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Background: Anthracycline/cyclophosphamide-taxane-containing chemotherapy (AC-T) is the standard of care in the adjuvant treatment of HER2-negative early breast cancer (EBC), but recent studies suggest omission of anthracyclines for reduced toxicity without compromising efficacy.Methods: Based on individual patient data (n = 5924) pooled from the randomised Phase III trials PlanB and SUCCESS C, we compared disease-free survival (DFS) and overall survival (OS) between intermediate to high-risk HER2-negative EBC-patients treated with either six cycles of docetaxel/cyclophosphamide (TC6) or an AC-T regime using univariable and adjusted multivariable Cox regression models.Results: AC-T conferred no significant DFS or OS advantage in univariable (DFS: hazard ratio (HR) for TC vs. AT 1.05, 95% confidence interval (CI): 0.89-1.24, P = 0.57; OS: HR 1.00, 95% CI: 0.80-1.26, P = 1.00) and adjusted multivariable analysis (DFS: HR 1.01, 95% CI: 0.86-1.19, P = 0.91; OS: HR 0.97, 95% CI: 0.77-1.22, P = 0.79). Patients receiving TC6 had significantly fewer grade 3-4 adverse events. Exploratory subgroup analysis showed that AC-T was associated with significantly better DFS and OS in pN2/3 patients, specifically in those with lobular histology.Conclusion: For most patients with HER2-negative EBC, AC-T is not associated with a survival benefit compared to TC6. However, patients with lobular pN2/pN3 tumours seem to benefit from anthracycline-containing chemotherapy. [ABSTRACT FROM AUTHOR]

The article offers information related to American Society of Clinical Oncology in Breast Cancer in 2019. Topics include what the most promising Treatment De-Escalation Tool in the early HER2-Positive Breast Cancer; what think about Neoadjuvant Adjuvant T-DM1 data; and what is definition of Clinical High Risk.

Purpose: Although dose-dense (dd) chemotherapy plays a fundamental role in the treatment of breast cancer (BC), a variety of trials have presented divergent survival results. Here, we present data of patients with more than 3 positive axillary lymph nodes (+aLN) receiving dd chemotherapy after a median follow-up period of 12.3 years. Methods: In the years 1996-2000, 231 patients with invasive BC, ≥pN2a and no evidence of distant metastases were recruited to receive treatment A, i.e. dd 3 × epirubicin (E, 90 mg/m2) + paclitaxel (P, 175 mg/m2) every 2 weeks (q2w) followed by 3 × cyclophosphamide (C)/methotrexate/5-fluorouracil (CMF, 600/40/600 mg/m2, q2w), or treatment B, i.e. 4 × E + C (C, 600 mg/m2) q3w followed by 3 × CMF q3w. Results: 113 patients in arm A and 113 patients in arm B were analysed after an updated median follow-up of 12.3 years. The median age was 55 years, with a median number of 6 +aLN, 50.4% had a T2 and 79.2% hormone receptor-positive BC. The disease-free survival (DFS) rate was 53.1% in arm A and 42.5% in arm B (adjusted p = 0.027). The overall survival (OS) rate was 54.9% in arm A and 48.7% in arm B (adjusted p = 0.058). In the multivariable analysis, the tumour burden was a significant predictor for DFS and OS. Conclusion: The adjuvant use of dd chemotherapy led to a statistically significant improvement of DFS after a follow-up of 12.3 years. [ABSTRACT FROM AUTHOR]

Background: Autologous fat transfer in breast reconstruction has become increasingly important in breast reconstructive surgery. Although the indication to obtain fat, the various operative procedures, and the risks for the patient have been addressed in a large number of studies, detailed information on the everyday use of autologous lipotransfer in breast units in Germany is still lacking. Methods: The objective of the study was to obtain primary data on the use of autologous lipotransfer to treat breast cancer patients in Germany and to determine measures for quality assurance in the daily practice. An online questionnaire concerning breast cancer and lipofilling was sent to specialists in gynecology and plastic surgery. Results: Two-thirds of the specialists who responded to the questionnaire use autologous lipotransfer for breast reconstruction and did not report an increase of local recurrence following lipotransfer. There were only small differences between gynecologists and plastic surgeons regarding the procedure and indication for lipotransfer. The method is highly accepted by patients and physicians, and both gynecologists and plastic surgeons rated the improvement achieved through lipofilling as 'high'. Conclusions: The lack of randomized controlled data, especially in high-risk patients, demonstrates the necessity for a registry study on this topic. Our survey describes, in detail, the indications for lipofilling as well as its appropriate application in breast cancer patients in Germany and may thereby reduce the present therapeutic uncertainties. [ABSTRACT FROM AUTHOR]

Background: Neoadjuvant chemotherapy (NACT) is widely used as an efficient breast cancer treatment. Ideally, a pathological complete response (pCR) can be achieved. Up to date, there is no reliable way of predicting a pCR. For the first time, we explore the ability of minimal invasive biopsy (MIB) techniques to diagnose pCR in patients with clinical complete response (cCR) to NACT in this study. This question is of high clinical relevance because a reliable pCR prediction could have direct implications for clinical practice.Methods: In all, 164 patients were included in this review-board approved, multicenter pooled analysis of prospectively assembled data. Core-cut (CC)-MIB or vacuum-assisted (VAB)-MIB were performed after NACT and before surgery. Negative predictive values (NPV) and false-negative rates (FNR) to predict a pCR in surgical specimen (diagnose pCR through MIB) were the main outcome measures.Results: Pathological complete response in surgical specimen was diagnosed in 93 (56.7%) cases of the whole cohort. The NPV of the MIB diagnosis of pCR was 71.3% (95% CI: (63.3%; 79.3%)). The FNR was 49.3% (95% CI: (40.4%; 58.2%)). Existence of a clip marker tended to improve the NPV (odds ratio 1.98; 95% CI: (0.81; 4.85)). None of the mammographically guided VABs (n=16) was false-negative (FNR 0%, NPV 100%).Conclusions: Overall accuracy of MIB diagnosis of pCR was insufficient to suggest changing clinical practice. However, subgroup analyses (mammographically guided VABs) suggest a potential capacity of MIB techniques to precisely diagnose pCR after NACT. Representativity of MIB could be a crucial factor to be focused on in further analyses. [ABSTRACT FROM AUTHOR]

Background: This study presents first feasibility experiences with a new 3-dimensional (3D) marker clip system in clinical practice. The rate of clinical complete responses in the treatment of breast cancer patients is increasing; additionally, a change to targeted axillary dissection is being considered after neoadjuvant chemotherapy (NACT). Consequently, marker clips are needed which are reliable and easy to handle even in the axillary lymph node system. Methods: A total of 50 patients from the Breast Care Unit of the Kliniken Essen Mitte were included. Clip marking of all 50 primary breast cancer lesions as well as 23 lymph nodes was performed using the Tumark Vision® clip. Following application, the position and visibility of the marker clip were monitored and documented in 2 axes. Results: The feasibility of the Tumark Vision clip was excellent in everyday clinical practice as none of the markers dislocated. After clip marking of the tumor region and/or suspicious lymph nodes, all Tumark Vision clips could be detected in both axes. The 3D shape could be observed in all cases after application. Conclusion: The new 3D-shaped marker clip seems to be a promising tool for marking breast cancer lesions and even lymph nodes before NACT. As there are many studies ongoing to prove the feasibility of a shift from standard axillary dissection after NACT towards targeted axillary dissection, the Tumark Vision clip seems to provide good visibility even in lymph nodes after NACT. Further studies are warranted. [ABSTRACT FROM AUTHOR]

Background:The aim of this meta-analysis was to systematically update the evidence for mindfulness-based stress reduction (MBSR) and mindfulness-based cognitive therapy (MBCT) in women with breast cancer. Material and methods:In October 2016, PubMed, Scopus, and Central were searched for randomized controlled trials on MBSR/MBCT in breast cancer patients. The primary outcome was health-related quality of life. Secondary outcomes were fatigue, sleep stress, depression, anxiety, and safety. For each outcome, standardized mean differences (SMD/Hedges’ g) and 95% confidence intervals (CI) were calculated. Risk of bias was assessed by the Cochrane risk of bias tool. Results:The Literature search identified 14 articles on 10 studies that included 1709 participants. The overall risk of bias was unclear, except for risk of low attrition bias and low other bias. Compared to usual care, significant post-intervention effects of MBSR/MBCT were found for health-related quality of life (SMD = .21; 95%CI = [.04–.39]), fatigue (SMD = −.28; 95%CI = [−.43 to −.14]), sleep (SMD = −.23; 95%CI = [−.40 to −.05]), stress (SMD = −.33; 95%CI = [−.61 to −.05]), anxiety (SMD = −.28; 95%CI = [−.39 to −.16]), and depression (SMD = −.34; 95%CI = [−.46 to −.21]). Up to 6 months after baseline effects were significant for: anxiety (SMD = −.28; 95%CI = [−.47 to −.09]) and depression (SMD = −.26; 95%CI = [−.47 to −.04]); and significant for anxiety (SMD = −.21; 95%CI = [−.40 to −.03]) up to 12 months after baseline. Compared to other active interventions, significant effects were only found post-intervention and only for anxiety (SMD = −.45; 95%CI = [−.71 to −.18]) and depression (SMD = −.39; 95%CI = [−.65 to −.14]). However, average effects were all below the threshold of minimal clinically important differences. Effects were robust against potential methodological bias. Adverse events were insufficiently reported. Conclusions:This meta-analysis revealed evidence for the short-term effectiveness and safety of mindfulness-based interventions in women with breast cancer. However, their clinical relevance remains unclear. Further research is needed. [ABSTRACT FROM PUBLISHER]

Background The GENEVIEVE study compared the pathological complete response (pCR) rate (ypT0/is ypN0/+) in patients with operable human epidermal growth factor receptor 2 (HER2)–negative breast cancer (BC) treated with either cabazitaxel or paclitaxel. Methods GENEVIEVE was a prospective, multicentre, randomised, open-label, phase II study comparing the efficacy and the safety of four 3-weekly cycles cabazitaxel versus 12 weeks of paclitaxel given as neoadjuvant treatment. Primary end-point was the pCR rate defined as the complete absence of invasive carcinoma on histological examination of the breast irrespective of lymph node involvement (ypT0/is, ypN0/+) after the taxane treatment. Patients could receive an anthracycline-based therapy thereafter. Results Overall, 333 patients were randomised and started treatment with 74.7% and 83.2% of patients completing treatment in the cabazitaxel and paclitaxel arms, respectively. Patients in cabazitaxel arm had a significantly lower pCR rate compared to the paclitaxel arm (1.2% versus 10.8%; p = 0.001). A total of 42 (25.3%) patients in the cabazitaxel arm and 17 (10.2%) in the paclitaxel arm had at least one serious adverse event (p < 0.001). Dose reductions were observed in 9.6% patients in the cabazitaxel arm compared to 11.4% in the paclitaxel arm (p = 0.721). Main reason for dose reductions was non-haematological toxicities in 3.0% versus 7.8% (p = 0.087), respectively. Conclusions The GENEVIEVE study showed no short-term effect of cabazitaxel in triple-negative or luminal B/HER2-negative primary BC, while there seemed to be no differences in drug exposure and patient compliance between the two arms. Clinical trials registration ClinicalTrials.gov NCT01779479 . [ABSTRACT FROM AUTHOR]

Rationale and Objectives: The goal of the present study was to compare the sensitivity and specificity of elastography with that of B-mode ultrasound (US) and mammography. Materials and Methods: A total of 300 patients with histologically confirmed breast lesions (168 benign, 132 malignant) were included. Evaluation was by means of the three-dimensional finite-element method. The data are color-coded and superimposed on the B-mode US scan. The images were evaluated by two independent readers. The results were compared with mammography, histology, and the data obtained by previous US investigations. Sensitivities and specificities were calculated. Results: Sensitivity and specificity in the differentiation of benign and malignant lesions were 87% and 85%, respectively, for mammography and 94% and 83% for B-mode US. The two examiners were in very good agreement in their evaluation of the elastograms (kappa: 0.86). Elastography had a sensitivity of 82% and a specificity of 87%. Elastography was superior to B-mode US in diagnosing Breast Imaging Reporting and Data System (BI-RADS) 3 lesions (92% vs. 82% specificity) and in lipomatous involution (80% vs. 69% specificity). Conclusion: Elastography in breast lesions showed a higher specificity and a lower sensitivity in comparison with B-mode sonography. Elastography may be beneficial in BI-RADS 3 lesions and in lipomatous involution. [ABSTRACT FROM AUTHOR]

The article discusses the review of the literature of the use of neoadjuvant dose-dense and dose-intensified chemotherapy for the treatment of breast cancer.

Background: Breast cancer survivors have only very limited treatment options for menopausal symptoms. The objective of this trial was to evaluate the effects of a 12-week traditional Hatha yoga and meditation intervention on menopausal symptoms in breast cancer survivors.Methods: Patients were randomly assigned either to a 12-week yoga and meditation intervention or to usual care. The primary outcome measure was total menopausal symptoms (Menopause Rating Scale [MRS] total score). Secondary outcome measures included MRS subscales, quality of life (Functional Assessment of Cancer Therapy-Breast), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue), depression, and anxiety (Hospital Anxiety and Depression Scale). Outcomes were assessed at week 12 and week 24 after randomization.Results: In total, 40 women (mean age ± standard deviation, 49.2 ± 5.9 years) were randomized to yoga (n = 19) or to usual care (n = 21). Women in the yoga group reported significantly lower total menopausal symptoms compared with the usual care group at week 12 (mean difference, -5.6; 95% confidence interval, -9.2 to -1.9; P = .004) and at week 24 (mean difference, -4.5; 95% confidence interval, -8.3 to -0.7; P = .023). At week 12, the yoga group reported less somatovegetative, psychological, and urogenital menopausal symptoms; less fatigue; and improved quality of life (all P < .05). At week 24, all effects persisted except for psychological menopausal symptoms. Short-term effects on menopausal symptoms remained significant when only women who were receiving antiestrogen medication (n = 36) were analyzed. Six minor adverse events occurred in each group.Conclusions: Yoga combined with meditation can be considered a safe and effective complementary intervention for menopausal symptoms in breast cancer survivors. The effects seem to persist for at least 3 months. [ABSTRACT FROM AUTHOR]

Background: Elderly breast cancer patients are underrepresented in clinical trials and this leads to a lack of knowledge regarding the tolerance and side effects of modern chemotherapy regimens, especially in dose-dense (dd) or dose-intensified combination. Patients and Methods: In this analysis, data from 4 German, randomized (neo-)adjuvant trials, including anthracycline-based chemotherapy, were evaluated for toxicity, compliance and feasibility. Patients were grouped according to age. Results: Of the 4,775 patients, 73.6% were < 60 years, 15.8% were 60-64 years and 10.6% were > 64 years. The patients' compliance decreased with increasing age, the rate of therapy discontinuations was 10.3%; 16.0% were > 64 years old (p < 0.001). The rate of dose reductions also increased with increasing age in the docetaxel/doxorubicin/cyclophosphamide (TAC) (p overall = 0.02) and 5-fluorouracil/epirubicin-cyclophosphamide (FE120C) (p overall < 0.001) treatment groups. Neutropenia grade 3 + 4 in patients of > 64 years was 77% in FE120C- compared to 55% in TAC-treated patients (with primary granulocyte colony-stimulating factors (G-CSFs)). The incidence of febrile neutropenia (FN) was lowest in the regimens without additional taxanes. FN in patients aged > 64 years was lower in the FE120C- than in TAC- and dd-doxorubicin/docetaxel-treated groups. Conclusion: The range and intensity of toxicity increased with age. Neutropenia did not increase significantly in the dd groups; the highest rate was seen in FE120C-treated patients. FE120C without G-CSFs is not an option in patients older than 64 years. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Simple Summary: Sleep problems impair up to 70% of breast cancer survivors. We studied whether ear acupuncture improves sleep quality in breast cancer survivors with sleeplessness. Fifty-two female breast cancer survivors were randomly distributed to either 10 group ear acupuncture sessions or a onetime psychoeducation group. We found that sleep quality improved over the 5 weeks of the study in the ear acupuncture group in comparison to the psychoeducation group. Stress, anxiety and fatigue improved as well. These effects were lost after 17 and 29 weeks. Among women, breast cancer is the most commonly diagnosed cancer worldwide. Sleep problems impair 40–70% of breast cancer survivors. This randomized controlled trial evaluates the effect of auricular acupuncture on sleep quality in breast cancer survivors suffering from insomnia. Fifty-two female breast cancer survivors with insomnia (mean age 55.73 ± 8.10 years) were randomized either to 10 treatments of auricular acupuncture within five weeks (n = 26), or to a single session of psychoeducation plus an insomnia advice booklet (n = 26). The primary outcome was sleep quality (measured by the Pittsburgh Sleep Quality Index) at week 5. Secondary outcomes were inflammation parameter (interleukin-6), stress, anxiety, depression, quality of life, and fatigue at week 5, and sleep quality, stress, anxiety, depression, quality of life, and fatigue 17 and 29 weeks after randomization. Intention-to-treat analysis showed a significantly stronger increase in sleep quality in the auricular acupuncture group compared to the psychoeducation group (p = 0.031; η2p = 0.094) at week 5. Furthermore, auricular acupuncture improved stress (p = 0.030; η2p = 0.094), anxiety (p = 0.001; η2p = 0.192), and fatigue (p = 0.006; η2p = 0.148) at week 5 compared to psychoeducation. No significant group difference was found concerning the other outcomes at week 5, or in any outcome at week 17 or week 29. No serious adverse events occurred during the study period. In conclusion, a semi-standardized group auricular acupuncture might be an effective and safe intervention in treating insomnia in breast cancer survivors in the short term, and may reduce stress, anxiety, and fatigue as well. Long-term effects remain questionable. [ABSTRACT FROM AUTHOR]

The monarchE and NATALEE trials demonstrated the benefit of CDK4/6 inhibitor (CDK4/6i) therapy in adjuvant breast cancer (BC) treatment. Patient selection, based on clinical characteristics, delineated those at high (monarchE) and high/intermediate recurrence risk (NATALEE). This study employed a historical patient cohort to describe the proportion and prognosis of patients eligible for adjuvant CDK4/6i trials. Between 2009 and 2011, 3529 patients were enrolled in the adjuvant PreFace clinical trial (NCT01908556). Eligibility criteria included postmenopausal patients with hormone receptor-positive (HRpos) BC for whom a five-year upfront therapy with letrozole was indicated. Patients were categorized into prognostic groups according to monarchE and NATALEE inclusion criteria, and their invasive disease-free survival (iDFS) and overall survival (OS) were assessed. Among 2891 HRpos patients, 384 (13.3 %) met the primary monarchE inclusion criteria. The majority (n = 261) qualified due to having ≥ 4 positive lymph nodes. For NATALEE, 915 out of 2886 patients (31.7 %) met the eligibility criteria, with 126 patients (13.7 %) being node-negative. Patients from monarchE with ≥ 4 positive lymph nodes and NATALEE with stage III BC exhibited the poorest prognosis (3-year iDFS rate 0.87). Patients ineligible for the trials demonstrated prognoses similar to the most favorable patient groups within the eligibility criteria. Patient populations eligible for monarchE and NATALEE trials differed. Nearly a third of the postmenopausal HRpos population, previously under upfront letrozole treatment, met the NATALEE prognostic eligibility criteria. As certain eligible groups had a prognosis similar to non-eligible patients, it might be interesting to explore additional patient groups for CDK4/6i therapy. • 13 % of postmenopausal HRpos patients qualify for CDK4/6i based on monarchE criteria. • 32 % of postmenopausal HRpos patients qualify for CDK4/6i based on NATALEE criteria. • Eligibility criteria for monarchE mainly correlate to a high-risk population. • Eligibility criteria for NATALEE correlate to an intermediate/high-risk population. • Prognosis of ineligible patients was similar to eligible subgroups with a good prognosis. [ABSTRACT FROM AUTHOR]

Background: The MINDACT trial showed excellent 5-year distant metastasis-free survival of 94·7% (95% CI 92·5-96·2) in patients with breast cancer of high clinical and low genomic risk who did not receive chemotherapy. We present long-term follow-up results together with an exploratory analysis by age.Methods: MINDACT was a multicentre, randomised, phase 3 trial done in 112 academic and community hospitals in nine European countries. Patients aged 18-70 years, with histologically confirmed primary invasive breast cancer (stage T1, T2, or operable T3) with up to three positive lymph nodes, no distant metastases, and a WHO performance status of 0-1 were enrolled and their genomic risk (using the MammaPrint 70-gene signature) and clinical risk (using a modified version of Adjuvant! Online) were determined. Patients with low clinical and low genomic risk results did not receive chemotherapy, and patients with high clinical and high genomic risk did receive chemotherapy (mostly anthracycline-based or taxane-based, or a combination thereof). Patients with discordant risk results (ie, patients with high clinical risk but low genomic risk, and those with low clinical risk but high genomic risk) were randomly assigned (1:1) to receive chemotherapy or not based on either the clinical risk or the genomic risk. Randomisation was done centrally and used a minimisation technique that was stratified by institution, risk group, and clinical-pathological characteristics. Treatment allocation was not masked. The primary endpoint was to test whether the distant metastasis-free survival rate at 5 years in patients with high clinical risk and low genomic risk not receiving chemotherapy had a lower boundary of the 95% CI above the predefined non-inferiority boundary of 92%. In the primary test population of patients with high clinical risk and low genomic risk who adhered to the treatment allocation of no chemotherapy and had no change in risk post-enrolment. Here, we present updated follow-up as well as an exploratory analysis of a potential age effect (≤50 years vs >50 years) and an analysis by nodal status for patients with hormone receptor-positive and HER2-negative disease. These analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT00433589, and the European Clinical Trials database, EudraCT2005-002625-31. Recruitment is complete and further long-term follow-up is ongoing.Findings: Between Feb 8, 2007, and July 11, 2011, 6693 patients were enrolled. On Feb 26, 2020, median follow-up was 8·7 years (IQR 7·8-9·7). The updated 5-year distant metastasis-free survival rate for patients with high clinical risk and low genomic risk receiving no chemotherapy (primary test population, n=644) was 95·1% (95% CI 93·1-96·6), which is above the predefined non-inferiority boundary of 92%, supporting the previous analysis and proving MINDACT as a positive de-escalation trial. Patients with high clinical risk and low genomic risk were randomly assigned to receive chemotherapy (n=749) or not (n=748); this was the intention-to-treat population. The 8-year estimates for distant metastasis-free survival in the intention-to-treat population were 92·0% (95% CI 89·6-93·8) for chemotherapy versus 89·4% (86·8-91·5) for no chemotherapy (hazard ratio 0·66; 95% CI 0·48-0·92). An exploratory analysis confined to the subset of patients with hormone receptor-positive, HER2-negative disease (1358 [90.7%] of 1497 randomly assigned patients, of whom 676 received chemotherapy and 682 did not) shows different effects of chemotherapy administration on 8-year distant metastasis-free survival according to age: 93·6% (95% CI 89·3-96·3) with chemotherapy versus 88·6% (83·5-92·3) without chemotherapy in 464 women aged 50 years or younger (absolute difference 5·0 percentage points [SE 2·8, 95% CI -0·5 to 10·4]) and 90·2% (86·8-92·7) versus 90·0% (86·6-92·6) in 894 women older than 50 years (absolute difference 0·2 percentage points [2·1, -4·0 to 4·4]). The 8-year distant metastasis-free survival in the exploratory analysis by nodal status in these patients was 91·7% (95% CI 88·1-94·3) with chemotherapy and 89·2% (85·2-92·2) without chemotherapy in 699 node-negative patients (absolute difference 2·5 percentage points [SE 2·3, 95% CI -2·1 to 7·2]) and 91·2% (87·2-94·0) versus 89·9% (85·8-92·8) for 658 patients with one to three positive nodes (absolute difference 1·3 percentage points [2·4, -3·5 to 6·1]).Interpretation: With a more mature follow-up approaching 9 years, the 70-gene signature shows an intact ability of identifying among women with high clinical risk, a subgroup, namely patients with a low genomic risk, with an excellent distant metastasis-free survival when treated with endocrine therapy alone. For these women the magnitude of the benefit from adding chemotherapy to endocrine therapy remains small (2·6 percentage points) and is not enhanced by nodal positivity. However, in an underpowered exploratory analysis this benefit appears to be age-dependent, as it is only seen in women younger than 50 years where it reaches a clinically relevant threshold of 5 percentage points. Although, possibly due to chemotherapy-induced ovarian function suppression, it should be part of informed, shared decision making. Further study is needed in younger women, who might need reinforced endocrine therapy to forego chemotherapy.Funding: European Commission Sixth Framework Programme. [ABSTRACT FROM AUTHOR]

Abstract 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/m2) followed by P (225 mg/m2) followed by C (2000 mg/m2), each q2w for 3 cycles or weekly P (80 mg/m2) plus M (20 mg/m2) 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. Highlights • In high-risk early breast cancer (BC), pathological complete response (pCR) rates of intense dose-dense epirubicin, paclitaxel, and cyclophosphamide (iddEPC) and weekly paclitaxel plus non-pegylated liposomal doxorubicin with additional carboplatin in triple-negative breast cancer PM(Cb) were similar. • Weekly PM(Cb) led to more dose reductions, treatment delays and overall toxicity. • In patients with lymphocyte-predominant BC, pCR rate was significantly higher with iddEPC. [ABSTRACT FROM AUTHOR]

Background: Tumour-infiltrating lymphocytes (TILs) are predictive for response to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) and HER2-positive breast cancer, but their role in luminal breast cancer and the effect of TILs on prognosis in all subtypes is less clear. Here, we assessed the relevance of TILs for chemotherapy response and prognosis in patients with TNBC, HER2-positive breast cancer, and luminal-HER2-negative breast cancer.Methods: Patients with primary breast cancer who were treated with neoadjuvant combination chemotherapy were included from six randomised trials done by the German Breast Cancer Group. Pretherapeutic core biopsies from 3771 patients included in these studies were assessed for the number of stromal TILs by standardised methods according to the guidelines of the International TIL working group. TILs were analysed both as a continuous parameter and in three predefined groups of low (0-10% immune cells in stromal tissue within the tumour), intermediate (11-59%), and high TILs (≥60%). We used these data in univariable and multivariable statistical models to assess the association between TIL concentration and pathological complete response in all patients, and between the amount of TILs and disease-free survival and overall survival in 2560 patients from five of the six clinical trial cohorts.Findings: In the luminal-HER2-negative breast cancer subtype, a pathological complete response (pCR) was achieved in 45 (6%) of 759 patients with low TILs, 48 (11%) of 435 with intermediate TILs, and 49 (28%) of 172 with high TILs. In the HER2-positive subtype, pCR was observed in 194 (32%) of 605 patients with low TILs, 198 (39%) of 512 with intermediate TILs, and 127 (48%) of 262 with high TILs. Finally, in the TNBC subtype, pCR was achieved in 80 (31%) of 260 patients with low TILs, 117 (31%) of 373 with intermediate TILs, and 136 (50%) of 273 with high TILs (p<0·0001 for each subtype, χ2 test for trend). In the univariable analysis, a 10% increase in TILs was associated with longer disease-free survival in TNBC (hazard ratio [HR] 0·93 [95% CI 0·87-0·98], p=0·011) and HER2-positive breast cancer (0·94 [0·89-0·99], p=0·017), but not in luminal-HER2-negative tumours (1·02 [0·96-1·09], p=0·46). The increase in TILs was also associated with longer overall survival in TNBC (0·92 [0·86-0·99], p=0·032), but had no association in HER2-positive breast cancer (0·94 [0·86-1·02], p=0·11), and was associated with shorter overall survival in luminal-HER2-negative tumours (1·10 [1·02-1·19], p=0·011).Interpretation: Increased TIL concentration predicted response to neoadjuvant chemotherapy in all molecular subtypes assessed, and was also associated with a survival benefit in HER2-positive breast cancer and TNBC. By contrast, increased TILs were an adverse prognostic factor for survival in luminal-HER2-negative breast cancer, suggesting a different biology of the immunological infiltrate in this subtype. Our data support the hypothesis that breast cancer is immunogenic and might be targetable by immune-modulating therapies. In light of the results in luminal breast cancer, further research investigating the interaction of the immune system with different types of endocrine therapy is warranted.Funding: Deutsche Krebshilfe and European Commission. [ABSTRACT FROM AUTHOR]

Aim The Neoadjuvant PI3K inhibition in HER2 OverExpressing Breast cancEr (NeoPHOEBE) trial evaluated the efficacy and safety of buparlisib, a pan-phosphatidylinositol 3-kinase (PI3K) inhibitor, plus trastuzumab and paclitaxel as neoadjuvant treatment for human epidermal growth factor receptor-2 positive (HER2+) breast cancer. Methods NeoPHOEBE was a neoadjuvant, phase II, randomised, double-blind study. Women with HER2+ breast cancer were randomised within two independent cohorts by PIK3CA mutation status and, in each cohort stratified by oestrogen receptor (ER) status to receive buparlisib or placebo plus trastuzumab (first 6 weeks) followed by buparlisib or placebo with trastuzumab and paclitaxel. Primary end-point was pathological complete response (pCR) rate; key secondary end-point was objective response rate (ORR) at 6 weeks. Exploratory end-points were evaluation of Ki67 levels and change in tumour infiltrating lymphocytes (TILs) in intermediate biopsies at day 15. Results Recruitment was suspended mainly due to liver toxicity after enrolment of 50 of the planned 256 patients. In each arm (buparlisib n = 25; placebo n = 25) 21 patients (84%) had wild type PIK3CA and 4 patients (16%) had mutant PIK3CA . Overall, pCR rate was similar between buparlisib and placebo arms (32.0% versus 40%; one-sided P = 0.811). A trend towards higher ORR (68.8% versus 33.3%; P = 0.053) and a significant decrease in Ki67 (75% versus 26.7%; P = 0.021) was observed in buparlisib versus placebo arm in the ER+ subgroup ( P interaction = 0.03). Conclusions Addition of the pan-PI3K inhibitor buparlisib to taxane-trastuzumab-based therapy in HER2+ early breast cancer was not feasible. However, the higher ORR and Ki67 reduction in the ER+, HER2+ subgroup indicates a potential role for PI3K-targeted therapy in this setting and may warrant further investigation with better-tolerated second-generation PI3K inhibitors. Trial registration identifier NCT01816594 . [ABSTRACT FROM AUTHOR]

Background: In metastatic breast cancer, nab-paclitaxel has been shown to significantly increase progression-free survival compared with solvent-based paclitaxel. The GeparSepto (GBG 69) trial assessed whether weekly nab-paclitaxel could increase the proportion of patients achieving pathological complete response compared with weekly solvent-based paclitaxel, both followed by epirubicin plus cyclophosphamide as neoadjuvant treatment.Method: In a phase 3 randomised trial, we enrolled patients with previously untreated unilateral or bilateral primary invasive breast cancer and randomly assigned them in a 1:1 ratio using dynamic allocation and Pocock minimisation by breast cancer subtype, Ki67 and SPARC expression. Patients were treated for 12 weeks with either intravenous nab-paclitaxel 150 mg/m(2) (after study amendment, 125 mg/m(2)) on days 1, 8, and 15 for four 3-week cycles, or solvent-based intravenous paclitaxel 80 mg/m(2) on days 1, 8, and 15 for four 3-week cycles. Taxane treatment was followed in both groups by intravenous epirubicin 90 mg/m(2) plus intravenous cyclophosphamide 600 mg/m(2) on day 1 for four 3-week cycles. Patients with HER2-positive tumours received concurrent trastuzumab 6 mg/kg (loading dose 8 mg/kg) and pertuzumab 420 mg (loading dose 840 mg) on day 1 of every 3-week cycle. Trastuzumab and pertuzumab were given every 3 weeks concomitantly with chemotherapy for all cycles. This report is the final analysis of the primary endpoint, pathological complete response (ypT0 ypN0), analysed for all patients who started treatment (modified intention to treat). We used a closed test procedure to test for non-inferiority, with the nab-paclitaxel group calculated as non-inferior to the solvent-based paclitaxel group if the lower 95% CI for the OR was above 0·858 (OR equivalent to pathological complete response [33%] minus a 10% non-inferiority margin [3·3%]; 29·7%). We planned to test for superiority only in case of a positive non-inferiority test, using an α of 0·05. Safety was assessed in all patients who received study drug. The trial is registered with ClinicalTrials.gov, number NCT01583426.Findings: Between July 30, 2012, and Dec 23, 2013, we randomly assigned 1229 women, of whom 1206 started treatment (606 with nab-paclitaxel and 600 with solvent-based paclitaxel). The nab-paclitaxel dose was reduced after enrolment of 464 participants to 125 mg/m(2) due to increased treatment discontinuation and sensory neuropathy in this group. Pathological complete response occurred more frequently in the nab-paclitaxel group (233 [38%, 95% CI 35-42] patients) than in the solvent-based paclitaxel group (174 [29%, 25-33] patients; OR 1·53, 95% CI 1·20-1·95; unadjusted p=0·00065). The incidence of grade 3-4 anaemia (13 [2%] of 605 patients in the nab-paclitaxel group vs four [1%] of patients in the solvent-based paclitaxel group; p=0·048) and peripheral sensory neuropathy grade 3-4 (63 [10%] patients receiving any nab-paclitaxel dose; 31 [8%] of patients starting with 125 mg/m(2) and 32 [15%] of patients starting with 150 mg/m(2); vs 16 [3%] in the solvent-based paclitaxel group, p<0·001) was significantly higher for nab-paclitaxel than for solvent-based paclitaxel. Overall, 283 (23%) patients were noted to have at least one serious adverse event (based on study drug received), 156 (26%) in the nab-paclitaxel group and 127 (21%) in the solvent-based paclitaxel group (p=0·057). There were three deaths (during epirubicin plus cyclophosphamide treatment) in the nab-paclitaxel group (due to sepsis, diarrhoea, and accident unrelated to the trial) versus one in the solvent-based paclitaxel group (during paclitaxel treatment; cardiac failure).Interpretation: Substituting solvent-based paclitaxel with nab-paclitaxel significantly increases the proportion of patients achieving a pathological complete response rate after anthracycline-based chemotherapy. These results might lead to an exchange of the preferred taxane, solvent-based paclitaxel, for nab-paclitaxel in therapy for primary breast cancer.Funding: Celgene, Roche. [ABSTRACT FROM AUTHOR]

Abstract: Background: We tested the oral mammalian target of rapamycin (mTOR) inhibitor everolimus in addition to paclitaxel in patients with HER2-negative tumours not responding to initial neoadjuvant cytotoxic and anti-angiogenic treatment. Methods: Patients with primary HER2-negative tumours received four neoadjuvant cycles of epirubicin/cyclophosphamide (EC) with or without bevacizumab. Patients without clinical response were randomised to receive weekly paclitaxel (80mg/m2) with or without everolimus (5mg p.o. daily, after a step-wise dose–escalation starting from 2.5mg bid) for 12weeks before surgery. To detect an increase in pathological complete response (pCR; ypT0 ypN0) from 5% to 12.1% (odds ratio 2.62) 566 patients had to be recruited. The trial was stopped prematurely due to completion of accrual in the main study. Findings: Of 1948 patients initially starting neoadjuvant treatment 403 were randomised. A total of 18 (4.6%) patients, 7 (3.6%) treated with paclitaxel and everolimus and 11 (5.6%) treated with paclitaxel alone had a pCR (odds ratio 0.36 (OR) (95% confidence interval (CI), 0.24–1.6) p =0.34). Overall response rate in breast and lymph nodes at surgery was 52.2% after paclitaxel plus everolimus and 61.7% after paclitaxel alone (p =0.063). Breast conserving treatment was performed in 54.4% of patients with the combination treatment and 61.9% with paclitaxel alone (p =0.20). Mucosal inflammation, thrombocytopenia, neutropenia, infection, and skin rash were more frequent when everolimus was added to paclitaxel. Interpretation: Neoadjuvant therapy with everolimus and paclitaxel for patients with HER2-negative disease unresponsive to EC with or without bevacizumab did not improve the pCR rate. Long-term outcome is awaited. Funding: Novartis, Roche, and Sanofi-Aventis. [Copyright &y& Elsevier]