mg/kg intravenously every 3 weeks). The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (QLQ-C30) and breast cancer module (QLQ-BR23) were completed at screening, at day 1 of cycles 5 and 11, within 30 days after study drug completion, and at 6- and 12-month follow-up visits.

Results: Of patients who were randomly assigned to T-DM1 (n = 743) and trastuzumab (n = 743), 612 (82%) and 640 (86%), respectively, had valid baseline and ≥1 postbaseline assessments. No clinically meaningful changes (≥10 points) from baseline in mean QLQ-C30 and QLQ-BR23 scores occurred in either arm. More patients receiving T-DM1 reported clinically meaningful deterioration at any assessment point in role functioning (49% vs 41%), appetite loss (38% vs 28%), constipation (47% vs 38%), fatigue (66% vs 60%), nausea/vomiting (39% vs 30%), and systemic therapy side effects (49% vs 36%). These differences were no longer apparent at the 6-month follow-up assessment, except for role functioning (23% vs 16%).

Conclusion: These data suggest that health-related quality of life was generally maintained in both study arms over the course of treatment.
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http://dx.doi.org/10.1002/cncr.32873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317721PMC
July 2020

PIK3CA H1047R Mutation Associated with a Lower Pathological Complete Response Rate in Triple-Negative Breast Cancer Patients Treated with Anthracycline-Taxane-Based Neoadjuvant Chemotherapy.

Cancer Res Treat 2020 Jul 4;52(3):689-696. Epub 2020 Feb 4.

Institute of Pathology, Charité Universitätsmedizin Berlin, Berlin, Germany.

Purpose: PIK3CA, encoding for subunit p110a of phosphatidylinositol 3 kinase, is frequently mutated in breast cancer. PIK3CA mutation was predictive for pathological complete response (pCR) in human epidermal growth factor 2 positive breast cancer. This study explores the association of PIK3CA mutation and pCR in triple-negative breast cancer (TNBC) treated with neoadjuvant chemotherapy.

Materials And Methods: A total of 92 patients with TNBC derived from a prospectively randomized phase II trial GeparSixto study (NCT01426880). Exon 9 and exon 20 of PIK3CA mutations were evaluated by using classical Sanger method with formalin-fixed paraffin-embedded tumor tissues.

Results: Seven of 90 tumors (7.8%) were detectable with a PIK3CA H1047R mutation. Overall, PIK3CA H1047R mutation was significantly associated with a lower pCR rate (14.3% vs. 56.6%; odds ratio, 0.128; 95% confidence interval [CI], 0.015 to 1.108; p=0.047). In carboplatin- containing treatment patients, H1047R mutation trended to predict a lower pCR rate (20% vs. 62.5%; p=0.146). In a multivariable analysis, H1047R mutation trended to predict a lower pCR rate (hazard ratio, 0.1; 95% CI, 0.01 to 1; p=0.056).

Conclusion: TNBC with a PIK3CA H1047R mutation was less likely to achieve pCR after anthracycline-based neoadjuvant chemotherapy. Development of H1047R mutant selective inhibitors might be helpful to conquer this subtype of breast cancer.
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http://dx.doi.org/10.4143/crt.2019.497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373870PMC
July 2020

Breast Conservation After Neoadjuvant Chemotherapy for Triple-Negative Breast Cancer: Surgical Results From the BrighTNess Randomized Clinical Trial.

JAMA Surg 2020 03 18;155(3):e195410. Epub 2020 Mar 18.

Department of Breast Surgery, Helios Klinikum Berlin-Buch, Berlin, Germany.

Importance: Neoadjuvant systemic therapy (NST) is often administered to enable breast-conserving therapy (BCT) in stages II to III breast cancer.

Objectives: To prospectively evaluate the role of NST in conversion from BCT ineligibility to BCT eligibility and to assess the association of response to NST, germline BRCA (gBRCA) status, and region of treatment with surgical choice in women with triple-negative breast cancer (TNBC).

Design, Setting, And Participants: This prespecified secondary analysis of a multicentered, phase 3, double-blind, randomized clinical trial (BrighTNess) enrolled 634 eligible women across 145 centers in 15 countries in North America, Europe, and Asia. Women with operable, clinical stages II to III TNBC who underwent gBRCA mutation testing before initiating NST were eligible to participate. Data were collected from April 1, 2014, to December 8, 2016. This preplanned analysis was performed from January 5, 2018, to October 28, 2019.

Interventions: Study participants were randomized to receive 12 weeks of weekly paclitaxel alone or with the addition of carboplatin and/or veliparib, followed by 4 cycles of doxorubicin hydrochloride and cyclophosphamide.

Main Outcomes And Measures: Surgeons assessed BCT candidacy by clinical and radiographic criteria before and after NST. Surgical choices and whether BCT eligibility was associated with the likelihood of pathologic complete response were then analyzed.

Results: Among the 634 randomized patients (median age, 51 [range, 22-78] years), pre- and post-NST assessments were available for 604 patients. Of 141 patients deemed BCT ineligible at baseline, 75 (53.2%) converted to BCT eligible. Overall, 342 (68.1%) of 502 patients deemed BCT eligible after NST underwent BCT, including 42 (56.0%) of the 75 who converted to BCT eligible. Patients treated in Europe and Asia were more likely to undergo BCT (odds ratio, 2.66; 95% CI, 1.84-3.84) compared with those treated in North America. Among patients without gBRCA mutation undergoing mastectomy, those treated in North America were more likely to undergo contralateral prophylactic mastectomy (57 of 81 [70.4%] vs 6 of 30 [20.0%]; P < .001). Rates of pathologic complete response were similar between patients deemed BCT eligible at baseline and those who were BCT ineligible but converted to BCT eligibility after NST (55.3 [235 of 425] vs 49.3% [37 of 75]; P = .38).

Conclusions And Relevance: This prospective analysis of NST and BCT eligibility in TNBC demonstrates a conversion from BCT ineligibility to BCT eligibility of 53.2%. Lower BCT rates among eligible patients and higher bilateral mastectomy rates among patients without gBRCA mutation in North America merit investigation.

Trial Registration: ClinicalTrials.gov identifier: NCT02032277.
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http://dx.doi.org/10.1001/jamasurg.2019.5410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990971PMC
March 2020

Human leucocyte antigen class I in hormone receptor-positive, HER2-negative breast cancer: association with response and survival after neoadjuvant chemotherapy.

Breast Cancer Res 2019 12 11;21(1):142. Epub 2019 Dec 11.

German Breast Group Forschungs GmbH, Neu-Isenburg, Germany.

Background: Clinical application of cancer immunotherapy requires a better understanding of tumor immunogenicity and the tumor microenvironment. HLA class I molecules present antigens to CD8 cytotoxic cells. Their loss or downregulation is frequently found in tumors resulting in reduced T cell responses and worse prognosis.

Methods: We evaluated HLA class I heavy chain expression by immunohistochemistry in 863 biopsies (GeparTrio trial). Patients received neoadjuvant chemotherapy and adjuvant endocrine treatment if tumors were hormone receptor-positive (HR+). In parallel, the expression of HLA-A was analyzed using a microarray cohort of 320 breast cancer patients from the MD Anderson Cancer Center. We evaluated its association with clinical outcome, tumor-infiltrating lymphocytes (TILs), and immune cell metagenes.

Results: In HR+/HER2- breast cancer, HLA class I heavy chain expression was associated with increased TILs and better response to chemotherapy (7% vs. 14% pCR rate, P = 0.029), but worse disease-free survival (hazard ratio (HR) 1.6 (1.1-2.4); P = 0.024). The effect was significant in a multivariate model adjusted for clinical and pathological variables (HR 1.7 (1.1-2.6); P = 0.016) and was confirmed by analysis of HLA-A in a microarray cohort. HLA-A was correlated to most immune cell metagenes. There was no association with response or survival in triple-negative or HER2+ disease.

Conclusions: The study confirms the negative prognostic role of lymphocytes in HR+ breast cancer and points at a complex interaction between chemotherapy, endocrine treatment, and tumor immunogenicity. The results point at a subtype-specific and potentially treatment-specific role of tumor-immunological processes in breast cancer with different implications in triple-negative and hormone receptor-positive disease.
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http://dx.doi.org/10.1186/s13058-019-1231-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907189PMC
December 2019

Early assessment with magnetic resonance imaging for prediction of pathologic response to neoadjuvant chemotherapy in triple-negative breast cancer: Results from the phase III BrighTNess trial.

Eur J Surg Oncol 2020 02 5;46(2):223-228. Epub 2019 Oct 5.

Helios Klinikum Berlin-Buch, Berlin, Germany.

Introduction: The ability of breast magnetic resonance imaging (MRI) to predict pathologic complete response (pCR) to neoadjuvant systemic therapy (NST) varies across biological subtypes. We sought to determine how well breast MRI findings following initial treatment on the phase III BrighTNess trial correlated with pCR in patients with triple negative breast cancer (TNBC).

Methods: Baseline and mid-treatment imaging and pathologic response data were available in 519 patients with stage II-III TNBC who underwent NST as per protocol. MRI complete response (mCR) was defined as disappearance of all target lesion(s) and MRI partial response (mPR) as a ≥50% reduction in the largest tumor diameter.

Results: Overall, mCR was demonstrated in 116 patients (22%), whereas 166 (32%) had mPR and 237 (46%) had stable/progressive disease (SD/PD). The positive predictive value (PPV), negative predictive value, and overall accuracy of the mid-treatment MRI for pCR were 78%, 56%, and 61%, respectively; accuracy did not differ significantly between gBRCA mutation carriers and non-carriers (52% vs. 63%, p = 0.10). When compared to patients with SD/PD, those with mPR or mCR were 3.35-fold (95% CI 2.07-5.41) more likely to have pCR at surgery. MRI response during NST was significantly associated with eligibility for breast-conserving surgery following completion of treatment (93.1% for mCR vs. 81.6% for SD/PD, p < 0.001).

Conclusions: Complete response on mid-treatment MRI in the BrighTNess trial had a PPV of 78% for demonstration of pCR after completion of NST in TNBC. However, a substantial proportion of patients with mPR or SD/PD also achieved a pCR.

Clinical Trial Registration: NCT02032277.
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http://dx.doi.org/10.1016/j.ejso.2019.10.002DOI Listing
February 2020

Post-Mastectomy Radiotherapy After Neoadjuvant Chemotherapy in Breast Cancer: A Pooled Retrospective Analysis of Three Prospective Randomized Trials.

Ann Surg Oncol 2019 Nov 26;26(12):3892-3901. Epub 2019 Jul 26.

German Breast Group, Neu-Isenburg, Germany.

Background: The impact of locoregional radiotherapy (RT) after neoadjuvant chemotherapy (NACT) and mastectomy in breast cancer patients is currently unclear. Several publications have suggested that patients with a favorable response to NACT might not benefit from RT after mastectomy.

Methods: A retrospective analysis of three prospective randomized NACT trials was performed. Information on the use of RT was available for 817 breast cancer patients with non-inflammatory breast cancer who underwent mastectomy after NACT within the GeparTrio, GeparQuattro, and GeparQuinto-trials. RT was administered to 676 of these patients (82.7%).

Results: The 5-year cumulative incidence of locoregional recurrence (LRR) was 15.2% (95% confidence interval [CI] 9.0-22.8%) in patients treated without RT and 11.3% in patients treated with RT (95% CI 8.7-14.3%). In the multivariate analysis, RT was associated with a lower risk of LRR (hazard ratio 0.51, 95% CI 0.27-1.0; p = 0.05). This effect was shown especially in patients with cT3/4 tumors, as well as in patients who were cN+ before neoadjuvant therapy, including those who converted to ypN0 after neoadjuvant therapy. In the bivariate analysis, disease-free survival was significantly worse in patients who received RT, however this was not confirmed in the multivariate analysis.

Conclusions: Our results suggest that RT reduces the LRR rates in breast cancer patients who receive a mastectomy after NACT without an improvement in DFS. Prospective randomized controlled trials such as the National Surgical Adjuvant Breast and Bowel Project B-51/RTOG 1304 trial will analyze whether RT has any benefit in patients who have a favorable response after NACT.
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http://dx.doi.org/10.1245/s10434-019-07635-xDOI Listing
November 2019

Fatal events during clinical trials: an evaluation of deaths during breast cancer studies.

Breast Cancer 2019 Nov 28;26(6):826-834. Epub 2019 Jun 28.

German Breast Group, GBG Forschungs GmbH, Martin Behaim Strasse 12, 63263, Neu-Isenburg, Germany.

Background: Information on deaths occurring during oncological clinical trials has never been systematically assessed. Here, we examine the incidence of death and the profile of patients who died during randomized clinical breast cancer (BC) trials.

Methods: Information on fatal events during German Breast Group (GBG) led BC trials was prospectively captured. Data were derived from the trial databases and death narratives. All deaths were evaluated for possible causes, underlying conditions, treatment relatedness, time point and rate of autopsies.

Results: From 12/1996 to 01/2017, 23,387 patients were treated within 32 trials. Of those 88 (0.4%) died on therapy within 17 trials. Median age was 64 [range 35-84] years, 63.2% of patients had a body mass index (BMI) ≥ 25 kg/m; 65.9% 1-3 and 22.7% ≥ 4 comorbidities; 61.4% 1-2 cardiovascular risk factors (CRFs); 26.4% took > 3 drugs; 81.7% had ECOG 0; 50.0% stage III, 76.7% luminal BC. The main causes of death were infection (38.6%; of those, 82.3% sepsis, 17.6% pneumonia), heart failure (14.8%), and pulmonary embolism (13.6%). Fatal events mainly occurred within the first 4 therapy cycles (55.7%), in the investigational arm (66.7%) and under anthracycline-taxane-based chemotherapy (51.1%). A relationship with the treatment was declared in 27.3% of the cases. An autopsy was performed in 13.6% of patients.

Conclusions: Death during study treatment was mainly related to infections, and patients with advanced disease, high BMI, underlying comorbidities, CRFs and concomitant medications. If considered for study participation these patients need careful monitoring due to their higher risk for death on study.
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http://dx.doi.org/10.1007/s12282-019-00990-3DOI Listing
November 2019

NAB-Paclitaxel Improves Disease-Free Survival in Early Breast Cancer: GBG 69-GeparSepto.

J Clin Oncol 2019 09 13;37(25):2226-2234. Epub 2019 May 13.

German Breast Group, Neu-Isenburg, Germany.

Purpose: The GeparSepto trial demonstrated that weekly nanoparticle albumin-bound (NAB)-paclitaxel significantly improves the pathologic complete remission rate compared with weekly solvent-based (sb) paclitaxel followed by epirubicin plus cyclophosphamide as neoadjuvant treatment in patients with primary breast cancer (BC). Here, we report data on long-term outcomes.

Methods: Patients with histologically confirmed primary BC were randomly assigned in a 1:1 ratio to 12 times weekly NAB-paclitaxel 150 mg/m (after study amendment, 125 mg/m) or weekly sb-paclitaxel 80 mg/m followed in both arms by four times epirubicin 90 mg/m plus cyclophosphamide 600 mg/m every 3 weeks. Patients with human epidermal growth factor receptor 2 (HER2)-positive BC received dual antibody treatment with trastuzumab (8 mg/kg loading dose followed by 6 mg/kg every 3 weeks) and pertuzumab (840 mg loading dose followed by 420 mg every 3 weeks) concurrently to chemotherapy and continued for 1 year.

Results: A total of 1,206 patients started treatment, 606 with NAB-paclitaxel and 600 with sb-paclitaxel. After a median follow-up of 49.6 months (range, 0.5 to 64.0 months), 243 invasive disease-free survival (iDFS) events were reported (143 in the sb-paclitaxel and 100 in the NAB-paclitaxel arm). At 4 years, overall patients treated with NAB-paclitaxel had a significantly better iDFS compared with sb-paclitaxel (84.0% 76.3%; hazard ratio, 0.66; 95% CI, 0.51 to 0.86; = .002), whereas overall survival did not significantly differ between the two treatment arms (89.7% 87.2%, respectively; hazard ratio, 0.82; 95% CI, 0.59 to 1.16; = .260). Long-term follow-up of the treatment-related peripheral sensory neuropathy (PSN) showed a significant decrease of the median time to resolve PSN after NAB-paclitaxel 125 mg/m compared with NAB-paclitaxel 150 mg/m.

Conclusion: The significantly higher pathologic complete response rate with NAB-paclitaxel translated into a significantly improved iDFS in patients with early BC as compared with sb-paclitaxel. PSN improved much faster under NAB-paclitaxel 125 mg/m compared with NAB-paclitaxel 150 mg/m.
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http://dx.doi.org/10.1200/JCO.18.01842DOI Listing
September 2019

Development of central nervous system metastases as a first site of metastatic disease in breast cancer patients treated in the neoadjuvant trials GeparQuinto and GeparSixto.

Breast Cancer Res 2019 05 10;21(1):60. Epub 2019 May 10.

German Breast Group GmbH, Martin Behaim Strasse 12, 63263, Neu-Isenburg, Germany.

Background: The incidence of central nervous system (CNS) metastases in breast cancer patients is rising and has become a major clinical challenge. Only few data are published concerning risk factors for the development of CNS metastases as a first site of metastatic disease in breast cancer patients. Moreover, the incidence of CNS metastases after modern neoadjuvant treatment is not clear.

Methods: We analyzed clinical factors associated with the occurrence of CNS metastases as the first site of metastatic disease in breast cancer patients after neoadjuvant treatment in the trials GeparQuinto and GeparSixto (n = 3160) where patients received targeted treatment in addition to taxane and anthracycline-based chemotherapy.

Results: After a median follow-up of 61 months, 108 (3%) of a total of 3160 patients developed CNS metastases as the first site of recurrence and 411 (13%) patients had metastatic disease outside the CNS. Thirty-six patients (1%) developed both CNS metastases and other distant metastases as the first site of metastatic disease. Regarding subtypes of the primary tumor, 1% of luminal A-like (11/954), 2% of luminal B-like (7/381), 4% of HER2-positive (34/809), and 6% of triple-negative patients (56/1008) developed CNS metastases as the first site of metastatic disease. In multivariate analysis, risk factors for the development of CNS metastases were larger tumor size (cT3-4; HR 1.63, 95% CI 1.08-2.46, p = 0.021), node-positive disease (HR 2.57, 95% CI 1.64-4.04, p < 0.001), no pCR after neoadjuvant chemotherapy (HR 2.29, 95% CI 1.32-3.97, p = 0.003), and HER2-positive (HR 3.80, 95% CI 1.89-7.64, p < 0.001) or triple-negative subtype (HR 6.38, 95% CI 3.28-12.44, p < 0.001).

Conclusions: Especially patients with HER2-positive and triple-negative tumors are at risk of developing CNS metastases despite effective systemic treatment. A better understanding of the underlying mechanisms is required in order to develop potential preventive strategies.
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http://dx.doi.org/10.1186/s13058-019-1144-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6509843PMC
May 2019

Clinical and analytical validation of Ki-67 in 9069 patients from IBCSG VIII + IX, BIG1-98 and GeparTrio trial: systematic modulation of interobserver variance in a comprehensive in silico ring trial.

Breast Cancer Res Treat 2019 Aug 7;176(3):557-568. Epub 2019 May 7.

International Breast Cancer Study Group Central Pathology Office, Department of Pathology and Laboratory Medicine, IEO European Institute of Oncology IRCCS, Milan, Italy.

Purpose: Ki-67 has been clinically validated for risk assessment in breast cancer, but the analytical validation and cutpoint-definition remain a challenge. Intraclass correlation coefficients (ICCs) are a statistical parameter for Ki-67 interobserver performance. However, the maximum degree of variance among pathologists allowed for meaningful biomarker results has not been defined.

Methods: Different amounts of variance were added to central pathology Ki-67 data (n = 9069) from three cohorts (IBCSGVIII + IX, BIG1-98, GeparTrio) by simulation of 4500 evaluations for each cohort, which were grouped by ICCs, ranging from excellent (ICC = 0.9) to poor concordance (ICC = 0.1). Endpoints were disease-free survival (DFS) and pathological complete response (pCR, GeparTrio).

Results: Ki-67 was a significant continuous prognostic marker for DFS over a wide range of cutpoints between 8% and 30% in all three cohorts. In our modelling approach, Ki-67 was a stable prognostic marker despite increased interpathologist variance. Even for a poor ICC of 0.5, one or more significant Ki-67 cutoffs were detected in 86.8% (GeparTrio), 92.4% (IBCSGVIII + IX) and 100% of analyses (BIG1-98). Similarly, in GeparTrio, even with an extremely low ICC of 0.2, 99.6% of analyses were significant for pCR.

Conclusions: Our study shows that Ki-67 is a continuous marker which is extremely robust to pathologist variation. Even if only 50% of variance is attributable to true Ki-67-based proliferation (ICC = 0.5), this information is sufficient to obtain statistically significant differences in clinical cohorts. This stable performance explains the observation that many Ki-67 studies achieve significant results despite relevant interobserver variance and points to a high clinical validity of this biomarker. For clinical decisions based on analysis of individual patient data, ongoing efforts to further reduce interobserver variability, including ring trials and standardized guidelines as well as image analysis approaches, should be continued.
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http://dx.doi.org/10.1007/s10549-018-05112-9DOI Listing
August 2019

Prospective, Multicenter, Randomized Phase III Trial Evaluating the Impact of Lymphoscintigraphy as Part of Sentinel Node Biopsy in Early Breast Cancer: SenSzi (GBG80) Trial.

J Clin Oncol 2019 06 1;37(17):1490-1498. Epub 2019 May 1.

15 Clinic Esslingen, Esslingen, Germany.

Purpose: The aim of the current work was to clarify whether a preoperative lymphoscintigraphy (LSG) enhances staging accuracy of sentinel lymph node biopsy (SLNB).

Patients And Methods: In a prospective, multicenter, randomized phase III trial, patients with cN0 early breast cancer or extensive/high-grade ductal carcinoma in situ planned for standard radioactive-labeled colloid LSG with subsequent SLNB were randomly assigned 1:1 to receive SLNB either with knowledge of the LSG findings or without. As the false-negative rate of SLNB correlates with the number of resected sentinel lymph nodes (SLNs), our primary end point was the mean number of histologically detected SLNs per patient. One thousand one hundred two evaluable patients were necessary to demonstrate noninferiority of SLNB without LSG. Stratified one-sided 95% CI for the difference (without LSG - with LSG) in the mean number of histologically detected SLNs had to be greater than -0.27 (10% noninferiority margin). Stratification was performed according to tumor focality and trial site. Additional predefined secondary end points (rates of node-positive patients and of completion axillary lymph node dissection) were analyzed to rule out differences in the reliable detection of nodal metastases.

Results: Between May 2014 and October 2015, 1,198 patients were randomly assigned in 23 German and Swiss breast centers. Modified intention-to-treat analysis (n = 1,163) showed a mean number of histologically detected SLNs of 2.21 with LSG and 2.26 without LSG (difference 0.05; stratified 95% CI, -0.18 to infinity), thus establishing noninferiority of omitting preoperative LSG. Secondary end points displayed no statistically significant differences.

Conclusion: We show that SLNB is equally effective irrespective of the surgeon's knowledge of preoperative LSG results. SLNB without LSG will speed up the preoperative workflow and reduce cost.
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http://dx.doi.org/10.1200/JCO.18.02092DOI Listing
June 2019

Mutational Diversity and Therapy Response in Breast Cancer: A Sequencing Analysis in the Neoadjuvant GeparSepto Trial.

Clin Cancer Res 2019 07 12;25(13):3986-3995. Epub 2019 Apr 12.

Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Pathology, Berlin, Germany.

Purpose: Next-generation sequencing (NGS) can be used for comprehensive investigation of molecular events in breast cancer. We evaluated the relevance of genomic alterations for response to neoadjuvant chemotherapy (NACT) in the GeparSepto trial.

Experimental Design: Eight hundred fifty-one pretherapeutic formalin-fixed paraffin-embedded (FFPE) core biopsies from GeparSepto study were sequenced. The panel included 16 genes for mutational (, and ) and 8 genes for copy-number alteration analysis (, and ).

Results: The most common genomic alterations were mutations of (38.4%) and (21.5%), and 8 different amplifications ( 34.9%; 30.6%; 30.1%; 21.9%; 24.1%; 17.7%; 14.9%; 12.6%). All other alterations had a prevalence of less than 5%. The genetic heterogeneity in different breast cancer subtypes [lum/HER2neg vs. HER2pos vs. triple-negative breast cancer (TNBC)] was significantly linked to differences in NACT response. A significantly reduced pathologic complete response rate was observed in -mutated breast cancer [mut: 23.0% vs. wild-type (wt) 38.8%, < 0.0001] in particular in the HER2pos subcohort [multivariate OR = 0.43 (95% CI, 0.24-0.79), = 0.006]. An increased response to nab-paclitaxel was observed only in wt breast cancer, with univariate significance for the complete cohort ( = 0.009) and the TNBC ( = 0.013) and multivariate significance in the HER2pos subcohort (test for interaction = 0.0074).

Conclusions: High genetic heterogeneity was observed in different breast cancer subtypes. Our study shows that FFPE-based NGS can be used to identify markers of therapy resistance in clinical study cohorts. mutations could be a major mediator of therapy resistance in breast cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3258DOI Listing
July 2019

Pharmacokinetic and exploratory exposure-response analysis of pertuzumab in patients with operable HER2-positive early breast cancer in the APHINITY study.

Cancer Chemother Pharmacol 2019 06 11;83(6):1147-1158. Epub 2019 Apr 11.

Genentech, 1 DNA Way, South San Francisco, CA, 94080, USA.

Purpose: To characterize the pharmacokinetics (PK) of, and perform an exploratory exposure-response (E-R) analysis for, pertuzumab in patients with HER2-positive early breast cancer (EBC) within the APHINITY study (NCT01358877, BIG 4-11/BO25126/TOC4939G).

Methods: A previously developed pertuzumab two-compartment linear population pharmacokinetic (popPK) model was subjected to external validation to examine appropriateness for describing pertuzumab concentrations from the APHINITY study. Pharmacokinetic drug-drug interactions (DDIs) between pertuzumab, trastuzumab, and chemotherapy were assessed by comparing observed serum or plasma C, C, and AUC geometric mean ratios with 90% CIs. Predictions of pertuzumab C, C, and AUC were derived from individual parameter estimates and used in an exploratory E-R analysis.

Results: Using data from 72 patients, based on goodness-of-fit, the popPK model was deemed appropriate for predictions of individual exposures for subsequent comparisons to historical data, assessment of DDIs, and E-R analyses. No evidence of DDIs for pertuzumab on trastuzumab, trastuzumab on pertuzumab, or pertuzumab on chemotherapy PK was observed. Analyses of differences in exposure between patients with and without invasive disease-free survival events did not indicate improved efficacy with increased exposure. Overall Grade ≥ 3 diarrhea prevalence was higher with pertuzumab versus placebo, but was not greater with increasing pertuzumab exposure. No apparent E-R relationship was suggested with respect to other grade ≥ 3 AEs.

Conclusion: Overall, the limited available data from this exploratory study suggest that no dose adjustments are needed for pertuzumab when administered in combination with trastuzumab and an EBC chemotherapy regimen.
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http://dx.doi.org/10.1007/s00280-019-03826-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499763PMC
June 2019

A randomized phase II study to determine the efficacy and tolerability of two doses of eribulin plus lapatinib in trastuzumab-pretreated patients with HER-2-positive metastatic breast cancer (E-VITA).

Anticancer Drugs 2019 04;30(4):394-401

German Breast Group, Neu-Isenburg.

The E-VITA study evaluated the efficacy and tolerability of two schedules of eribulin and lapatinib in patients with trastuzumab-pretreated HER-2-positive metastatic breast cancer. This multicenter, open-label phase II trial, randomly assigned patients with trastuzumab-pretreated HER-2-positive metastatic breast cancer to lapatinib 1000 mg daily with eribulin 1.23 mg/m (equivalent to 1.4 mg/m eribulin mesylate) days 1+8 every 21 days (split-dose arm) or eribulin 1.76 mg/m (equivalent to 2.0 mg/m eribulin mesylate) day 1 every 21 days (3-weekly arm). Time to progression and tolerability were defined as primary end points; no sample size calculation for formal comparison of efficacy data has been performed. Secondary end points included objective response rate, clinical benefit rate, and overall survival. Overall, 43 patients of a planned number of 80 patients were recruited. At a median follow-up of 28.7 months, the median time to progression was 8.1 months [95% confidence interval (CI): 4.8-9.4] in the split-dose arm and 6.5 months (95% CI: 4.6-13.4) in the 3-weekly arm. Objective response rate was 52.4% (95% CI: 31.0-73.7) in the split-dose arm and 45.0% (95% CI: 23.2-66.8) in the 3-weekly arm, and clinical benefit rate was 71.4% (95% CI: 52.1-90.8) and 75.0% (95% CI: 56.0-94.0), respectively. Overall survival was also similar in both arms. The most frequent grade 3-4 adverse events were neutropenia (58.5%) and leukopenia (39.0%). The combination of eribulin and lapatinib showed an acceptable safety profile with less toxicity observed in the eribulin 1.23 mg/m day 1+8 group. This might be an alternative regimen when other treatment options are exhausted. Therefore, further clinical studies are warranted.
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http://dx.doi.org/10.1097/CAD.0000000000000722DOI Listing
April 2019

PIK3CA alterations and benefit with neratinib: analysis from the randomized, double-blind, placebo-controlled, phase III ExteNET trial.

Breast Cancer Res 2019 03 11;21(1):39. Epub 2019 Mar 11.

Breast Cancer Research Centre-WA, Perth & Curtin University, Nedlands, Australia.

Background: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor that inhibits PI3K/Akt and MAPK signaling pathways after HER2 receptor activation. The ExteNET study showed that neratinib significantly improved 5-year invasive disease-free survival (iDFS) in women who completed trastuzumab-based adjuvant therapy for early breast cancer (EBC). We assessed the prognostic and predictive significance of PIK3CA alterations in patients in ExteNET.

Methods: Participants were women aged ≥ 18 years (≥ 20 years in Japan) with stage 1-3c (modified to stage 2-3c in February 2010) operable breast cancer, who had completed (neo)adjuvant chemotherapy plus trastuzumab ≤ 2 years before randomization, with no evidence of disease recurrence or metastatic disease at study entry. Patients were randomized to oral neratinib 240 mg/day or placebo for 1 year. Formalin-fixed, paraffin-embedded primary tumor specimens underwent polymerase chain reaction (PCR) PIK3CA testing for two hotspot mutations in exon 9, one hot-spot mutation in exon 20, and fluorescence in situ hybridization (FISH) analysis for PIK3CA amplification. The primary endpoint (iDFS) was tested with log-rank test and hazard ratios (HRs) estimated using Cox proportional-hazards models.

Results: Among the intent-to-treat population (n = 2840), tumor specimens were available for PCR testing (991 patients) and PIK3CA FISH (702 patients). Overall, 262 samples were PIK3CA altered: 201 were mutated (77%), 52 (20%) were amplified, and 9 (3%) were mutated and amplified. iDFS was non-significantly worse in placebo-treated patients with altered vs wild-type PIK3CA (HR 1.34; 95% CI 0.72-2.50; P = 0.357). Neratinib's effect over placebo was significant in patients with PIK3CA-altered tumors (HR 0.41; 95% CI 0.17-0.90, P = 0.028) but not PIK3CA wild-type tumors (HR 0.72; 95% CI 0.36-1.41; P = 0.34). The interaction test was non-significant (P = 0.309).

Conclusions: Although there was a greater absolute risk reduction associated with neratinib treatment of patients with PIK3CA-altered tumors in ExteNET, current data do not support PIK3CA alteration as a predictive biomarker of response to neratinib in HER2-positive EBC.

Trial Registration: ClinicalTrials.gov , NCT00878709 . Trial registered April 9, 2009.
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http://dx.doi.org/10.1186/s13058-019-1115-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6417207PMC
March 2019

Validation of a Nomogram Predicting Non-Sentinel Lymph Node Metastases among Patients with Breast Cancer after Primary Systemic Therapy - a transSENTINA Substudy.

Breast Care (Basel) 2018 Dec 6;13(6):440-446. Epub 2018 Nov 6.

Interdisciplinary Breast Centre, Department of Gynecology and Obstetrics, Klinikum Esslingen, Esslingen, Germany.

Background: Prediction of non-sentinel lymph node (SLN) status after primary systemic therapy (PST) may allow tailored axillary staging. The aim of this analysis was to compare established nomograms from i) the primary operative (n = 6) and ii) the neoadjuvant (n = 1) setting with an optimized nomogram to predict non-SLN status in patients after PST.

Methods: 181 patients converting from cN1 prior to PST to ycN0 but found to have a histologically positive SLN in the SENTINA trial were analyzed. Established models were applied. An optimized model was compiled using univariate and subsequent multivariable logistic regression (backward selection, likelihood ratio test).

Results: Area-under-the-curve (AUC) values from the primary operative models showed sufficient performance (0.82-0.71). For the neoadjuvant model, the AUC was found to be inferior to prior analyses (0.66) but within published confidence intervals. The SENTINA nomogram comprised the diameter of the largest lymph node (p = 0.006, odds ratio (OR) = 1.19), tumor size prior to PST (p = 0.085, OR = 1.31), and number of all positive SLN (p = 0.083, OR = 2.04). This model was validated using a separate cohort of arm C (n = 168, AUC 0.79, 95% confidence interval 0.74-0.85).

Conclusion: We validated 7 models of prediction of non-SLN among patients showing axillary conversion through PST. Our own 'SENTINA nomogram' yielded AUC values comparable to previous nomograms.
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http://dx.doi.org/10.1159/000489565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381911PMC
December 2018

Phase 3 LILAC study sets standard for clinical evaluation of oncology biosimilars.

Oncotarget 2019 Jan 1;10(1):8-9. Epub 2019 Jan 1.

Hans-Christian Kolberg: Marienhospital Bottrop gGmbH, Bottrop, Germany.

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http://dx.doi.org/10.18632/oncotarget.26528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343751PMC
January 2019

Evaluation of soluble carbonic anhydrase IX as predictive marker for efficacy of bevacizumab: A biomarker analysis from the geparquinto phase III neoadjuvant breast cancer trial.

Int J Cancer 2019 08 4;145(3):857-868. Epub 2019 Mar 4.

Department of Oncology, Hematology and Bone Marrow Transplantation with section Pneumology, Hubertus Wald Tumorzentrum, University Comprehensive Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

We analyzed the predictive potential of pretreatment soluble carbonic anhydrase IX levels (sCAIX) for the efficacy of bevacizumab in the phase III neoadjuvant GeparQuinto trial. sCAIX was determined by enzyme-linked immunosorbent assay (ELISA). Correlations between sCAIX and pathological complete response (pCR), disease-free and overall survival (DFS, OS) were assessed with logistic and Cox proportional hazard regression models using bootstrapping for robust estimates and internal validation. 1,160 HER2-negative patient sera were analyzed, of whom 577 received bevacizumab. Patients with low pretreatment sCAIX had decreased pCR rates (12.1 vs. 20.1%, p = 0.012) and poorer DFS (adjusted 5-year DFS 71.4 vs. 80.5 months, p = 0.010) compared to patients with high sCAIX when treated with neoadjuvant chemotherapy (NCT). For patients with low sCAIX, pCR rates significantly improved upon addition of bevacizumab to NCT (12.1 vs. 20.4%; p = 0.017), which was not the case in patients with high sCAIX (20.1% for NCT vs. 17.0% for NCT-B, p = 0.913). When analyzing DFS we found that bevacizumab improved 5-year DFS for patients with low sCAIX numerically but not significantly (71.4 vs. 78.5 months; log rank 0.234). In contrast, addition of bevacizumab worsened 5-year DFS for patients with high sCAIX (81 vs. 73.6 months, log-rank 0.025). By assessing sCAIX levels we identified a patient cohort in breast cancer that is potentially undertreated with NCT alone. Bevacizumab improved pCR rates in this group, suggesting sCAIX is a predictive biomarker for bevacizumab with regards to treatment response. Our data also show that bevacizumab is not beneficial in patients with high sCAIX.
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http://dx.doi.org/10.1002/ijc.32163DOI Listing
August 2019

Interdisciplinary Screening, Diagnosis, Therapy and Follow-up of Breast Cancer. Guideline of the DGGG and the DKG (S3-Level, AWMF Registry Number 032/045OL, December 2017) - Part 2 with Recommendations for the Therapy of Primary, Recurrent and Advanced Breast Cancer.

Authors:
Achim Wöckel Jasmin Festl Tanja Stüber Katharina Brust Mathias Krockenberger Peter U Heuschmann Steffi Jírů-Hillmann Ute-Susann Albert Wilfried Budach Markus Follmann Wolfgang Janni Ina Kopp Rolf Kreienberg Thorsten Kühn Thomas Langer Monika Nothacker Anton Scharl Ingrid Schreer Hartmut Link Jutta Engel Tanja Fehm Joachim Weis Anja Welt Anke Steckelberg Petra Feyer Klaus König Andrea Hahne Traudl Baumgartner Hans H Kreipe Wolfram Trudo Knoefel Michael Denkinger Sara Brucker Diana Lüftner Christian Kubisch Christina Gerlach Annette Lebeau Friederike Siedentopf Cordula Petersen Hans Helge Bartsch Rüdiger Schulz-Wendtland Markus Hahn Volker Hanf Markus Müller-Schimpfle Ulla Henscher Renza Roncarati Alexander Katalinic Christoph Heitmann Christoph Honegger Kerstin Paradies Vesna Bjelic-Radisic Friedrich Degenhardt Frederik Wenz Oliver Rick Dieter Hölzel Matthias Zaiss Gudrun Kemper Volker Budach Carsten Denkert Bernd Gerber Hans Tesch Susanne Hirsmüller Hans-Peter Sinn Jürgen Dunst Karsten Münstedt Ulrich Bick Eva Fallenberg Reina Tholen Roswita Hung Freerk Baumann Matthias W Beckmann Jens Blohmer Peter Fasching Michael P Lux Nadia Harbeck Peyman Hadji Hans Hauner Sylvia Heywang-Köbrunner Jens Huober Jutta Hübner Christian Jackisch Sibylle Loibl Hans-Jürgen Lück Gunter von Minckwitz Volker Möbus Volkmar Müller Ute Nöthlings Marcus Schmidt Rita Schmutzler Andreas Schneeweiss Florian Schütz Elmar Stickeler Christoph Thomssen Michael Untch Simone Wesselmann Arno Bücker Andreas Buck Stephanie Stangl

Geburtshilfe Frauenheilkd 2018 Nov 26;78(11):1056-1088. Epub 2018 Nov 26.

Institut für Klinische Epidemiologie und Biometrie (IKE-B), Universität Würzburg, Würzburg, Germany.

The aim of this official guideline coordinated and published by the German Society for Gynecology and Obstetrics (DGGG) and the German Cancer Society (DKG) was to optimize the screening, diagnosis, therapy and follow-up care of breast cancer. The process of updating the S3 guideline published in 2012 was based on the adaptation of identified source guidelines. They were combined with reviews of evidence compiled using PICO (Patients/Interventions/Control/Outcome) questions and with the results of a systematic search of literature databases followed by the selection and evaluation of the identified literature. The interdisciplinary working groups took the identified materials as their starting point and used them to develop suggestions for recommendations and statements, which were then modified and graded in a structured consensus process procedure. Part 2 of this short version of the guideline presents recommendations for the therapy of primary, recurrent and metastatic breast cancer. Loco-regional therapies are de-escalated in the current guideline. In addition to reducing the safety margins for surgical procedures, the guideline also recommends reducing the radicality of axillary surgery. The choice and extent of systemic therapy depends on the respective tumor biology. New substances are becoming available, particularly to treat metastatic breast cancer.
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http://dx.doi.org/10.1055/a-0646-4630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6261741PMC
November 2018

Intense dose-dense epirubicin, paclitaxel, cyclophosphamide versus weekly paclitaxel, liposomal doxorubicin (plus carboplatin in triple-negative breast cancer) for neoadjuvant treatment of high-risk early breast cancer (GeparOcto-GBG 84): A randomised phase III trial.

Eur J Cancer 2019 01 5;106:181-192. Epub 2018 Dec 5.

Praxis Bethanien, Frankfurt, Germany; German Breast Group, Neu-Isenburg, Germany. Electronic address:

Background: GeparOcto compared efficacy and safety of two chemotherapy regimens in high-risk early breast cancer (BC): sequential treatment with intense dose-dense epirubicin, paclitaxel, and cyclophosphamide (iddEPC) and weekly treatment with paclitaxel plus non-pegylated liposomal doxorubicin (M, Myocet®) with additional carboplatin (PM(Cb)) in triple-negative BC (TNBC).

Patients And Methods: Patients with cT1c-cT4a-d and centrally assessed human epidermal growth factor receptor (HER)2-positive BC or TNBC were eligible, irrespective of nodal status, luminal B-like tumours only if pN+. Patients were randomised (stratified by BC subtype, Ki67, lymphocyte-predominant BC) to receive 18 weeks of E (150 mg/m) followed by P (225 mg/m) followed by C (2000 mg/m), each q2w for 3 cycles or weekly P (80 mg/m) plus M (20 mg/m) plus, in TNBC, Cb (area under curve (AUC) 1.5). HER2-positive BC patients additionally received trastuzumab (6 [loading dose 8]mg/kg q3w) and pertuzumab (420 [840]mg q3w) with all P and C cycles. Primary end-point was pathological complete response (pCR, ypT0/is ypN0), secondary end-points included other pCR definitions, pCR in stratified subpopulations, tolerability and compliance. This trial is registered with ClinicalTrials.gov number NCT02125344.

Results: 945/961 randomised patients started treatment. The median age was 48 years; 7.6% had cT3-4, 46% cN+, 66% G3, 40% HER2-positive, 43% TNBC. pCR rate with iddEPC was 48.3%, with PM(Cb) 48.0%, respectively (PM(Cb) versus iddEPC odds ratio 0.99; 95% confidence interval 0.77-1.28, P = 0.979) with no significant differences observed in TNBC, HER2-positive, luminal B-like subtypes. 16.4% with iddEPC and 34.1% with PM(Cb) discontinued treatment (P < 0.001), mainly due to adverse events; two patients on PM(Cb) died.

Conclusions: In high-risk early BC there is no difference in pCR rates following neoadjuvant treatment with iddEPC or weekly PM(Cb), respectively. iddEPC is one of the effective dose-dense regimens feasible in daily practice.
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http://dx.doi.org/10.1016/j.ejca.2018.10.015DOI Listing
January 2019

Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer.

N Engl J Med 2019 02 5;380(7):617-628. Epub 2018 Dec 5.

From the German Breast Group, Neu-Isenburg (G.M., S.L., H.H.F., P.W.), the Center for Hematology and Oncology Bethanien, Frankfurt (S.L.), the AGO-B and HELIOS Klinikum Berlin-Buch, Berlin (M.U.), the National Center for Tumor Diseases, Heidelberg University Hospital and German Cancer Research Center, Heidelberg (A.S.), Evangelische Kliniken Gelsenkirchen, Gelsenkirchen (H.H.F.), the Arbeitsgemeinschaft Gynäkologische Onkologie - Breast and Sana Klinikum Offenbach, Offenbach (C.J.), the Department of Gynecology and Obstetrics, University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen (P.A.F.), and Mammazentrum Hamburg am Krankenhaus Jerusalem, Hamburg (P.W.) - all in Germany; the National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan (C.-S.H.); Instituto do Câncer do Estado de São Paulo, São Paulo (M.S.M.); the National Surgical Adjuvant Breast and Bowel Project (NSABP) Foundation and Orlando Health University of Florida Health Cancer Center, Orlando (E.P.M.); the NSABP Foundation and Allegheny Health Network Cancer Institute (N.W.) and the NSABP Foundation and University of Pittsburgh Cancer Institute, School of Medicine (P.R.), Pittsburgh; Hospital Universitario La Paz-Instituto de Investigación Hospital Universitario La Paz, Madrid (A.R.); Institut Régional du Cancer de Montpellier, Université de Montpellier, INSERM Unité 1194, Montpellier, France (W.J.); the NSABP Foundation and Providence Portland Medical Center, Portland, OR (A.K.C.); the National Cancer Institute, Mexico City (C.A.-S.); the NSABP Foundation and Stanford University School of Medicine, Stanford (I.L.W.), and Genentech, South San Francisco (L.H.L., D.T., M.S., S.M.S.) - both in California; Yale University School of Medicine, Yale Cancer Center, and Smilow Cancer Hospital, New Haven, CT (M.P.D.); the Ireland Cooperative Oncology Research Group, Dublin (J.P.C.); Fudan University Shanghai Cancer Center (Z.S.) and Roche (China) Holding (H.W.), Shanghai; the Cancer Center Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy (E.R.C.); F. Hoffmann-La Roche, Welwyn Garden City, United Kingdom (H.D.); and the NSABP Foundation and Virginia Commonwealth University Massey Cancer Center, Richmond (C.E.G.).

Background: Patients who have residual invasive breast cancer after receiving neoadjuvant chemotherapy plus human epidermal growth factor receptor 2 (HER2)-targeted therapy have a worse prognosis than those who have no residual cancer. Trastuzumab emtansine (T-DM1), an antibody-drug conjugate of trastuzumab and the cytotoxic agent emtansine (DM1), a maytansine derivative and microtubule inhibitor, provides benefit in patients with metastatic breast cancer that was previously treated with chemotherapy plus HER2-targeted therapy.

Methods: We conducted a phase 3, open-label trial involving patients with HER2-positive early breast cancer who were found to have residual invasive disease in the breast or axilla at surgery after receiving neoadjuvant therapy containing a taxane (with or without anthracycline) and trastuzumab. Patients were randomly assigned to receive adjuvant T-DM1 or trastuzumab for 14 cycles. The primary end point was invasive disease-free survival (defined as freedom from ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause).

Results: At the interim analysis, among 1486 randomly assigned patients (743 in the T-DM1 group and 743 in the trastuzumab group), invasive disease or death had occurred in 91 patients in the T-DM1 group (12.2%) and 165 patients in the trastuzumab group (22.2%). The estimated percentage of patients who were free of invasive disease at 3 years was 88.3% in the T-DM1 group and 77.0% in the trastuzumab group. Invasive disease-free survival was significantly higher in the T-DM1 group than in the trastuzumab group (hazard ratio for invasive disease or death, 0.50; 95% confidence interval, 0.39 to 0.64; P<0.001). Distant recurrence as the first invasive-disease event occurred in 10.5% of patients in the T-DM1 group and 15.9% of those in the trastuzumab group. The safety data were consistent with the known safety profile of T-DM1, with more adverse events associated with T-DM1 than with trastuzumab alone.

Conclusions: Among patients with HER2-positive early breast cancer who had residual invasive disease after completion of neoadjuvant therapy, the risk of recurrence of invasive breast cancer or death was 50% lower with adjuvant T-DM1 than with trastuzumab alone. (Funded by F. Hoffmann-La Roche/Genentech; KATHERINE ClinicalTrials.gov number, NCT01772472 .).
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http://dx.doi.org/10.1056/NEJMoa1814017DOI Listing
February 2019

Interdisciplinary Screening, Diagnosis, Therapy and Follow-up of Breast Cancer. Guideline of the DGGG and the DKG (S3-Level, AWMF Registry Number 032/045OL, December 2017) - Part 1 with Recommendations for the Screening, Diagnosis and Therapy of Breast Cancer.

Geburtshilfe Frauenheilkd 2018 Oct 19;78(10):927-948. Epub 2018 Oct 19.

Universitätsfrauenklinik Würzburg, Universität Würzburg, Würzburg, Germany.

The aim of this official guideline coordinated and published by the German Society for Gynecology and Obstetrics (DGGG) and the German Cancer Society (DKG) was to optimize the screening, diagnosis, therapy and follow-up care of breast cancer. The process of updating the S3 guideline dating from 2012 was based on the adaptation of identified source guidelines which were combined with reviews of evidence compiled using PICO (Patients/Interventions/Control/Outcome) questions and the results of a systematic search of literature databases and the selection and evaluation of the identified literature. The interdisciplinary working groups took the identified materials as their starting point to develop recommendations and statements which were modified and graded in a structured consensus procedure. Part 1 of this short version of the guideline presents recommendations for the screening, diagnosis and follow-up care of breast cancer. The importance of mammography for screening is confirmed in this updated version of the guideline and forms the basis for all screening. In addition to the conventional methods used to diagnose breast cancer, computed tomography (CT) is recommended for staging in women with a higher risk of recurrence. The follow-up concept includes suggested intervals between physical, ultrasound and mammography examinations, additional high-tech diagnostic procedures, and the determination of tumor markers for the evaluation of metastatic disease.
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http://dx.doi.org/10.1055/a-0646-4522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202580PMC
October 2018

Systematic analysis of parameters predicting pathological axillary status (ypN0 vs. ypN+) in patients with breast cancer converting from cN+ to ycN0 through primary systemic therapy (PST).

Clin Exp Metastasis 2018 12 15;35(8):777-783. Epub 2018 Oct 15.

Department of Gynecology and Obstetrics, Interdisciplinary Breast Centre, Klinikum Esslingen, Esslingen, Germany.

Optimization of axillary staging among patients converting from clinically node-positive disease to clinically node-negative disease through primary systemic therapy is needed. We aimed at developing a nomogram predicting the probability of positive axillary status after chemotherapy based on clinical/pathological parameters. Patients from study arm C of the SENTINA trial were included. Univariable/multivariable analyses were performed for 13 clinical/pathological parameters to predict a positive pathological axillary status after chemotherapy using logistic regression models. Odds ratios and 95%-confidence-intervals were reported. Model performance was assessed by leave-one-out cross-validation. Calculations were performed using the SAS Software (Version 9.4, SAS Institute Inc., Cary, NC, USA). 369 of 553 patients in Arm C were included in multivariable analysis. Stepwise backward variable selection based on a multivariable analysis resulted in a model including estrogen receptor (ER) status (odds ratio (OR) 3.916, 95% confidence interval (CI) 2.318-6.615, p < 0.001), multifocality (OR 2.106, 95% CI 1.203-3.689, p = 0.0092), lymphovascular invasion (OR 9.196, 95% CI 4.734-17.864, p < 0.001), and sonographic tumor diameter after PST (OR 1.034, 95% CI 1.010-1.059, p = 0.0051). When validated, our model demonstrated an accuracy of 70.2% using 0.5 as cut-point. An area under the curve of 0.81 was calculated. The use of individual parameters as predictors of lymph node status after chemotherapy resulted in an inferior accuracy. Our model was able to predict the probability of a positive axillary nodal status with a high accuracy. The use of individual parameters showed reduced predictive performance. Overall, tumor biology was the strongest parameter in our models.
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http://dx.doi.org/10.1007/s10585-018-9938-2DOI Listing
December 2018

Trial-level prediction of long-term outcome based on pathologic complete response (pCR) after neoadjuvant chemotherapy for early-stage breast cancer (EBC).

Contemp Clin Trials 2018 08 26;71:194-198. Epub 2018 Jun 26.

Celgene Corporation, Summit, NJ, USA. Electronic address:

Background: The US Food and Drug Administration and European Medicines Agency have published guidance for industry on the use of pathologic complete response (pCR) as a surrogate endpoint to accelerate the regulatory approval of neoadjuvant agents in high-risk early-stage breast cancer (EBC). Three meta-analyses, the CTNeoBC consortium (Cortazar 2014), Berruti (2014), and Korn (2016), evaluated the association between the pCR odds ratio and the event hazards ratio but did not identify strong trial-level associations. Thus, uncertainties remain with respect to whether the magnitude of effect-size increase in pCR reasonably predicts long-term clinical benefit.

Findings: Trial-level data from CTNeoBC were used as the training data set to derive an empirical nonlinear model for predicting long-term outcomes based on pCR results. A Cox regression model was used to evaluate the relationship among treatments, event hazards, and pCR as joint covariates. The trial-level association between treatment and event hazard was derived and then linked with pCR rates. Magnitude of the patient-level association was also included in the analysis. Additional published trials were used to validate the predictive model. Numerical differences between the perfect surrogate prediction and observed effect followed normal distribution based on the Kolmogorov-Smirnov test. For event-free survival (EFS), the Student t-test P value of 0.02 suggested a statistically significant nonzero difference, with a mean value of -0.163 (SE 0.058). For overall survival (OS), the Student t-test P value of 0.0027 suggested a statistically significant nonzero difference, with a mean value of -0.153 (SE 0.038). Three studies, including GeparSixto, BOOG, and Neo-tAnGo, were used for validation. The F test suggested the model fit the test data well.

Implications: The observed hazard ratios fit well with the predicted hazard ratios for both EFS and OS and suggest plausible trial-level associations with the new predictor.

Major Findings: Our model predicted the correlation between pCR and EFS as well as OS. This model could be used as a supporting tool to help interpret positive pCR results in neoadjuvant clinical studies in patients with high-risk EBC.
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http://dx.doi.org/10.1016/j.cct.2018.06.016DOI Listing
August 2018

Efficacy and safety of ABP 980 compared with reference trastuzumab in women with HER2-positive early breast cancer (LILAC study): a randomised, double-blind, phase 3 trial.

Lancet Oncol 2018 07 4;19(7):987-998. Epub 2018 Jun 4.

Amgen, Thousand Oaks, CA, USA.

Background: ABP 980 (Amgen Inc, Thousand Oaks, CA, USA) is a biosimilar of trastuzumab, with analytical, functional, and pharmacokinetic similarities. We compared the clinical safety and efficacy of ABP 980 with that of trastuzumab in women with HER2-positive early breast cancer.

Methods: We did a randomised, multicentre, double-blind, active-controlled equivalence trial at 97 study centres in 20 countries, mainly in Europe and South America. Eligible women were aged 18 years or older, had histologically confirmed HER2-positive invasive early breast cancer, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and were planning to have surgical resection of the breast tumour with sentinel or axillary lymph node dissection and neoadjuvant chemotherapy. After four cycles of run-in anthracycline-based chemotherapy, patients were assigned 1:1 to receive ABP 980 or trastuzumab with a permuted block design (blocks of four) computer-generated randomisation schedule. Patients received neoadjuvant therapy with a loading dose (8 mg/kg) of ABP 980 or trastuzumab plus paclitaxel 175 mg/m in a 90 min intravenous infusion, followed by three cycles of 6 mg/kg intravenous ABP 980 or trastuzumab plus paclitaxel 175 mg/m every 3 weeks in 30 min intravenous infusions (or 80 mg/m paclitaxel once per week for 12 cycles if that was the local standard of care). Randomisation was stratified by T stage, node status, hormone receptor status, planned paclitaxel dosing schedule, and geographical region. Surgery was completed 3-7 weeks after the last dose of neoadjuvant treatment, after which adjuvant treatment with ABP 980 or trastuzumab was given every 3 weeks for up to 1 year after the first dose in the study. Patients had been randomly assigned at baseline to continue APB 980, continue trastuzumab, or switch from trastuzumab to APB 980 as their adjuvant treatment. The co-primary efficacy endpoints were risk difference and risk ratio (RR) of pathological complete response in breast tissue and axillary lymph nodes assessed at a local laboratory in all patients who were randomly assigned and received any amount of neoadjuvant investigational product and underwent surgery. We assessed safety in all patients who were randomly assigned and received any amount of investigational product. This trial is registered with ClinicalTrials.gov, number NCT01901146 and Eudra, number CT 2012-004319-29.

Findings: Of 827 patients enrolled, 725 were randomly assigned to receive ABP 980 (n=364) or trastuzumab (n=361). The primary endpoint was assessable in 696 patients (358 who received ABP 980 and 338 who received trastuzumab). Pathological complete response was recorded in 172 (48%, 95% CI 43-53) of 358 patients in the ABP 980 group and 137 (41%, 35-46) of 338 in the trastuzumab group (risk difference 7·3%, 90% CI 1·2-13·4; RR 1·188, 90% CI 1·033-1·366), with the upper bounds of the CIs exceeding the predefined equivalence margins of 13% and 1·318, respectively. Pathological complete response in the central laboratory assessment was seen in 162 (48%) of 339 patients assigned to ABP 980 at baseline and 138 (42%) of 330 assigned to trastuzumab at baseline (risk difference 5·8%, 90% CI -0·5 to 12·0, and RR 1·142, 90% CI 0·993 to 1·312). Grade 3 or worse adverse events during the neoadjuvant phase occurred in 54 (15%) of 364 patients in the ABP 980 group and 51 (14%) of 361 patients in the trastuzumab group, of which the most frequent grade 3 or worse event of interest was neutropenia, occurring in 21 (6%) patients in both groups. In the adjuvant phase, grade 3 or worse adverse events occurred in 30 (9%) of 349 patients continuing ABP 980, 11 (6%) of 171 continuing trastuzumab, and 13 (8%) of 171 who switched from trastuzumab to ABP 980, the most frequent grade 3 or worse events of interest were infections and infestations (four [1%], two [1%], and two [1%]), neutropenia (three [1%], two [1%], and one [1%]), and infusion reactions (two [1%], two [1%], and three [2%]). Two patients died from adverse events judged to be unrelated to the investigational products: one died from pneumonia while receiving neoadjuvant ABP 980 and one died from septic shock while receiving adjuvant ABP 980 after trastuzumab.

Interpretation: Although the lower bounds of the 90% CIs for RR and risk difference showed non-inferiority, the upper bounds exceeded the predefined equivalence margins when based on local laboratory review of tumour samples, meaning that non-superiority was non-conclusive. In our sensitivity analyses based on central laboratory evaluation of tumour samples, estimates for the two drugs were contained within the predefined equivalence margins, indicating similar efficacy. ABP 980 and trastuzumab had similar safety outcomes in both the neoadjuvant and adjuvant phases of the study.

Funding: Amgen.
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http://dx.doi.org/10.1016/S1470-2045(18)30241-9DOI Listing
July 2018

BRCA1/2 Mutations and Bevacizumab in the Neoadjuvant Treatment of Breast Cancer: Response and Prognosis Results in Patients With Triple-Negative Breast Cancer From the GeparQuinto Study.

J Clin Oncol 2018 08 23;36(22):2281-2287. Epub 2018 May 23.

Peter A. Fasching and Matthias Rübner, Erlangen University Hospital, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen; Sibylle Loibl, Valentina Nekljudova, Karsten E. Weber, and Gunter von Minckwitz, German Breast Group Forschungs, Neu-Isenburg; Christian Schem, University Medical Center Schleswig-Holstein, Kiel; Hans Tesch, Centrum für Hämatologie und Onkologie Bethanien, Frankfurt; Michael Untch, Helios-Klinikum, Berlin-Buch; Jörn Hilfrich, Eilenriede-Klinik, Hannover; Mahdi Rezai, Luisenkrankenhaus; Tanja Fehm, Düsseldorf University Hospital, Heinrich-Heine University of Düsseldorf, Düsseldorf; Bernd Gerber, University of Rostock, Rostock; Serban Dan Costa, Magdeburg University Hospital, Magdeburg; Jens-Uwe Blohmer and Cornelia Liedtke, Charité University Hospital Campus Charité-Mitte, Berlin; Jens Huober, University of Ulm; Brigitte Rack, University Hospital Ulm, Ulm; Volkmar Müller, Hamburg University Hospital, Hamburg, Germany; Chunling Hu, Steven N. Hart, Hermela Shimelis, Raymond Moore, James N. Ingle, and Fergus J. Couch, Mayo Clinic; and Richard M. Weinshilboum and Liewei Wang, Mayo Clinic College of Medicine, Mayo Foundation, Rochester, MN.

Purpose BRCA1/2 mutations are frequent in patients with triple-negative breast cancer (TNBC). These patients are often treated with primary systemic chemotherapy. The aim of this study was to analyze the effects of BRCA1/2 mutations on pathologic complete response (pCR) and disease-free survival (DFS) in a cohort of patients with TNBC treated with anthracycline and taxane-containing chemotherapy, with or without bevacizumab. Patients and Methods Germline DNA was sequenced to identify mutations in BRCA1 and BRCA2 in 493 patients with TNBC from the GeparQuinto study. The pCR rates were compared in patients with and without mutation, as well as in patients treated with and without bevacizumab. In addition, the influence of BRCA1/2 mutation status and pCR status on DFS was evaluated relative to treatment. Results BRCA1/2 mutations were detected in 18.3% of patients with TNBC. Overall, patients with mutations had a pCR rate of 50%, compared with 31.5% in patients without a mutation (odds ratio [OR], 2.17; 95% CI, 1.37 to 3.46; P = .001). The pCR rate among patients treated with bevacizumab was 61.5% for BRCA1/2 mutation carriers and 35.6% for those without mutations (OR, 2.90; 95% CI, 1.43 to 5.89; P = .004). pCR was a strong predictor of DFS for patients without BRCA1/2 mutations (hazard ratio, 0.18; 95% CI, 0.11 to 0.31) but not for patients with BRCA1/2 mutations (hazard ratio, 0.74; 95% CI, 0.32 to 1.69). Conclusion The addition of bevacizumab may increase the pCR after standard neoadjuvant chemotherapy for patients with TNBC with BRCA1/2 mutations. In patients treated with anthracycline and taxane-based chemotherapy (with or without bevacizumab), pCR was a weaker predictor of DFS for BRCA1/2 mutation carriers than for patients without mutations.
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http://dx.doi.org/10.1200/JCO.2017.77.2285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6067803PMC
August 2018

Germline genome-wide association studies in women receiving neoadjuvant chemotherapy with or without bevacizumab.

Pharmacogenet Genomics 2018 06;28(6):147-152

Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota.

Neoadjuvant chemotherapy (NAC) for breast cancer is widely utilized, and we performed genome-wide association studies (GWAS) to determine whether germ-line genetic variability was associated with benefit in terms of pathological complete response (pCR), disease-free survival, and overall survival in patients entered on the NSABP B-40 NAC trial, wherein patients were randomized to receive, or not, bevacizumab in addition to chemotherapy. Patient DNA samples were genotyped with the Illumina OmniExpress BeadChip. Replication was attempted with genotyping data from 1398 HER2-negative patients entered on the GeparQuinto NAC study in which patients were also randomized to receive, or not, bevacizumab in addition to chemotherapy. A total of 920 women from B-40 were analyzed, and 237 patients achieved a pCR. GWAS with three phenotypes (pCR, disease-free survival, overall survival) revealed no single nucleotide polymorphisms (SNPs) that were genome-wide significant (i.e. P≤5E-08) signals; P values for top SNPs were 2.04E-07, 5.61E-08, and 5.63E-08, respectively, and these SNPs were not significant in the GeparQuinto data. An ad-hoc GWAS was performed in the patients randomized to bevacizumab (457 patients with 128 pCR) who showed signals on chromosome 6, located within a gene, CDKAL1, that approached, but did not reach, genome-wide significance (top SNP rs7453577, P=2.97E-07). However, this finding was significant when tested in the GeparQuinto data set (P=0.04). In conclusion, we identified no SNPs significantly associated with NAC. The observation, in a hypothesis-generating GWAS, of an SNP in CDKAL1 associated with pCR in the bevacizumab arm of both B-40 and GeparQuinto requires further validation and study.
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http://dx.doi.org/10.1097/FPC.0000000000000337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5965682PMC
June 2018

Outcome after neoadjuvant chemotherapy in elderly breast cancer patients - a pooled analysis of individual patient data from eight prospectively randomized controlled trials.

Oncotarget 2018 Mar 26;9(20):15168-15179. Epub 2018 Feb 26.

Department of Gynecology and Breast Center, Charité University Hospital, Berlin, Germany.

Introduction: Recent studies showed the high and independent impact of age (<40 years) on pathologic complete response (pCR) and prognosis for patients undergoing neoadjuvant chemotherapy (NACT). Some physicians might not consider elderly patients (>65 years) for NACT due to poor prognosis or higher toxicity. The aim of this analysis is to help selecting appropriately elderly women who would benefit from NACT. Secondly, survival parameters are investigated in several histological subgroups.

Methods: From 1998 to 2010, eight prospectively randomized German Breast Group (GBG) trials of anthracycline- and taxane-based NACT were performed and analyzed in this study.

Results: Compared to the overall average, elderly women had significant larger tumors and more overall lymph node involvement. Histologically, they had more G2 tumors, more estrogen-receptor positive tumors. pCR (ypT0 ypN0) was strongly associated with age. The multivariable logistic regression analysis of clinical parameters showed that young age, clinical stage T4, invasive ductal cancer and poor differentiated breast cancer are predictive for high pCR. The multivariate analyses of molecular subgroups showed that age >65years is a predictor of significant lower pCR in HER2 breast cancers. Nonetheless, HER2+ patients showed pCR rates as high and HR+/HER2+ even higher - pCR rates compared to younger patients.

Discussion: This study underlines the unfavorable impact of higher age on pCR, but it shows a realistic chance for pCR if NACT is applied - especially for HER2+ patients. Furthermore, elderly patients with non-TNBC showed a good prognosis (comparable to younger patients) regarding overall survival, even if they do not have pCR.
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http://dx.doi.org/10.18632/oncotarget.24586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5880594PMC
March 2018