HER2-targeted treatments have improved outcomes in patients with HER2-positive breast cancer in the neoadjuvant, adjuvant, and metastatic settings; however, some patients remain at risk of relapse or ...death for many years after treatment of early-stage disease. Therefore, new strategies are needed. We did a phase 3 trial to assess a neoadjuvant regimen for HER2-positive breast cancer that replaces traditional systemic chemotherapy with targeted treatment.
We did a randomised, open-label phase 3 KRISTINE trial in 68 Translational Research In Oncology centres (hospitals and specialty cancer centres in Asia, Europe, USA, and Canada). Eligible participants were aged 18 years or older with centrally confirmed HER2-positive stage II–III operable breast cancer (>2 cm tumour size), an Eastern Cooperative Oncology Group performance status of 0–1, and a baseline left ventricular ejection fraction of at least 55% (by echocardiogram or multiple-gated acquisition scan). We randomly assigned participants (1:1) to receive either trastuzumab emtansine plus pertuzumab or docetaxel, carboplatin, and trastuzumab plus pertuzumab. We did the randomisation via an interactive response system under a permuted block randomisation scheme (block size of four), stratified by hormone receptor status, stage at diagnosis, and geographical location. Patients received six cycles (every 3 weeks) of neoadjuvant trastuzumab emtansine plus pertuzumab (trastuzumab emtansine 3·6 mg/kg; pertuzumab 840 mg loading dose, 420 mg maintenance doses) or docetaxel, carboplatin, and trastuzumab plus pertuzumab (docetaxel 75 mg/m2; carboplatin area under the concentration–time curve 6 mg/mL × min; trastuzumab 8 mg/kg loading dose, 6 mg/kg maintenance doses) plus pertuzumab same dosing as in the other group). All treatments were administered intravenously. The primary objective was to compare the number of patients who achieved a pathological complete response (ypT0/is, ypN0), between groups in the intention-to-treat population (two-sided assessment), based on local evaluation of tumour samples taken at breast cancer surgery done between 14 days and 6 weeks after completion of neoadjuvant therapy. Safety was analysed in patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT02131064, and follow-up of the adjuvant phase is ongoing.
Between June 25, 2014, and June 15, 2015, we randomly assigned 444 patients to neoadjuvant treatment with trastuzumab emtansine plus pertuzumab (n=223) or docetaxel, carboplatin, and trastuzumab plus pertuzumab (n=221). A pathological complete response was achieved by 99 (44·4%) of 223 patients in the trastuzumab emtansine plus pertuzumab group and 123 (55·7%) of 221 patients in the docetaxel, carboplatin, and trastuzumab plus pertuzumab group (absolute difference −11·3 percentage points, 95% CI −20·5 to −2·0; p=0·016). During neoadjuvant treatment, compared with patients receiving docetaxel, carboplatin, and trastuzumab plus pertuzumab, fewer patients receiving trastuzumab emtansine plus pertuzumab had a grade 3–4 adverse event (29 13% of 223 vs 141 64% of 219) or a serious adverse event (11 5% of 223 vs 63 29% of 219). The most common grade 3–4 adverse events in the trastuzumab emtansine plus pertuzumab group were decreased platelet count (three 1% of 223 patients vs 11 5% of 219 with docetaxel, carboplatin, and trastuzumab plus pertuzumab), fatigue (three 1% vs seven 3%), alanine aminotransferase increase (three 1% vs four 2%), and hypokalaemia (three 1% vs five 2%). The most common grade 3–4 adverse events in the docetaxel, carboplatin, and trastuzumab plus pertuzumab group were neutropenia (55 25% of 219 vs one <1% of 223 with trastuzumab emtansine plus pertuzumab), diarrhoea (33 15% vs 2 <1%), and febrile neutropenia (33 15% vs 0). No deaths were reported during neoadjuvant treatment.
Traditional neoadjuvant systemic chemotherapy plus dual HER2-targeted blockade (docetaxel, carboplatin, and trastuzumab plus pertuzumab) resulted in significantly more patients achieving a pathological complete response than HER2-targeted chemotherapy plus HER2-targeted blockade (trastuzumab emtansine plus pertuzumab); however, numerically more grade 3–4 and serious adverse events occurred in the chemotherapy plus trastuzumab and pertuzumab group. Further efforts to improve the efficacy of chemotherapy without imparting more toxicity are warranted.
F Hoffmann-La Roche and Genentech.
Adjuvant abemaciclib plus endocrine therapy previously showed a significant improvement in invasive disease-free survival and distant relapse-free survival in hormone receptor-positive, human ...epidermal growth factor receptor 2 (HER2; also known as ERBB2)-negative, node-positive, high-risk, early breast cancer. Here, we report updated results from an interim analysis to assess overall survival as well as invasive disease-free survival and distant relapse-free survival with additional follow-up.
In monarchE, an open-label, randomised, phase 3 trial, adult patients (aged ≥18 years) who had hormone receptor-positive, HER2-negative, node-positive, early breast cancer at a high risk of recurrence with an Eastern Cooperative Oncology Group performance status of 0 or 1 were recruited from 603 sites including hospitals and academic and community centres in 38 countries. Patients were randomly assigned (1:1) by means of an interactive web-based response system (block size of 4), stratified by previous chemotherapy, menopausal status, and region, to receive standard-of-care endocrine therapy of physician's choice for up to 10 years with or without abemaciclib 150 mg orally twice a day for 2 years (treatment period). All therapies were administered in an open-label manner without masking. High-risk disease was defined as either four or more positive axillary lymph nodes, or between one and three positive axillary lymph nodes and either grade 3 disease or tumour size of 5 cm or larger (cohort 1). A smaller group of patients were enrolled with between one and three positive axillary lymph nodes and Ki-67 of at least 20% as an additional risk feature (cohort 2). This was a prespecified overall survival interim analysis planned to occur 2 years after the primary outcome analysis for invasive disease-free survival. Efficacy was assessed in the intention-to-treat population. Safety was assessed in all treated patients. The study is registered with ClinicalTrials.gov, NCT03155997, and is ongoing.
Between July 17, 2017, and Aug 12, 2019, 5637 patients were randomly assigned (5601 99·4% were women and 36 0·6% were men). 2808 were assigned to receive abemaciclib plus endocrine therapy and 2829 were assigned to receive endocrine therapy alone. At a median follow-up of 42 months (IQR 37–47), median invasive disease-free survival was not reached in either group and the invasive disease-free survival benefit previously reported was sustained: HR 0·664 (95% CI 0·578–0·762, nominal p<0·0001). At 4 years, the absolute difference in invasive disease-free survival between the groups was 6·4% (85·8% 95% CI 84·2–87·3 in the abemaciclib plus endocrine therapy group vs 79·4% 77·5–81·1 in the endocrine therapy alone group). 157 (5·6%) of 2808 patients in the abemaciclib plus endocrine therapy group died compared with 173 (6·1%) of 2829 patients in the endocrine therapy alone group (HR 0·929, 95% CI 0·748–1·153; p=0·50). The most common grade 3–4 adverse events were neutropenia (in 548 19·6% of 2791 patients receiving abemaciclib plus endocrine therapy vs 24 0·9% of 2800 patients in the endocrine therapy alone group), leukopenia (318 11·4% vs 11 0·4%), and diarrhoea (218 7·8% vs six 0·2%). Serious adverse events occurred in 433 (15·5%) of 2791 patients receiving abemaciclib plus endocrine therapy versus 256 (9·1%) of 2800 receiving endocrine therapy. There were two treatment-related deaths in the abemaciclib plus endocrine therapy group (diarrhoea and pneumonitis) and none in the endocrine therapy alone group.
Adjuvant abemaciclib reduces the risk of recurrence. The benefit is sustained beyond the completion of treatment with an absolute increase at 4 years, further supporting the use of abemaciclib in patients with high-risk hormone receptor-positive, HER2-negative early breast cancer. Further follow-up is needed to establish whether overall survival can be improved with abemaciclib plus endocrine therapy in these patients.
Eli Lilly.
neoMONARCH assessed the biological effects of abemaciclib in combination with anastrozole in the neoadjuvant setting.
Postmenopausal women with stage I-IIIB HR
/HER2
breast cancer were randomized to ...a 2-week lead-in of abemaciclib, anastrozole, or abemaciclib plus anastrozole followed by 14 weeks of the combination. The primary objective evaluated change in Ki67 from baseline to 2 weeks of treatment. Additional objectives included clinical, radiologic, and pathologic responses, safety, as well as gene expression changes related to cell proliferation and immune response.
Abemaciclib, alone or in combination with anastrozole, achieved a significant decrease in Ki67 expression and led to potent cell-cycle arrest after 2 weeks of treatment compared with anastrozole alone. More patients in the abemaciclib-containing arms versus anastrozole alone achieved complete cell-cycle arrest (58%/68% vs. 14%,
< 0.001). At the end of treatment, following 2 weeks lead-in and 14 weeks of combination therapy, 46% of intent-to-treat patients achieved a radiologic response, with pathologic complete response observed in 4%. The most common all-grade adverse events were diarrhea (62%), constipation (44%), and nausea (42%). Abemaciclib, anastrozole, and the combination inhibited cell-cycle processes and estrogen signaling; however, combination therapy resulted in increased cytokine signaling and adaptive immune response indicative of enhanced antigen presentation and activated T-cell phenotypes.
Abemaciclib plus anastrozole demonstrated biological and clinical activity with generally manageable toxicities in patients with HR
/HER2
early breast cancer. Abemaciclib led to potent cell-cycle arrest, and in combination with anastrozole, enhanced immune activation.
Background
The phase 3 KATHERINE trial demonstrated significantly improved invasive disease–free survival with adjuvant trastuzumab emtansine (T‐DM1) versus trastuzumab in patients with HER2‐positive ...early breast cancer and residual invasive disease after neoadjuvant chemotherapy plus HER2‐targeted therapy.
Methods
Patients who received taxane‐ and trastuzumab‐containing neoadjuvant therapy (with/without anthracyclines) and had residual invasive disease (breast and/or axillary nodes) at surgery were randomly assigned to 14 cycles of adjuvant T‐DM1 (3.6 mg/kg intravenously every 3 weeks) or trastuzumab (6 mg/kg intravenously every 3 weeks). The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 (QLQ‐C30) and breast cancer module (QLQ‐BR23) were completed at screening, at day 1 of cycles 5 and 11, within 30 days after study drug completion, and at 6‐ and 12‐month follow‐up visits.
Results
Of patients who were randomly assigned to T‐DM1 (n = 743) and trastuzumab (n = 743), 612 (82%) and 640 (86%), respectively, had valid baseline and ≥1 postbaseline assessments. No clinically meaningful changes (≥10 points) from baseline in mean QLQ‐C30 and QLQ‐BR23 scores occurred in either arm. More patients receiving T‐DM1 reported clinically meaningful deterioration at any assessment point in role functioning (49% vs 41%), appetite loss (38% vs 28%), constipation (47% vs 38%), fatigue (66% vs 60%), nausea/vomiting (39% vs 30%), and systemic therapy side effects (49% vs 36%). These differences were no longer apparent at the 6‐month follow‐up assessment, except for role functioning (23% vs 16%).
Conclusion
These data suggest that health‐related quality of life was generally maintained in both study arms over the course of treatment.
Patient‐reported outcomes are reported from the randomized, phase 3 KATHERINE trial, which demonstrated significantly improved invasive disease–free survival with adjuvant T‐DM1 compared with trastuzumab in patients who had residual invasive disease following neoadjuvant chemotherapy plus HER2‐targeted therapy. Patients who are treated with T‐DM1 have a greater incidence of any grade and grade ≥3 adverse events compared with trastuzumab‐treated patients; however, these adverse events appear to have a minimal impact on patient‐reported quality of life.
Automated whole breast ultrasound (ABUS) has been widely used as a screening modality for examination of breast abnormalities. Reviewing hundreds of slices produced by ABUS, however, is time ...consuming. Therefore, in this paper, a fast and effective computer-aided detection system based on 3-D convolutional neural networks (CNNs) and prioritized candidate aggregation is proposed to accelerate this reviewing. First, an efficient sliding window method is used to extract volumes of interest (VOIs). Then, each VOI is estimated the tumor probability with a 3-D CNN, and VOIs with higher estimated probability are selected as tumor candidates. Since the candidates may overlap each other, a novel scheme is designed to aggregate the overlapped candidates. During the aggregation, candidates are prioritized based on estimated tumor probability to alleviate over-aggregation issue. The relationship between the sizes of VOI and target tumor is optimally exploited to effectively perform each stage of our detection algorithm. On evaluation with a test set of 171 tumors, our method achieved sensitivities of 95% (162/171), 90% (154/171), 85% (145/171), and 80% (137/171) with 14.03, 6.92, 4.91, and 3.62 false positives per patient (with six passes), respectively. In summary, our method is more general and much faster than preliminary works and demonstrates promising results.
•PFOS was associated with breast cancer risk in Taiwanese women.•Young women (age ≤ 50 years) had a high risk of breast cancer by PFOS exposure.•Women in the age less than 50 years had a higher risk ...of estrogen receptor positive tumors than those in the age over 50 years by PFHxS and PFOS exposure.
Breast cancer (BC) is a common cancer in women worldwide; however, the incidence of BC is increasing in younger women, possibly associated with the environment. Perfluoroalkyl substances (PFAS) are one of endocrine disruptors that accumulate in environment and impact human health. This study aimed to investigate whether the PFAS and BC are associated. We enrolled 120 BCE patients and 119 controls at National Taiwan University Hospital (NTUH) and also collected bio-specimen and questionnaire from 2013 to 2015. All subjects’ plasma PFAS levels were analyzed by ultra-performance liquid chromatography tandem mass spectrometry method with electrospray ionization (UHPLC-ESI-MS/MS). A logistic regression model was used to estimate the association between PFAS and BC. In the ≤50 years age group, the adjusted odds ratio (OR) was 2.34 (95% CI = 1.02, 5.38) for perfluorooctane sulfonate (PFOS) exposure per natural log unit increase. After stratifying the estrogen receptor (ER) status and age group, we obtained a positive association for PFHxS and PFOS concentrations with respect to the risk of ER positive tumors for ≤50 years age group. In conclusion, we found that PFAS were associated with the BC risk of ER positive tumors in young Taiwanese women. Further studies are needed to follow and explore whether these associations are causal.
Axillary lymph node dissection (ALND) for breast cancer has been considered to be associated with a variety of complications, such as excessive postoperative wound drainage, prolonged drain ...placement, or seroma formation in the short term, or arm lymphedema in the long run. Immediate lymphedema reconstruction (ILR) has been proposed to reduce the occurrence of arm lymphedema by anastomosing the transected arm lymphatics to nearby branches of the axillary vein immediately after ALND. This study aims to demonstrate that ILR can also reduce the postoperative drainage amount.
Between April 2020 and January 2022, a total of 76 breast cancer patients receiving ALND were reviewed. Forty four of them also received ILR immediately after ALND. The assignment of ILR surgery was non-random, based on patients' willingness and plastic surgeons' availability. The lymphatic vessels in the axillary wound were anastomosed with nearby terminal branches of the axillary vein under surgical microscope. Patients' characteristics, including age, body mass index (BMI), neoadjuvant therapy, type of breast surgery, the occurrence of seroma formation, number of removed lymph nodes, number of positive nodes, and the drainage amount from the operative wounds were compared between ILR and non-ILR groups.
No statistically significant difference was noted between groups in terms of age (56.5 ± 9.8 vs. 60.9 ± 10.7, p = .09), BMI (22.6 ± 3.7 vs. 23.7 ± 3.8, p = .27), type of breast surgery (p = .32), the occurrence of seroma formation (p = 1.0), the likelihood of receiving neoadjuvant therapy (p = .12), number of lymph nodes removed (17.5 ± 7.6 vs. 17.4 ± 8.3, p = .96), or number of positive nodes on final pathology (3.7 ± 5.4 vs. 4.8 ± 8.5, p = .53) except the ILR group had statistically significantly less drainage amount than non-ILR group (39.3 ± 2.6 vs. 48.3 ± 3.7, p = .046).
For breast cancer patients receiving ALND, the immediate lymphatic reconstruction can reduce the postoperative drainage amount from the operative wound.
Automated whole breast ultrasound (ABUS) is an emerging screening tool for detecting breast abnormalities. In this study, a computer-aided detection (CADe) system based on multi-scale blob detection ...was developed for analyzing ABUS images. The performance of the proposed CADe system was tested using a database composed of 136 breast lesions (58 benign lesions and 78 malignant lesions) and 37 normal cases. After speckle noise reduction, Hessian analysis with multi-scale blob detection was applied for the detection of tumors. This method detected every tumor, but some nontumors were also detected. The tumor likelihoods for the remaining candidates were estimated using a logistic regression model based on blobness, internal echo, and morphology features. The tumor candidates with tumor likelihoods higher than a specific threshold (0.4) were considered tumors. By using the combination of blobness, internal echo, and morphology features with 10-fold cross-validation, the proposed CAD system showed sensitivities of 100%, 90%, and 70% with false positives per pass of 17.4, 8.8, and 2.7, respectively. Our results suggest that CADe systems based on multi-scale blob detection can be used to detect breast tumors in ABUS images.
Deep learning (DL) algorithms have been proven to be very effective in a wide range of computer vision applications, such as segmentation, classification, and detection. DL models can automatically ...assess complex medical image scenes without human intervention and can be applied as a second reader to provide an additional opinion for the physician. To predict the axillary lymph node (ALN) metastatic status in patients with early-stage breast cancer, a deep learning-based computer-aided prediction system for ultrasound (US) images was proposed. A total of 153 women with breast tumor US images were involved in this study; there were 59 patients with metastasis and 94 patients without ALN metastasis. A deep learning-based computer-aided prediction (CAP) system using the tumor region and peritumoral tissue in ultrasound (US) images were employed to determine the ALN status in breast cancer. First, we adopted Mask R–CNN as our tumor detection and segmentation model to obtain the tumor localization and region. Second, the peritumoral tissue was extracted from the US image, which reflects metastatic progression. Third, we used the DL model to predict ALN metastasis. Finally, the simple linear iterative clustering (SLIC) superpixel segmentation method and the LIME explanation algorithm were employed to explain how the model makes decisions. The experimental results indicated that the DL model had the best prediction performance on tumor regions with 3 mm thick peritumoral tissue, and the accuracy, sensitivity, specificity, and AUC were 81.05% (124/153), 81.36% (48/59), 80.85% (76/94), and 0.8054, respectively. The results indicated that the proposed CAP system could help determine the ALN status in patients with early-stage breast cancer. The results reveal that the proposed CAP model, which combines primary tumor and peritumoral tissue, is an effective method to predict the ALN status in patients with early-stage breast cancer.
•We developed and trained a computer-aided prediction system based on ultrasound images to predict axillary lymph node metastasis status in patients with early-stage breast cancer.•The peritumoral tissue included abnormal tissue (it combine with connective tissue deterioration, tissue fibrillated, lymphangiogenesis, angiogenesis, fibroblast accumulation, etc.), which might implicitly indicate the metastasis process was launched.•Our computer-aided prediction system (CAP) system using the tumor region with peritumor tissue to predict axillary lymph node metastasis status.
PDF
