Combining immune-checkpoint inhibitors with chemotherapy yielded an increased response rates in patients with metastatic triple-negative breast cancer (TNBC). Therefore, we evaluated the addition of ...durvalumab to standard neoadjuvant chemotherapy (NACT) in primary TNBC.
GeparNuevo is a randomised phase II double-blind placebo-controlled study randomising patients with TNBC to durvalumab or placebo given every 4weeks in addition to nab-paclitaxel followed by standard EC. In the window-phase durvalumab/placebo alone was given 2 weeks before start of nab-paclitaxel. Randomisation was stratified by stromal tumour-infiltrating lymphocyte (sTILs). Patients with primary cT1b-cT4a-d disease, centrally confirmed TNBC and sTILs were included. Primary objective was pathological complete response (pCR) (ypT0 ypN0).
A total of 174 patients were randomised, 117 participated in the window-phase. Median age was 49.5years (range 23–76); 47 patients (27%) were younger than 40years; 113 (65%) had stage ≥IIA disease, 25 (14%) high sTILs, 138 of 158 (87%) were PD-L1-positive. pCR rate with durvalumab was 53.4% (95% CI 42.5% to 61.4%) versus placebo 44.2% (95% CI 33.5% to 55.3%; unadjusted continuity corrected χ2P=0.287), corresponding to OR=1.45 (95% CI 0.80–2.63, unadjusted Wald P=0.224). Durvalumab effect was seen only in the window cohort (pCR 61.0% versus 41.4%, OR=2.22, 95% CI 1.06–4.64, P=0.035; interaction P=0.048). In both arms, significantly increased pCR (P<0.01) were observed with higher sTILs. There was a trend for increased pCR rates in PD-L1-positive tumours, which was significant for PD-L1-tumour cell in durvalumab (P=0.045) and for PD-L1-immune cell in placebo arm (P=0.040). The most common immune-related adverse events were thyroid dysfunction any grade in 47%.
Our results suggest that the addition of durvalumab to anthracycline-/taxane-based NACT increases pCR rate particularly in patients treated with durvalumab alone before start of chemotherapy.
ClinicalTrials.gov number: NCT02685059.
Response rates in HER2-overexpressing EBC treated with neoadjuvant chemotherapy and trastuzumab (T) have been improved by addition of pertuzumab (P). The prospective, phase II, neoadjuvant WSG-ADAPT ...HER2+/HR- trial assessed whether patients with strong early response to dual blockade alone might achieve pathological complete response (pCR) comparable to that of patients receiving dual blockade and chemotherapy.
Female patients with HER2+/HR- EBC (M0) were randomized (5:2) to 12 weeks of T + P ± weekly paclitaxel (pac) at 80 mg/m2. Early response was defined as proliferation decrease ≥30% of Ki-67 (versus baseline) or low cellularity (<500 invasive tumor cells) in the 3-week biopsy. The trial was designed to test non-inferiority for pCR in early responding patients of the T + P arm versus all chemotherapy-treated patients.
From February 2014 to December 2015, 160 patients were screened, 92 were randomized to T + P and 42 to T + P+pac. Baseline characteristics were well balanced (median age 54 versus 51.5 years, cT2 51.1 versus 52.4%, cN0 54.3 versus 61.9%); 91.3% of patients completed T + P per protocol and 92.9% T + P+pac. The pCR rate in the T + P+pac arm was 90.5%, compared with 36.3% in the T + P arm as a whole. In the T + P arm, 24/92 were classified as non-responders, and their pCR rate was only 8.3% compared with 44.7% in responders (38/92) and 42.9% in patients with unclassified early response (30/92). No new safety signals were observed in the study population.
Addition of taxane monotherapy to dual HER2 blockade in a 12-week neoadjuvant setting substantially increases pCR rates in HER2+/HR- EBC compared with dual blockade alone, even within early responders to dual blockade. Early non-response under dual blockade strongly predicts failure to achieve pCR.
Electrochemotherapy (ECT) is a treatment for both primary and secondary cutaneous tumours. The international Network for sharing practices on ECT group investigates treatment outcomes after ECT using ...a common database with defined parameters.
Twenty-eight centres across Europe prospectively uploaded data over an 11-year period. Response rates were investigated in relation to primary diagnosis, tumour size, choice of electrode type, route of bleomycin administration, electrical parameters recorded and previous irradiation in the treated field.
Nine hundred eighty-seven patients, with 2482 tumour lesions were included in analysis. The overall response (OR) rate was 85% (complete response CR: 70%, partial response rate: 15%, stable disease: 11%, and progressive disease: 2%). For different histologies, OR and CR rates for metastases of malignant melanoma were 82% and 64%, basal cell carcinoma were 96% and 85%, breast cancer metastases were 77% and 62%, squamous cell carcinoma were 80% and 63% as well as Kaposi's sarcoma were 98% and 91%, respectively. Variance was demonstrated across histotypes (p < 0.0001) and in accordance with size of lesion treated (dichotomised at diameter of 3 cm (p < 0.0001). Hexagonal electrodes were generally used for larger tumours, but for tumours up to 3 cm, linear array electrodes provided better tumour control than hexagonal electrodes (80%:74%, p < 0.003). For tumours more than 2 cm, intravenous administration was superior to intratumoural (IT) administration (p < 0.05). Current recorded varied across tumour histologies and size but did not influence response rate. In previously irradiated areas, responses were selectively lower for IT administration.
These cumulative data endorse efficiency of ECT across a broad range of histotypes. Analysis of 2482 lesions details subgroup analysis on treatment response informing future treatment choices.
•Electrochemotherapy (ECT) is highly efficient in the treatment of cutaneous metastases.•ECT is efficient across tumour histologies.•ECT response is higher for smaller tumours.•Intravenous bleomycin was more efficient than intratumoural, in tumours more than 2 cm size.•Linear array electrodes were more efficient in tumours less than 3 cm size.
The inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) could potentially overcome or delay resistance to endocrine therapy in advanced breast cancer that is positive for hormone receptor (HR) ...and negative for human epidermal growth factor receptor 2 (HER2).
In this randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of the selective CDK4/6 inhibitor ribociclib combined with letrozole for first-line treatment in 668 postmenopausal women with HR-positive, HER2-negative recurrent or metastatic breast cancer who had not received previous systemic therapy for advanced disease. We randomly assigned the patients to receive either ribociclib (600 mg per day on a 3-weeks-on, 1-week-off schedule) plus letrozole (2.5 mg per day) or placebo plus letrozole. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, overall response rate, and safety. A preplanned interim analysis was performed on January 29, 2016, after 243 patients had disease progression or died. Prespecified criteria for superiority required a hazard ratio of 0.56 or less with P<1.29×10
.
The duration of progression-free survival was significantly longer in the ribociclib group than in the placebo group (hazard ratio, 0.56; 95% CI, 0.43 to 0.72; P=3.29×10
for superiority). The median duration of follow-up was 15.3 months. After 18 months, the progression-free survival rate was 63.0% (95% confidence interval CI, 54.6 to 70.3) in the ribociclib group and 42.2% (95% CI, 34.8 to 49.5) in the placebo group. In patients with measurable disease at baseline, the overall response rate was 52.7% and 37.1%, respectively (P<0.001). Common grade 3 or 4 adverse events that were reported in more than 10% of the patients in either group were neutropenia (59.3% in the ribociclib group vs. 0.9% in the placebo group) and leukopenia (21.0% vs. 0.6%); the rates of discontinuation because of adverse events were 7.5% and 2.1%, respectively.
Among patients receiving initial systemic treatment for HR-positive, HER2-negative advanced breast cancer, the duration of progression-free survival was significantly longer among those receiving ribociclib plus letrozole than among those receiving placebo plus letrozole, with a higher rate of myelosuppression in the ribociclib group. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT01958021 .).
Abstract
Introduction:
Detection of sentinel lymph nodes (SLN) is the standard procedure to evaluate axillary lymph node status in breast cancer. In addition to known and established procedures such ...as the blue dye method and scintigraphy, this study investigated the efficacy of a method based on use of the fluorescent dye indocyanine green (ICG).
Patients and Method:
A total of 126 women with breast cancer histologically verified by punch biopsy were studied during surgical removal of SLN. In addition to SLN marking with technetium and scintigraphy, intra-individual comparison was done using indocyanine green (ICG) for marking instead of the standard blue dye.
Results:
Scintigraphy had a detection rate of 96 %; the detection rate with ICG was just under 89 %. A body mass index (BMI) > 40 was found to be a limiting factor for the fluorescent method. Investigation into potential toxicities associated with the use of the fluorescent dye ICG revealed no systemic or even local side effects. The fluorescent method was found to be significantly less expensive than the scintigraphy method.
Conclusion:
The ICG fluorescence technique for the detection of SLN was found to be a valid and feasible method in clinical practice when compared directly with the blue dye method and scintigraphy.
Purpose
The WSG-PRIMe Study prospectively evaluated the impact of the 70-gene signature MammaPrint® (MP) and the 80-gene molecular subtyping assay BluePrint® on clinical therapy decisions in luminal ...early breast cancer.
Methods
452 hormone receptor (HR)-positive and HER2-negative patients were recruited (N0, N1). Physicians provided initial therapy recommendations based on clinicopathological factors. After prospective risk classification by MammaPrint/BluePrint was revealed, post-test treatment recommendations and actual treatment were recorded. Decisional Conflict and anxiety were measured by questionnaires.
Results
Post-test switch (in chemotherapy (CT) recommendation) occurred in 29.1% of cases. Overall, physician adherence to MP risk assessment was 92.3% for low-risk and 94.3% for high-risk MP scores. Adherence was remarkably high in “discordant” groups: 74.7% of physicians initially recommending CT switched to CT omission following low-risk MP scores; conversely, 88.9% of physicians initially recommending CT omission switched to CT recommendations following high-risk MP scores. Most patients (99.2%) recommended to forgo CT post-test and 21.3% of patients with post-test CT recommendations did not undergo CT; among MP low-risk patients with pre-test and post-test CT recommendations, 40% did not actually undergo CT. Luminal subtype assessment by BluePrint was discordant with IHC assessment in 34% of patients. Patients’ State Anxiety scores improved significantly overall, particularly in MP low-risk patients. Trait Anxiety scores increased slightly in MP high risk and decreased slightly in MP low-risk patients.
Conclusions
MammaPrint and BluePrint test results strongly impacted physicians’ therapy decisions in luminal EBC with up to three involved lymph nodes. The high adherence to genetically determined risk assessment represents a key prerequisite for achieving a personalized cost-effective approach to disease management of early breast cancer.
Highlights • Pazopanib with cyclophosphamide had a MTD of 600 mg per day. • Main side effects were elevation of the liver enzymes, diarrhea, leukopenia. • Quality of life was not reduced during ...treatment. • One patient experienced durable benefit from therapy for more than two years.
In high-risk hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) early breast cancer (EBC), nanoparticle albumin-bound (nab)-paclitaxel showed promising efficacy ...versus solvent-based (sb)-paclitaxel in neoadjuvant trials; however, optimal patient and therapy selection remains a topic of ongoing research. Here, we investigate the potential of Oncotype DX® recurrence score (RS) and endocrine therapy (ET) response (low post-endocrine Ki67) for therapy selection.
Within the WSG-ADAPT trial (NCT01779206), high-risk HR+/HER2− EBC patients were randomized to (neo)adjuvant 4× sb-paclitaxel 175 mg/m2 q2w or 8× nab-paclitaxel 125 mg/m2 q1w, followed by 4× epirubicin + cyclophosphamide (90 mg + 600 mg) q2w; inclusion criteria: (i) cN0-1, RS 12-25, and post-ET Ki67 >10%; (ii) cN0-1 with RS >25. Patients with cN2-3 or (G3, baseline Ki67 ≥40%, and tumor size >1 cm) were allowed to be included without RS and/or ET response testing. Associations of key factors with pathological complete response (pCR) (primary) and survival (secondary) endpoints were analyzed using statistical mediation and moderation models.
Eight hundred and sixty-four patients received neoadjuvant nab-paclitaxel (n= 437) or sb-paclitaxel (n = 427); nab-paclitaxel was superior for pCR (20.8% versus 12.9%, P = 0.002). pCR was higher for RS >25 versus RS ≤25 (16.0% versus 8.4%, P = 0.021) and for ET non-response versus ET response (15.1% versus 6.0%, P = 0.027); no factors were predictive for the relative efficacy of nab-paclitaxel versus sb-paclitaxel. Patients with pCR had longer distant disease-free survival dDFS; hazard ratio 0.42, 95% confidence interval (CI) 0.20-0.91, P = 0.024. Despite favorable prognostic association of RS >25 versus RS ≤25 with pCR (odds ratio 3.11, 95% CI 1.71-5.63, P ≤ 0.001), higher RS was unfavorably associated with dDFS (hazard ratio 1.03, 95% CI 1.01-1.05, P = 0.010).
In high-risk HR+/HER2− EBC, neoadjuvant nab-paclitaxel q1w appears superior to sb-paclitaxel q2w regarding pCR. Combining RS and ET response assessment appears to select patients with highest pCR rates. The disadvantage of higher RS for dDFS is reduced in patients with pCR. These are the first results from a large neoadjuvant randomized trial supporting the use of RS to help select patients for neoadjuvant chemotherapy in high-risk HR+/HER2− EBC.
•16-week neoadjuvant nab-paclitaxel induces higher pCR than sb-paclitaxel–epirubicin/cyclophosphamide in high-risk HR+/HER2− breast cancer.•First prospective phase III trial showed that higher RS is predictive for pCR.•Associations of higher RS and ET non-response with pCR are moderated by menopausal status (and/or ET agent used).•pCR mitigates the unfavorable impact of higher RS on dDFS.•Further trials should investigate therapy de-escalation in patients with RS >25, ET response, and lower clinical risk.
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