Computer-aided diagnosis (CAD) systems in gray-scale breast ultrasound images have the potential to reduce unnecessary biopsy of breast masses. The purpose of our study is to develop a robust CAD ...system based on the texture analysis. First, gray-scale invariant features are extracted from ultrasound images via multi-resolution ranklet transform. Thus, one can apply linear support vector machines (SVMs) on the resulting gray-level co-occurrence matrix (GLCM)-based texture features for discriminating the benign and malignant masses. To verify the effectiveness and robustness of the proposed texture analysis, breast ultrasound images obtained from three different platforms are evaluated based on cross-platform training/testing and leave-one-out cross-validation (LOO-CV) schemes. We compare our proposed features with those extracted by wavelet transform in terms of receiver operating characteristic (ROC) analysis. The AUC values derived from the area under the curve for the three databases via ranklet transform are 0.918 (95% confidence interval CI, 0.848 to 0.961), 0.943 (95% CI, 0.906 to 0.968), and 0.934 (95% CI, 0.883 to 0.961), respectively, while those via wavelet transform are 0.847 (95% CI, 0.762 to 0.910), 0.922 (95% CI, 0.878 to 0.958), and 0.867 (95% CI, 0.798 to 0.914), respectively. Experiments with cross-platform training/testing scheme between each database reveal that the diagnostic performance of our texture analysis using ranklet transform is less sensitive to the sonographic ultrasound platforms. Also, we adopt several co-occurrence statistics in terms of quantization levels and orientations (i.e., descriptor settings) for computing the co-occurrence matrices with 0.632+ bootstrap estimators to verify the use of the proposed texture analysis. These experiments suggest that the texture analysis using multi-resolution gray-scale invariant features via ranklet transform is useful for designing a robust CAD system.
Background
The clinicopathological features and prognosis of breast cancer in Asia are different from those in the Western countries. Tumor‐infiltrating immune cells can influence the outcome of ...patients with breast cancer, but they have not been systemically evaluated in Asian patients with breast cancer.
Methods
We compared the immune score, composition, and prognostic impact of infiltrating immune cells between Asian and Western patients with breast cancer by analyzing gene expression profiles from eight Gene Expression Omnibus data sets and The Cancer Genome Atlas data set. The Estimation of Stromal and Immune Cells in Malignant Tumours Using Expression Data (ESTIMATE) and Cell Type Identification by Estimating Relative Subsets of Known RNA Transcripts (CIBERSORT) algorithms were used to determine the immune score and composition of tumor‐infiltrating immune cells, respectively.
Findings
This study included 462 Asian patients and 2,186 Western patients. Tumors of Asian patients had significantly higher immune score, particularly in the luminal B and HER2‐enriched subtypes. High immune score was associated with favorable prognosis in both Asian and Western patients, and Asian race with a high ESTIMATE immune score provided additional power to predict longer disease‐free survival. Activated CD4 T cells and M2 macrophages were the most strongly associated with survival in both Asian and Western patients.
Interpretation
Our study highlights the difference in tumor immune microenvironments between Asian and Western patients. The higher ESTIMATE immune score, which represents more abundant tumor‐infiltrating immune cells, in tumors of Asian patients partly explains their favorable prognosis.
Implications for Practice
The tumor microenvironment serves as an interface that affects the human body's reaction to cancer cells. Evidence has revealed that tumor‐infiltrating immune cells were associated with patient prognosis. This study demonstrated the disparity of tumor microenvironments and their prognostic impact between Asian and Western patients with breast cancer. The differences in immune score partially explained the racial survival differences noted in recent studies. Integrated analysis of tumor cells, tumor microenvironment, and racial effect may significantly improve recurrence risk prediction for patients with stage I–III breast cancer. Because the effect of tumor microenvironment varies across different populations, a model of interaction between immune score and race/ethnicity is recommended in accessing the risk of patients with cancer.
Statistics indicate that the incidence of breast cancer in Asia has increased in the past three decades. This article evaluates tumor‐infiltrating immune cells of breast cancer, comparing a representative amount and the composition of infiltrating immune cells in breast cancer between Asian and Western patients.
Lapatinib (L) plus trastuzumab (T) improves outcomes for metastatic human epidermal growth factor 2-positive breast cancer and increases the pathologic complete response in the neoadjuvant setting, ...but their role as adjuvant therapy remains uncertain.
In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial, patients with centrally confirmed human epidermal growth factor 2-positive early breast cancer were randomly assigned to 1 year of adjuvant therapy with T, L, their sequence (T→L), or their combination (L+T). The primary end point was disease-free survival (DFS), with 850 events required for 80% power to detect a hazard ratio (HR) of 0.8 for L+T versus T.
Between June 2007 and July 2011, 8,381 patients were enrolled. In 2011, due to futility to demonstrate noninferiority of L versus T, the L arm was closed, and patients free of disease were offered adjuvant T. A protocol modification required P ≤ .025 for the two remaining pairwise comparisons. At a protocol-specified analysis with a median follow-up of 4.5 years, a 16% reduction in the DFS hazard rate was observed with L+T compared with T (555 DFS events; HR, 0.84; 97.5% CI, 0.70 to 1.02; P = .048), and a 4% reduction was observed with T→L compared with T (HR, 0.96; 97.5% CI, 0.80 to 1.15; P = .61). L-treated patients experienced more diarrhea, cutaneous rash, and hepatic toxicity compared with T-treated patients. The incidence of cardiac toxicity was low in all treatment arms.
Adjuvant treatment that includes L did not significantly improve DFS compared with T alone and added toxicity. One year of adjuvant T remains standard of care.
Metaplastic breast carcinoma (MpBC) typically consists of carcinoma of no special type (NST) with various metaplastic components. Although previous transcriptomic and proteomic studies have reported ...subtype-related heterogeneity, the intracase transcriptomic alterations between metaplastic components and paired NST components, which are critical for understanding the pathogenesis underlying the metaplastic processes, remain unclear.
Fifty-nine NST components and paired metaplastic components (spindle carcinomatous SPS, matrix-producing, rhabdoid RHA, and squamous carcinomatous SQC components) were microdissected from specimens obtained from 27 patients with MpBC for gene expression profiling using the NanoString Breast Cancer 360 Panel on a NanoString nCounter FLEX platform. BC360-defined signatures were scored using nSolver software.
Hierarchical clustering and principal component analysis revealed a heterogeneous gene expression profile (GEP) corresponding to the NST components, but the GEP of metaplastic components exhibited subtype dependence. Compared with the paired NST components, the SPS components demonstrated the upregulation of genes related to stem cells and epithelial-mesenchymal transition and displayed enrichment in claudin-low and macrophage signatures. Despite certain overlaps in the enriched functions and signatures between the RHA and SPS components, the specific differentially expressed genes differed. We observed the RHA-specific upregulation of genes associated with vascular endothelial growth factor signaling. The chondroid matrix-producing components demonstrated the upregulation of hypoxia-related genes and the downregulation of the immune-related MHC2 signature and the TIGIT gene. In the SQC components, TGF-β and genes associated with cell adhesion were upregulated. The differentially expressed genes among metaplastic components in the 22 MpBC cases with one or predominantly one metaplastic component clustered paired NST samples into clusters with correlation with their associated metaplastic types. These genes could be used to separate the 31 metaplastic components according to respective metaplastic types with an accuracy of 74.2%, suggesting that intrinsic signatures of NST may determine paired metaplastic type. Finally, the EMT activity and stem cell traits in the NST components were correlated with specimens displaying lymph node metastasis.
We presented the distinct transcriptomic alterations underlying metaplasia into specific metaplastic components in MpBCs, which contributes to the understanding of the pathogenesis underlying morphologically distinct metaplasia in MpBCs.
Immune checkpoint blockade (ICB) benefits some patients with triple-negative breast cancer, but what distinguishes responders from non-responders is unclear
. Because ICB targets cell-cell ...interactions
, we investigated the impact of multicellular spatial organization on response, and explored how ICB remodels the tumour microenvironment. We show that cell phenotype, activation state and spatial location are intimately linked, influence ICB effect and differ in sensitive versus resistant tumours early on-treatment. We used imaging mass cytometry
to profile the in situ expression of 43 proteins in tumours from patients in a randomized trial of neoadjuvant ICB, sampled at three timepoints (baseline, n = 243; early on-treatment, n = 207; post-treatment, n = 210). Multivariate modelling showed that the fractions of proliferating CD8
TCF1
T cells and MHCII
cancer cells were dominant predictors of response, followed by cancer-immune interactions with B cells and granzyme B
T cells. On-treatment, responsive tumours contained abundant granzyme B
T cells, whereas resistant tumours were characterized by CD15
cancer cells. Response was best predicted by combining tissue features before and on-treatment, pointing to a role for early biopsies in guiding adaptive therapy. Our findings show that multicellular spatial organization is a major determinant of ICB effect and suggest that its systematic enumeration in situ could help realize precision immuno-oncology.
Automated whole breast ultrasound (ABUS) is becoming a popular screening modality for whole breast examination. Compared to conventional handheld ultrasound, ABUS achieves operator-independent and is ...feasible for mass screening. However, reviewing hundreds of slices in an ABUS image volume is time-consuming. A computer-aided detection (CADe) system based on watershed transform was proposed in this study to accelerate the reviewing. The watershed transform was applied to gather similar tissues around local minima to be homogeneous regions. The likelihoods of being tumors of the regions were estimated using the quantitative morphology, intensity, and texture features in the 2-D/3-D false positive reduction (FPR). The collected database comprised 68 benign and 65 malignant tumors. As a result, the proposed system achieved sensitivities of 100% (133/133), 90% (121/133), and 80% (107/133) with FPs/pass of 9.44, 5.42, and 3.33, respectively. The figure of merit of the combination of three feature sets is 0.46 which is significantly better than that of other feature sets (p-value <; 0.05). In summary, the proposed CADe system based on the multi-dimensional FPR using the integrated feature set is promising in detecting tumors in ABUS images.
The cyclin-dependent kinase 4/6 inhibitor palbociclib has demonstrated efficacy and a manageable safety profile in combination with endocrine therapy in women with oestrogen receptor–positive ...(ER+)/human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC) in international phase 3 trials. The phase 3 PALOMA-4 trial evaluated the efficacy and safety of palbociclib plus letrozole versus placebo plus letrozole in Asian women with ER+/HER2– ABC.
Postmenopausal women (n = 340) with no prior systemic treatment for advanced disease were randomised 1:1 to palbociclib (125 mg/d orally; 3 weeks on, 1 week off) plus letrozole (2.5 mg/d orally; continuously) or placebo plus letrozole. The primary end-point was investigator-assessed progression-free survival (PFS). Secondary end-points included tumour response and safety.
Median (95% CI) PFS was 21.5 (16.6–24.9) months with palbociclib plus letrozole and 13.9 (13.7–16.6) months with placebo plus letrozole (hazard ratio, 0.68 95% CI, 0.53–0.87; P = 0.0012). Consistent with the established safety profile, the most common adverse events (AEs) with palbociclib plus letrozole were neutropenia, leukopenia, thrombocytopaenia, and anaemia. Grade 3/4 neutropenia was reported in 84.5% of patients in the palbociclib arm versus 1.2% in the placebo arm. One serious AE of febrile neutropenia in the palbociclib group was reported.
Findings from PALOMA-4 support the efficacy and safety of first-line palbociclib plus letrozole in postmenopausal Asian women with ER+/HER2– ABC. No new safety concerns of palbociclib plus letrozole were identified.
Clinicaltrials. gov, NCT02297438.
•Addition of palbociclib to letrozole prolonged PFS in Asian women with ER+/HER2– ABC.•No new safety concerns of palbociclib plus letrozole were identified in Asian women.•Findings support first-line palbociclib in postmenopausal Asians with ER+/HER2– ABC.
We aimed to improve efficacy and reduce toxicity of high-risk human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC) treatment by replacing taxanes and trastuzumab with ...trastuzumab emtansine (T-DM1).
The phase III KAITLIN study (NCT01966471) included adults with excised HER2-positive EBC (node-positive or node-negative, hormone receptor-negative, and tumor > 2.0 cm). Postsurgery, patients were randomly assigned 1:1 to anthracycline-based chemotherapy (three-four cycles) and then 18 cycles of T-DM1 plus pertuzumab (AC-KP) or taxane (three-four cycles) plus trastuzumab plus pertuzumab (AC-THP). Adjuvant radiotherapy/endocrine therapy was permitted. Coprimary end points were invasive disease-free survival (IDFS) in the intention-to-treat node-positive and overall populations with hierarchical testing.
The median follow-up was 57.1 months (interquartile range, 52.1-60.1 months) for AC-THP (n = 918) and 57.0 months (interquartile range, 52.1-59.8 months) for AC-KP (n = 928). There was no significant IDFS difference between arms in the node-positive (n = 1,658; stratified hazard ratio HR, 0.97; 95% CI, 0.71 to 1.32) or overall population (n = 1846; stratified HR, 0.98; 95% CI, 0.72 to 1.32). In the overall population, the three-year IDFS was 94.2% (95% CI, 92.7 to 95.8) for AC-THP and 93.1% (95% CI, 91.4 to 94.7) for AC-KP. Treatment completion rates (ie, 18 cycles) were 88.4% for AC-THP and 65.0% for AC-KP (difference driven by T-DM1 discontinuation because of laboratory abnormalities 12.5%). Similar rates of grade ≥ 3 (55.4%
51.8%) and serious adverse events (23.3%
21.4%) occurred with AC-THP and AC-KP, respectively. KP decreased clinically meaningful deterioration in global health status versus THP (stratified HR, 0.71; 95% CI, 0.62 to 0.80).
The primary end point was not met. Both arms achieved favorable IDFS. Trastuzumab plus pertuzumab plus chemotherapy remains the standard of care for high-risk HER2-positive EBC.
Purpose
Resistance to HER2 (ErbB2)-targeted therapy may be mediated by other members of the ErbB family. We investigated the efficacy and safety of the irreversible ErbB family blocker, afatinib, ...alone as first-line therapy in the advanced setting and in combination with vinorelbine or paclitaxel for those who progressed on afatinib monotherapy, in female patients with metastatic breast cancer who had failed or progressed on prior HER2-targeted therapy in the early disease setting.
Methods
In this phase II, single-arm, two-part study (ClinicalTrials.gov: NCT01271725), patients in part A received afatinib 40 mg/day in 21-day cycles until disease progression or intolerable adverse events (AEs). Patients with progressive disease could then receive afatinib plus weekly vinorelbine 25 mg/m
2
or paclitaxel 80 mg/m
2
until disease progression or intolerable AEs (part B). The primary endpoint was confirmed objective response rate (RECIST v1.1).
Results
Eighty-seven patients were enrolled and 74 were treated in part A (median age: 51 years range 27–76; 31 42% estrogen receptor-positive, 26 35% progesterone receptor-positive). Of these, 39 (53%) patients went on to receive afatinib plus vinorelbine (13 patients) or paclitaxel (26 patients) in part B. Thirteen (18%) and 12 (31%) patients achieved an objective response in parts A and B, respectively. The most common treatment-related AEs with afatinib monotherapy (any/grade ≥ 3) were diarrhea (68%/8%) and rash (49%/4%). Combination therapy was generally well tolerated, with no additive toxicity observed.
Conclusion
Afatinib treatment, alone or in combination with vinorelbine or paclitaxel, was associated with objective responses in ≥ 18% of patients with metastatic breast cancer for whom prior HER2-targeted therapy has failed. Treatment-related AEs were generally manageable, with few grade ≥ 3 AEs reported.
Trial registration
ClinicalTrials.gov, NCT01271725, registered 1 July 2011.
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