Intensified alkylating chemotherapy for patients with oligometastatic breast cancer harboring homologous recombination deficiency: Primary outcomes from the randomized phase III OLIGO study.

Background: Oligometastatic breast cancer (OMBC) is a clinical entity with a prospect of long-term survival, but uncertainty remains on its optimal treatment. We studied whether intensified alkylating chemotherapy (IACT) improves long-term outcome compared to conventional-dose chemotherapy (CDCT) as part of a multimodality approach for patients with OMBC harboring homologous recombination deficiency (HRD).

Patients And Methods: Eligible patients had HER2-negative OMBC, harboring HRD, with ≤ 3 distant metastases, pathologic proof of distant disease and a favorable response to three cycles CDCT.

Predictive gene expression profile for adjuvant taxane benefit in breast cancer in the MATADOR trial.

The primary objective of the prospective, randomized, multicenter, phase 3 biomarker Microarray Analysis in breast cancer to Taylor Adjuvant Drugs Or Regimens trial (MATADOR: ISRCTN61893718) is to generate a gene expression profile that can predict benefit from either docetaxel, doxorubicin, and cyclophosphamide (TAC) or dose-dense scheduled doxorubicin and cyclophosphamide (ddAC). Patients with a pT1-3, pN0-3 tumor were randomized 1:1 between ddAC and TAC. The primary endpoint was a gene profile-treatment interaction for recurrence-free survival (RFS).

MRI-guided optimisation of neoadjuvant chemotherapy duration in stage II-III HER2-positive breast cancer (TRAIN-3): a multicentre, single-arm, phase 2 study.

Background: Patients with stage II-III HER2-positive breast cancer have good outcomes with the combination of neoadjuvant chemotherapy and HER2-targeted agents. Although increasing the number of chemotherapy cycles improves pathological complete response rates, early complete responses are common. We investigated whether the duration of chemotherapy could be tailored on the basis of radiological response.

High-dose alkylating chemotherapy in BRCA-altered triple-negative breast cancer: the randomized phase III NeoTN trial.

Exploratory analyses of high-dose alkylating chemotherapy trials have suggested that BRCA1 or BRCA2-pathway altered (BRCA-altered) breast cancer might be particularly sensitive to this type of treatment. In this study, patients with BRCA-altered tumors who had received three initial courses of dose-dense doxorubicin and cyclophosphamide (ddAC), were randomized between a fourth ddAC course followed by high-dose carboplatin-thiotepa-cyclophosphamide or conventional chemotherapy (initially ddAC only or ddAC-capecitabine/decetaxel [CD] depending on MRI response, after amendment ddAC-carboplatin/paclitaxel [CP] for everyone). The primary endpoint was the neoadjuvant response index (NRI).

Unleashing NK- and CD8 T cells by combining monalizumab and trastuzumab for metastatic HER2-positive breast cancer: Results of the MIMOSA trial.

The large majority of patients with HER2-positive metastatic breast cancer (MBC) will eventually develop resistance to anti-HER2 therapy and die of this disease. Despite, relatively high levels of stromal tumor infiltrating lymphocytes (sTILs), PD1-blockade has only shown modest responses. Monalizumab targets the inhibitory immune checkpoint NKG2A, thereby unleashing NK- and CD8 T cells.

PD-L1 blockade in combination with carboplatin as immune induction in metastatic lobular breast cancer: the GELATO trial.

Invasive lobular breast cancer (ILC) is the second most common histological breast cancer subtype, but ILC-specific trials are lacking. Translational research revealed an immune-related ILC subset, and in mouse ILC models, synergy between immune checkpoint blockade and platinum was observed. In the phase II GELATO trial ( NCT03147040 ), patients with metastatic ILC were treated with weekly carboplatin (area under the curve 1.

Limiting systemic endocrine overtreatment in postmenopausal breast cancer patients with an ultralow classification of the 70-gene signature.

Purpose: Guidelines recommend endocrine treatment for estrogen receptor-positive (ER+) breast cancers for up to 10 years. Earlier data suggest that the 70-gene signature (MammaPrint) has potential to select patients that have an excellent survival without chemotherapy and limited or no tamoxifen treatment. The aim was to validate the 70-gene signature ultralow-risk classification for endocrine therapy decision making.

Carboplatin-Cyclophosphamide or Paclitaxel without or with Bevacizumab as First-Line Treatment for Metastatic Triple-Negative Breast Cancer (BOOG 2013-01).

Background: The addition of bevacizumab to chemotherapy conferred a modest progression-free survival (PFS) benefit in metastatic triple-negative breast cancer (mTNBC). However, no overall survival (OS) benefit has been reported. Also, its combination with carboplatin-cyclophosphamide (CC) has never been investigated.

Differential Survival and Therapy Benefit of Patients with Breast Cancer Are Characterized by Distinct Epithelial and Immune Cell Microenvironments.

Purpose: Extensive work in preclinical models has shown that microenvironmental cells influence many aspects of cancer cell behavior, including metastatic potential and their sensitivity to therapeutics. In the human setting, this behavior is mainly correlated with the presence of immune cells. Here, in addition to T cells, B cells, macrophages, and mast cells, we identified the relevance of nonimmune cell types for breast cancer survival and therapy benefit, including fibroblasts, myoepithelial cells, muscle cells, endothelial cells, and seven distinct epithelial cell types.

IHC-based Ki67 as response biomarker to tamoxifen in breast cancer window trials enrolling premenopausal women.

Window studies are gaining traction to assess (molecular) changes in short timeframes. Decreased tumor cell positivity for the proliferation marker Ki67 is often used as a proxy for treatment response. Immunohistochemistry (IHC)-based Ki67 on tissue from neo-adjuvant trials was previously reported to be predictive for long-term response to endocrine therapy for breast cancer in postmenopausal women, but none of these trials enrolled premenopausal women.

Three-Year Follow-up of Neoadjuvant Chemotherapy With or Without Anthracyclines in the Presence of Dual ERBB2 Blockade in Patients With ERBB2-Positive Breast Cancer: A Secondary Analysis of the TRAIN-2 Randomized, Phase 3 Trial.

Importance: Primary analysis of the TRAIN-2 study showed high pathologic complete response rates after neoadjuvant chemotherapy with or without anthracyclines plus dual ERBB2 (formerly HER2) blockade.

Objective: To evaluate 3-year event-free survival (EFS) and overall survival (OS) of an anthracycline-free and anthracycline-containing regimen with dual ERBB2 blockade in patients with stage II and III ERBB2-positive breast cancer.

Design, Setting, And Participants: A total of 438 patients with stage II and III ERBB2-positive breast cancer were enrolled in this randomized, clinical, open-label phase 3 trial across 37 hospitals in the Netherlands from December 9, 2013, until January 14, 2016.

POSEIDON Trial Phase 1b Results: Safety, Efficacy and Circulating Tumor DNA Response of the Beta Isoform-Sparing PI3K Inhibitor Taselisib (GDC-0032) Combined with Tamoxifen in Hormone Receptor Positive Metastatic Breast Cancer Patients.

Purpose: The strategy of combining endocrine therapy with PI3K-mTOR inhibition has shown promise in estrogen receptor (ER)-positive breast cancer, but new agents and combinations with a better therapeutic index are urgently needed. Taselisib is a potent, selective, beta-isoform-sparing PI3 kinase inhibitor.

Patients And Methods: 30 patients with ER-positive, metastatic breast cancer who had failed prior endocrine therapy were treated with escalating doses of taselisib (2 or 4 mg in an intermittent or continuous schedule) combined with tamoxifen 20 mg once daily in this phase 1b study using a "rolling six" design.

Publisher Correction: Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial.

In the version of this article originally published, there was an error in Fig. 3j. A label on the heatmap read "TGF-α signaling via NF-κB".

Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial.

The efficacy of programmed cell death protein 1 (PD-1) blockade in metastatic triple-negative breast cancer (TNBC) is low, highlighting a need for strategies that render the tumor microenvironment more sensitive to PD-1 blockade. Preclinical research has suggested immunomodulatory properties for chemotherapy and irradiation. In the first stage of this adaptive, non-comparative phase 2 trial, 67 patients with metastatic TNBC were randomized to nivolumab (1) without induction or with 2-week low-dose induction, or with (2) irradiation (3 × 8 Gy), (3) cyclophosphamide, (4) cisplatin or (5) doxorubicin, all followed by nivolumab.

Neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): a multicentre, open-label, randomised, phase 3 trial.

Background: The optimal chemotherapy backbone for dual HER2 blockade in the neoadjuvant setting for early breast cancer is unknown. We investigated whether the addition of anthracyclines would improve pathological complete response compared with a carboplatin-taxane regimen, when given in combination with the HER2-targeted agents trastuzumab and pertuzumab.

Methods: The TRAIN-2 study is an open-label, randomised, controlled, phase 3 trial being done in 37 hospitals in the Netherlands.

Adjuvant dose-dense doxorubicin-cyclophosphamide versus docetaxel-doxorubicin-cyclophosphamide for high-risk breast cancer: First results of the randomised MATADOR trial (BOOG 2004-04).

Background: Dose-dense administration of chemotherapy and the addition of taxanes to anthracycline-based adjuvant chemotherapy have improved breast cancer survival substantially. However, clinical trials directly comparing the additive value of taxanes with dose-dense anthracycline-based chemotherapy are lacking.

Patients And Methods: In the multicentre, randomised, biomarker discovery Microarray Analysis in breast cancer to Tailor Adjuvant Drugs Or Regimens (MATADOR) trial, patients with pT1-3, pN0-3 breast cancer were randomised (1:1) between six adjuvant cycles of doxorubicin 60 mg/m and cyclophosphamide 600 mg/m every 2 weeks (ddAC) and six cycles of docetaxel 75 mg/m, doxorubicin 50 mg/m and cyclophosphamide 500 mg/m every 3 weeks (TAC).

Independent replication of polymorphisms predicting toxicity in breast cancer patients randomized between dose-dense and docetaxel-containing adjuvant chemotherapy.

Introduction: Although pharmacogenomics has evolved substantially, a predictive test for chemotherapy toxicity is still lacking. We compared the toxicity of adjuvant dose-dense doxorubicin-cyclophosphamide (ddAC) and docetaxel-doxorubicin-cyclophosphamide (TAC) in a randomized multicenter phase III trial and replicated previously reported associations between genotypes and toxicity.

Results: 646 patients (97%) were evaluable for toxicity (grade 2 and higher).

Trastuzumab in combination with weekly paclitaxel and carboplatin as neo-adjuvant treatment for HER2-positive breast cancer: The TRAIN-study.

Aim: To determine the efficacy and safety of an anthracycline-free neo-adjuvant regimen consisting of weekly paclitaxel, carboplatin and trastuzumab in HER2-positive breast cancer.

Patients And Methods: Patients with stage II or III HER2-positive breast cancer received weekly paclitaxel ([P], 70 mg/m), trastuzumab ([T], 2 mg/kg, loading dose 4 mg/kg) and carboplatin ([C], AUC = 3 mg ml min) for 24 weeks. In weeks 7, 8, 15, 16, 23 and 24, trastuzumab was administered without chemotherapy.

Toxicity of dual HER2-blockade with pertuzumab added to anthracycline versus non-anthracycline containing chemotherapy as neoadjuvant treatment in HER2-positive breast cancer: The TRAIN-2 study.

Background: The addition of pertuzumab to neoadjuvant trastuzumab-based chemotherapy improves pathologic complete response rates in HER2-positive breast cancer. However, increased toxicity has been reported with the addition of pertuzumab, and this may differ between various chemotherapy backbone regimens. We evaluated toxicities of pertuzumab when added to either FEC-T (5-fluorouracil, epirubicin, cyclophosphamide, trastuzumab) or weekly paclitaxel, trastuzumab, carboplatin (PTC).

Copy number profiling by array comparative genomic hybridization identifies frequently occurring BRCA2-like male breast cancer.

Genomic aberrations can be used to subtype breast cancer. In this study, we investigated DNA copy number (CN) profiles of 69 cases of male breast cancer (MBC) by array comparative genomic hybridization (aCGH) to detect recurrent gains and losses in comparison with female breast cancers (FBC). Further, we classified these profiles as BRCA1-like, BRCA2-like or non-BRCA-like profiles using previous classifiers derived from FBC, and correlated these profiles with pathological characteristics.

The prognostic value of the neoadjuvant response index in triple-negative breast cancer: validation and comparison with pathological complete response as outcome measure.

The Neoadjuvant response index (NRI) has been proposed as a simple measure of downstaging by neoadjuvant treatment in breast cancer. It was previously found to predict recurrence-free survival (RFS) in triple-negative (TN) breast cancer. It was at least as accurate as the standard binary system, the absence or presence of a pathological complete remission (pCR), which is the commonly employed outcome measure.

Neoadjuvant chemotherapy adaptation and serial MRI response monitoring in ER-positive HER2-negative breast cancer.

Background: Changing the neoadjuvant chemotherapy regimen in insufficiently responding breast cancer is not a standard policy. We analysed a series of patients with 'luminal'-type breast cancer in whom the second half of neoadjuvant chemotherapy was selected based on the response to the first half.

Methods: Patients with oestrogen receptor-positive (ER+) human epidermal growth factor receptor 2-negative (HER2-) breast cancer received three courses of neoadjuvant dose-dense doxorubicin and cyclophosphamide (ddAC).

Breast cancer subtyping by immunohistochemistry and histological grade outperforms breast cancer intrinsic subtypes in predicting neoadjuvant chemotherapy response.

Intrinsic subtypes are widely accepted for the classification of breast cancer. Lacking gene expression data, surrogate classifications based on immunohistochemistry (IHC) have been proposed. A recent St.

Paclitaxel, carboplatin, and trastuzumab in a neo-adjuvant regimen for HER2-positive breast cancer.

To evaluate a nonanthracycline-containing regimen consisting of 24 weekly administrations of paclitaxel, carboplatin, and trastuzumab as neo-adjuvant therapy for human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Patients with stage II or III breast cancer, including inflammatory disease, with HER2 overexpression (immunohistochemistry and/or fluorescent in situ hybridization) were treated with 24 weekly administrations of paclitaxel 70 mg/m(2) , carboplatin AUC = 3 mg/mL/minute, and trastuzumab 2 mg/kg (loading dose 4 mg/kg). In cycles 7, 8, 15, 16, 23, and 24, only trastuzumab was given.