Deep learning to predict breast cancer sentinel lymph node status on INSEMA histological images.

BACKGROUND: Sentinel lymph node (SLN) status is a clinically important prognostic biomarker in breast cancer and is used to guide therapy, especially for hormone receptor-positive, HER2-negative cases. However, invasive lymph node staging is increasingly omitted before therapy, and studies such as the randomised Intergroup Sentinel Mamma (INSEMA) trial address the potential for further de-escalation of axillary surgery. Therefore, it would be helpful to accurately predict the pretherapeutic sentinel status using medical images. METHODS: Using a ResNet 50 architecture pretrained on ImageNet and a previously successful strategy, we trained deep learning (DL)-based image analysis algorithms to predict sentinel status on hematoxylin/eosin-stained images of predominantly luminal, primary breast tumours from the INSEMA trial and three additional, independent cohorts (The Cancer Genome Atlas (TCGA) and cohorts from the University hospitals of Mannheim and Regensburg), and compared their performance with that of a logistic regression using clinical data only. Performance on an INSEMA hold-out set was investigated in a blinded manner. RESULTS: None of the generated image analysis algorithms yielded significantly better than random areas under the receiver operating characteristic curves on the test sets, including the hold-out test set from INSEMA. In contrast, the logistic regression fitted on the Mannheim cohort retained a better than random performance on INSEMA and Regensburg. Including the image analysis model output in the logistic regression did not improve performance further on INSEMA. CONCLUSIONS: Employing DL-based image analysis on histological slides, we could not predict SLN status for unseen cases in the INSEMA trial and other predominantly luminal cohorts.

Anti-hormonal maintenance treatment with the CDK4/6 inhibitor ribociclib after 1st line chemotherapy in hormone receptor positive / HER2 negative metastatic breast cancer: A phase II trial (AMICA).

PURPOSE: This phase II study evaluated the impact of adding ribociclib to maintenance endocrine therapy (ET) treatment of physicians' choice following the first palliative chemotherapy in pre- and post-menopausal women with hormone receptor positive (HR+)/human epidermal growth factor 2 negative (HER2-) metastatic breast cancer (mBC). PATIENTS AND METHODS: The initial randomized study design was later amended into a single-arm study, and all subsequent patients received ribociclib and ET. The primary end point was locally assessed progression-free survival (PFS). Secondary end points included overall survival (OS), clinical benefit rate (CBR), safety, compliance, and quality of life (QoL). RESULTS: A total of 43 patients received ribociclib + ET and 10 patients received ET only. Median PFS was 12.4 months [95% CI 8.7-24.4] for patients who received ribociclib + ET and 4.75 months [95% CI 1.0-10.3] for those who received ET only. Median OS was not reached for patients who received ribociclib + ET, and 28 (65.1%) patients experienced clinical benefit [95% CI 49.1-79.0]. For patients who received ribociclib + ET, grade 3-4 hematological adverse events (AEs) occurred in 25 (58.1%) patients, and grade 3-4 non-hematological AEs occurred in 17 (39.5%) patients. During the study, 15 patients died - 14 of whom due to tumor-related reasons, and one patient due to pneumonia, which was not treatment-related. CONCLUSION: The results of the AMICA study show a promising efficacy and safety of maintenance treatment with ribociclib added to ET after at least stable disease following the first metastatic chemotherapy in patients with HR+/HER2-mBC. TRIAL REGISTRATION: Anti-hormonal Therapy With Ribociclib in HR-positive/HER2- Negative Metastatic Breast Cancer (AMICA), NCT03555877, https://clinicaltrials.gov/ct2/show/NCT03555877.

Patient-reported outcomes for the Intergroup Sentinel Mamma study (INSEMA): A randomised trial with persistent impact of axillary surgery on arm and breast symptoms in patients with early breast cancer.

Background: In clinically node-negative breast cancer patients, the INSEMA trial (NCT02466737) assessed the non-inferiority of avoiding sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND). Here we present patient-reported outcomes (PROs) as a secondary endpoint. Methods: PROs were assessed for patients with no axillary surgery, SLNB alone, and ALND. Quality of life (QoL) questionnaire EORTC QLQ-C30 and its breast cancer module (BR23) were used at baseline (pre-surgery) and 1, 3, 6, 12, and 18 months after surgery. The QoL scores were compared using repeated measures mixed models based on the safety set. Findings: Between 2015 and 2019, 5502 patients were recruited for the first randomization, and 5154 were included in the intent-to-treat set (4124 SLNB versus 1030 no SLNB). In the case of one to three macrometastases after SLNB, 485 patients underwent second randomization (242 SLNB alone versus 243 ALND). Questionnaire completion response remained high throughout the trial: over 70% at all time points for the first randomization. There were significant differences for the BRBS (breast symptoms) and BRAS (arm symptoms) scores favoring the no SLNB group in all post-baseline assessments. Patients in the SLNB group showed significantly and clinically relevant higher scores for BRAS (differences in mean values ≥5.0 points at all times), including pain, arm swelling, and impaired mobility in all postoperative visits, with the highest difference at one month after surgery. Scoring of the QLQ-C30 questionnaire revealed no relevant differences between the treatment groups, although some comparisons were statistically significant. Interpretation: This is one of the first randomized trials investigating the omission of SLNB in clinically node-negative patients and the first to report comprehensive QoL data. Patients with no SLNB benefitted regarding arm symptoms/functioning, while no relevant differences in other scales were seen. Funding: Supported by German Cancer Aid (Deutsche Krebshilfe, Bonn, Germany), Grant No. 110580 and Grant No. 70110580 to University Medicine Rostock.

Correction: MGMT promoter methylation in triple negative breast cancer of the GeparSixto trial.

[This corrects the article DOI: 10.1371/journal.pone.0238021.].

Efficacy of Endocrine Therapy for the Treatment of Breast Cancer in Men: Results from the MALE Phase 2 Randomized Clinical Trial.

IMPORTANCE: The extent of changes in estradiol levels in male patients with hormone receptor-positive breast cancer receiving standard endocrine therapies is unknown. The sexual function and quality of life related to those changes have not been adequately evaluated. OBJECTIVE: To assess the changes in estradiol levels in male patients with breast cancer after 3 months of therapy. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, phase 2 randomized clinical trial assessed 56 male patients with hormone receptor-positive breast cancer. Patients were recruited from 24 breast units across Germany between October 2012 and May 2017. The last patient completed 6 months of treatment in December 2017. The analysis data set was locked on August 24, 2018, and analysis was completed on December 19, 2018. INTERVENTIONS: Patients were randomized to 1 of 3 arms: tamoxifen alone or tamoxifen plus gonadotropin-releasing hormone analogue (GnRHa) or aromatase inhibitor (AI) plus GnRHa for 6 months. MAIN OUTCOMES AND MEASURES: The primary end point was the change in estradiol levels from baseline to 3 months. Secondary end points were changes of estradiol levels after 6 months, changes of additional hormonal parameters, adverse effects, sexual function, and quality of life after 3 and 6 months. RESULTS: In this phase 2 randomized clinical trial, a total of 52 of 56 male patients with a median (range) age of 61.5 (37-83) years started treatment. A total of 3 patients discontinued study treatment prematurely, 1 in each arm. A total of 50 patients were evaluable for the primary end point. After 3 months the patients' median estradiol levels increased by 67% (a change of +17.0 ng/L) with tamoxifen, decreased by 85% (-23.0 ng/L) with tamoxifen plus GnRHa, and decreased by 72% (-18.5 ng/L) with AI plus GnRHa (P < .001). After 6 months, median estradiol levels increased by 41% (a change of +12 ng/L) with tamoxifen, decreased by 61% (-19.5 ng/L) with tamoxifen plus GnRHa, and decreased by 64% (-17.0 ng/L) with AI plus GnRHa (P < .001). Sexual function and quality of life decreased when GnRHa was added but were unchanged with tamoxifen alone. CONCLUSIONS AND RELEVANCE: This phase 2 randomized clinical trial found that AI or tamoxifen plus GnRHa vs tamoxifen alone led to a sustained decrease of estradiol levels. The decreased hormonal parameters were associated with impaired sexual function and quality of life. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01638247.

Immune-related Gene Expression Predicts Response to Neoadjuvant Chemotherapy but not Additional Benefit from PD-L1 Inhibition in Women with Early Triple-negative Breast Cancer.

PURPOSE: We evaluated mRNA signatures to predict response to neoadjuvant PD-L1 inhibition in combination with chemotherapy in early triple-negative breast cancer. EXPERIMENTAL DESIGN: Targeted mRNA sequencing of 2,559 transcripts was performed in formalin-fixed, paraffin-embedded samples from 162 patients of the GeparNuevo trial. We focused on validation of four predefined gene signatures and differential gene expression analyses for new predictive markers. RESULTS: Two signatures [GeparSixto signature (G6-Sig) and IFN signature (IFN-Sig)] were predictive for treatment response in a multivariate model including treatment arm [G6-Sig: OR, 1.558; 95% confidence interval (CI), 1.130-2.182; P = 0.008 and IFN-Sig: OR, 1.695; 95% CI, 1.234-2.376; P = 0.002), while the CYT metric predicted pathologic complete response (pCR) in the durvalumab arm, and the proliferation-associated gene signature in the placebo arm. Expression of PD-L1 mRNA was associated with better response in both arms, indicating that increased levels of PD-L1 are a general predictor of neoadjuvant therapy response. In an exploratory analysis, we identified seven genes that were higher expressed in responders in the durvalumab arm, but not the placebo arm: HLA-A, HLA-B, TAP1, GBP1, CXCL10, STAT1, and CD38. These genes were associated with cellular antigen processing and presentation and IFN signaling. CONCLUSIONS: Immune-associated signatures are associated with pCR after chemotherapy, but might be of limited use for the prediction of response to additional immune checkpoint blockade. Gene expressions related to antigen presentation and IFN signaling might be interesting candidates for further evaluation.

Germline BRCA1/2 mutations and severe haematological toxicities in patients with breast cancer treated with neoadjuvant chemotherapy.

BACKGROUND: BRCA1 and BRCA2 play a central role in DNA repair. Therefore, patients harbouring germline (g) BRCA1/2 mutations (m) treated with chemotherapy might be at higher risk of haematological toxicities. METHODS: Patients from German Breast Group (GBG) and Arbeitsgemeinschaft Gynäkologische Onkologie-breast group studies with early triple-negative breast cancer (TNBC) and known gBRCA1/2m status treated with anthracycline-taxane-based neoadjuvant chemotherapy were analysed. Primary objective was the rate of neutropenia grade (G)III-IV in cycle 1 (C1). Secondary objectives included effects on overall and other haematological toxicities GIII-IV in C1, cumulative haematological toxicity across all cycles, relative total dose intensity, and granulocyte-colony stimulating factor prophylaxis. Haematological toxicities under taxanes, carboplatin, and cyclophosphamide were explored. RESULTS: Two hundred nine of 1171 (17.8%) evaluated patients had gBRCA1/2m. In C1, 37.4% gBRCA1/2m versus 35.7% wild-type patients had neutropenia GIII-IV (P = 0.683). For C1, gBRCA1/2m predicted neither for neutropenia GIII-IV (odds ratio [OR]: 1.26, 95% confidence intervals [CI]: 0.87-1.82, P = 0.226) nor for other haematological toxicities GIII-IV (OR: 0.91, 95% CI: 0.64-1.31, P = 0.625) in multivariable regression models. Analyses of cumulative toxicities across all cycles yielded similar results except thrombocytopaenia GIII-IV, which was increased in gBRCA1m patients. In patients treated with taxanes, the rate of haematological toxicities GIII-IV was higher in gBRCA1/2m compared with wild-type (59.5% versus 43.1%; p < 0.001). No difference was seen under cyclophosphamide or platinum-containing chemotherapies. CONCLUSIONS: gBRCA1/2m was not associated with higher risk of overall severe haematological toxicities in the first cycle or cumulatively across all cycles under standard chemotherapy for TNBC. Under taxane, patients with gBRCA1/2m might have a higher risk of haematological toxicities GIII-IV, requiring further research.

Differential effect on different immune subsets of neoadjuvant chemotherapy in patients with TNBC.

BACKGROUND: Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer (BC). Due to the absence of targets such as HER2 or hormone receptors, early TNBC is treated with surgery and chemotherapy. Since TNBC is also considered the most immunogenic type of BC with tumor infiltrating lymphocytes that are predictive for chemotherapy response and prognostic for patients' survival, many different immunotherapeutic strategies are currently explored in clinical trials for the treatment of this disease. In order to efficiently combine chemotherapy with immunotherapy, it is important to evaluate the effect of chemotherapy on immune cells in vivo. METHODS: Peripheral blood was taken from 56 patients with TNBC undergoing neoadjuvant chemotherapy with nanoparticle albumin-bound paclitaxel (Nab-Pac) followed by epirubicin and cyclophosphamide (EC) at three different time points. Multicolor flow cytometry was used to characterize the immune cell composition and functional properties along neoadjuvant chemotherapy. RESULTS: Whereas the first phase of the neoadjuvant chemotherapy did not significantly alter the patients' immune cell composition, after the second phase of chemotherapeutic administration most B cells (>90%) were lost and the frequency of natural killer (NK) cells and CD4+ T lymphocytes decreased approximately to 50%. In contrast, the frequency of CD8+ T cells were less affected. CONCLUSIONS: Despite late consequences of Nab-Pac cannot be ruled out, these data suggest that different chemotherapeutics might have distinct effects on the immune cell repertoire and that different immune cell populations exhibit a specific susceptibility to these chemotherapies with B and NK cells being more affected than T cells. This might also have an impact on the combination of chemotherapies with immunotherapies. TRIAL REGISTRATION NUMBER: NCT02685059.

MGMT promoter methylation in triple negative breast cancer of the GeparSixto trial.

Triple-negative breast cancer (TNBC) is typically treated with chemotherapeutic agents, including carboplatin (Cb), an DNA platinating agent. The O6-methylguanine-DNA-methyltransferase gene (MGMT) encodes for the protein O6-alkylguanine-DNA-alkyltransferase (MGMT protein). MGMT protein is involved in DNA repair mechanisms to remove mutagenic and cytotoxic adducts from O6-guanine in DNA. In glioblastoma multiforme, MGMT methylation status is a predictive biomarker for increased response to temozolomide therapy. It has been suggested, that MGMT protein may have relevance for cellular adaptation and could have an influence on resistance to carboplatin therapy. We investigated the influence of MGMT promoter methylation on pathologic complete response and survival of patients with TNBC treated in the neoadjuvant GeparSixto trial. In 174 of 210 available TNBC tumors a valid MGMT promoter methylation status was determined by pyrosequencing of 5 CpG islands. In 21.8%, we detected a mean MGMT promoter methylation >10%. Overall, MGMT promoter methylation was not significantly associated with pathological complete response (pCR) rate. After stratification for the two therapy arms with and without Cb no statistically significant differences in therapy response rates between the two MGMT promoter methylation groups could be observed. Our results show that different MGMT promoter methylation status is not related to different chemotherapy response rates in the TNBC setting in GeparSixto.

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.

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.

Response to neoadjuvant treatment of invasive ductal breast carcinomas including outcome evaluation: MRI analysis by an automatic CAD system in comparison to visual evaluation.

BACKGROUND: The aim of this study was to evaluate imaging-based response to standardized neoadjuvant chemotherapy (NACT) regimen by dynamic contrast-enhanced magnetic resonance mammography (DCE-MRM), whereas MR images were analyzed by an automatic computer-assisted diagnosis (CAD) system in comparison to visual evaluation. MRI findings were correlated with histopathologic response to NACT and also with the occurrence of metastases in a follow-up analysis. PATIENTS AND METHODS: Fifty-four patients with invasive ductal breast carcinomas received two identical MRI examinations (before and after NACT; 1.5T, contrast medium gadoteric acid). Pre-therapeutic images were compared with post-therapeutic examinations by CAD and two blinded human observers, considering morphologic and dynamic MRI parameters as well as tumor size measurements. Imaging-assessed response to NACT was compared with histopathologically verified response. All clinical, histopathologic, and DCE-MRM parameters were correlated with the occurrence of distant metastases. RESULTS: Initial and post-initial dynamic parameters significantly changed between pre- and post-therapeutic DCE-MRM. Visually evaluated DCE-MRM revealed sensitivity of 85.7%, specificity of 91.7%, and diagnostic accuracy of 87.0% in evaluating the response to NACT compared to histopathology. CAD analysis led to more false-negative findings (37.0%) compared to visual evaluation (11.1%), resulting in sensitivity of 52.4%, specificity of 100.0%, and diagnostic accuracy of 63.0%. The following dynamic MRI parameters showed significant associations to occurring metastases: Post-initial curve type before NACT (entire lesions, calculated by CAD) and post-initial curve type of the most enhancing tumor parts after NACT (calculated by CAD and manually). CONCLUSIONS: In the accurate evaluation of response to neoadjuvant treatment, CAD systems can provide useful additional information due to the high specificity; however, they cannot replace visual imaging evaluation. Besides traditional prognostic factors, contrast medium-induced dynamic MRI parameters reveal significant associations to patient outcome, i.e. occurrence of distant metastases.

Response-guided neoadjuvant chemotherapy for breast cancer.

PURPOSE: We investigated disease-free survival (DFS) and overall survival (OS) after response-guided neoadjuvant chemotherapy in patients with early breast cancer. PATIENTS AND METHODS: We treated 2,072 patients with two cycles of docetaxel, doxorubicin, and cyclophosphamide (TAC) and randomly assigned early responders to four (n = 704) or six (n = 686) additional TAC cycles, and early nonresponders to four cycles of TAC (n = 321) or vinorelbine and capecitabine (NX; n = 301) before surgery. RESULTS: DFS was longer in early responders receiving TAC × 8 than in those receiving TAC × 6 (hazard ratio [HR], 0.78; 95% CI, 0.62 to 0.97; P = .026), and in early nonresponders receiving TAC-NX than in those receiving TAC × 6 (HR, 0.59; 95% CI, 0.49 to 0.82; P = .001). Exploratory analysis showed that DFS after response-guided chemotherapy (TAC × 8 or TAC-NX) was significantly longer (HR, 0.71; 95% CI, 0.60 to 0.85; P < .003), as was OS (HR, 0.79; 95% CI, 0.63 to 0.99; P = .048), than on conventional chemotherapy (TAC × 6). DFS was longer after response-guided chemotherapy in all hormone receptor-positive tumors (luminal A HR = 0.55, luminal B [human epidermal growth factor receptor 2 (HER2) negative] HR = 0.40, and luminal B [HER2 positive] HR = 0.56), but not in hormone receptor-negative tumors (HER2 positive [nonluminal] HR = 1.01 and triple negative HR = 0.87). Pathologic complete response did not predict these survival effects. pCR predicted an improved DFS in triple-negative (HR = 6.67), HER2-positive (nonluminal; HR 5.24), or luminal B (HER2-negative) tumors (HR = 3.74). CONCLUSION: This exploratory analysis suggests that response-guided neoadjuvant chemotherapy might improve survival and is most effective in hormone receptor-positive tumors. If confirmed, the response-guided approach could provide a clinically meaningful advantage for the neoadjuvant over the adjuvant approach in early breast cancer.

Cytoplasmic poly(adenosine diphosphate-ribose) polymerase expression is predictive and prognostic in patients with breast cancer treated with neoadjuvant chemotherapy.

PURPOSE: Poly(adenosine diphosphate-ribose) polymerase (PARP) plays a key role in DNA repair and cellular stress response. Inhibitors of PARP show promising clinical activity in metastatic, triple-negative or BRCA-mutated breast cancer. PATIENTS AND METHODS: We investigated cytoplasmic PARP (cPARP) and nuclear PARP (nPARP) expression by immunohistochemistry in 638 pretreatment biopsies from patients on the GeparTrio study and evaluated its predictive and prognostic value after neoadjuvant anthracycline/taxane-based chemotherapy. RESULTS: cPARP expression was high in 23.7%, intermediate in 50.9%, and negative in 25.4% of tumors. High cPARP expression was significantly correlated with nonlobular histology (P < .001), undifferentiated grade (P < .001), positive nodal status (P = .049), and negative hormone receptor (HR) status (P < .001) but not with human epidermal growth factor receptor 2 (HER2) status. Expression was high in 35.5% of triple-negative tumors, 24.6% of HER2-positive tumors, and 18.0% of HR-positive/HER2-negative tumors (P < .001). Pathologic complete response (pCR) rates were 26.5%, 19.1%, and 8.0% in patients with high, intermediate, or negative expression, respectively (P < .001). This predictive effect was most prominent in HR-positive tumors (P = .035) or HER2-negative tumors (P < .001). High cPARP expression was a negative, but not independent, prognostic factor for disease-free survival (DFS; P = .0025) and overall survival (OS; P = .0022). cPARP expression was highly prognostic in patients without a pCR (DFS, P < .001; OS, P < .001) and in patients with HR-positive tumors (DFS, P < .001; OS, P < .001). No such correlations were found for nPARP expression. CONCLUSION: High cPARP expression correlates with aggressive tumor pattern and predicts high sensitivity to neoadjuvant taxane/anthracycline-based chemotherapy but also unfavorable long-term prognosis. As a potential target for PARP inhibitors, cPARP-positive breast cancer might become a new, clinically relevant entity.

Effect of neoadjuvant anthracycline-taxane-based chemotherapy in different biological breast cancer phenotypes: overall results from the GeparTrio study.

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.

Neoadjuvant chemotherapy shows similar response in patients with inflammatory or locally advanced breast cancer when compared with operable breast cancer: a secondary analysis of the GeparTrio trial data.

PURPOSE Neoadjuvant chemotherapy followed by mastectomy is the treatment of choice in patients with inflammatory breast cancer (IBC) or locally advanced breast cancer (LABC), but it is considered less effective in these diseases than in operable breast cancer (OBC). We report a prospective comparison of the GeparTrio trial of patients with IBC (cT4 days) or LABC (cT4a-c or cN3; stage IIIB or IIIC) and patients with OBC (cT2-3). PATIENTS AND METHODS Participants were stratified by stage and were randomly assigned to six or eight cycles of docetaxel/doxorubicin/cyclophosphamide (TAC) or to two cycles of TAC followed by four cycles of vinorelbine/capecitabine. We present results of a secondary aim of the study, which was to compare pathologic complete response (pCR; ie, no remaining invasive/noninvasive tumor in breast and lymph nodes) in different stage groups. Results A total of 287 patients with IBC (n = 93) or LABC (n = 194) and 1,777 patients with OBC were entered onto the trial. At baseline, parameters were as follows for the three types of cancer, respectively: median tumor sizes: 8.0 cm, 7.0 cm, and 4.0 cm (P < .001); multiple lesions: 31.2%, 27.3%, and 19.6% (P < .001); nodal involvement: 86.6%, 71.2%, and 51.6% (P < .001); grade 3: 44.4%, 30.4%, and 39.9% (P = .178); lobular-invasive type: 7.5%, 17.5%, and 13.3% (P = .673); negative hormone receptor status: 38.0%, 20.0%, and 36.4% (P = .008); and positive human growth factor receptor 2 status: 45.1%, 38.9%, and 35.7% (P = .158). Response rates for IBC, LABC, and OBC, respectively, were 8.6%, 11.3%, and 17.7% for pCR (P = .002); 71.0%, 69.6%, and 83.4% for overall response by physical or sonographic examination (P < .001); and 12.9%, 33.0%, and 69.9% for breast conservation (P < .001). All P values were for IBC and LABC versus OBC. However, tumor stage itself was not an independent predictor for pCR in multivariable analysis (odds ratio, 1.51; 95% CI, 0.88 to 2.59; P = .13). CONCLUSION No evidence of a difference in response to neoadjuvant chemotherapy was found by tumor stage when analysis was adjusted for baseline characteristics.