Neoadjuvant Chemotherapy with Concurrent Letrozole for Estrogen Receptor-Positive and HER2-Negative Breast Cancer: An Open-Label, Single-Center, Nonrandomized Phase II Study (NeoCHAI).

The role of combining neoadjuvant endocrine therapy with conventional chemotherapy remains unclear; therefore, we conducted an open-label, single-center, nonrandomized phase II trial to assess the effect of this combination. Patients with previously untreated stage II or III HR-positive, HER2-negative breast cancer received concurrent letrozole 2.5 mg with standard neoadjuvant chemotherapy. The primary endpoint was pathologic complete response (pCR) at the time of surgery. We used Simon's minimax two-stage design; a pCR rate > 6% was necessary at the first stage to continue. Between November 2017 and November 2020, 53 women were enrolled in the first stage of the trial. Their median age was 49 years (range, 33-63), and 60% of them were premenopausal. Subsequently, 66% and 34% of patients with clinical stages II and III, respectively, were included; 93% had clinically node-positive disease. Two patients (4%) achieved pCR after neoadjuvant chemo-endocrine treatment, which did not satisfy the criteria for continuing to the second stage. The overall response rate was 83%. During the median follow-up of 53.7 months, the 3-year disease-free survival and overall survival rates were 87% and 98%, respectively. Neutropenia was the most common grade 3/4 adverse event (40%), but rarely led to febrile neutropenic episodes (4%). Myalgia (32%), nausea (19%), constipation (17%), heartburn (11%), oral mucositis (9%), and sensory neuropathy (9%) were frequently observed, but classified as grade 1 or 2. No deaths occurred during preoperative treatment. The addition of letrozole to standard neoadjuvant chemotherapy was safe and beneficial in terms of overall response rate, but did not provide a higher pCR rate in locally advanced HR-positive, HER2-negative breast cancer. Further research is needed to enhance neoadjuvant treatment strategies for this cancer subtype.

Criteria for identifying residual tumours after neoadjuvant chemotherapy of breast cancers: a magnetic resonance imaging study.

We investigated magnetic resonance imaging (MRI) criteria identifying residual tumours in patients with triple-negative and human epidermal growth factor receptor type 2-positive (HER2+) breast cancer following neoadjuvant chemotherapy. Retrospectively, 290 patients were included who had undergone neoadjuvant chemotherapy and definitive surgery. Clinicopathological features, as well as lesion size and lesion-to-background parenchymal signal enhancement ratio (SER) in early- and late-phase MRIs, were analysed. Receiver operating characteristic (ROC) analyses evaluated diagnostic performances. Maximal MRI values showing over 90% sensitivity and negative predictive value (NPV) were set as cut-off points. Identified MRI criteria were prospectively applied to 13 patients with hormone receptor-negative (HR-) tumours. The lesion size in HR-HER2-tumours had the highest area under the ROC curve value (0.92), whereas this parameter in HR + HER2 + tumours was generally low (≤ 0.75). For HR-tumours, both sensitivity and NPV exceeded the 90% threshold for early size > 0.2 cm (HR-HER2-) or > 0.1 cm (HR-HER2 +), late size > 0.4 cm, and early SER > 1.3. In the prospective pilot cohort, the criteria size and early SER did not find false negative cases, but one case was false negative with late SER. Distinguishing residual tumours based on MRI is feasible in selected triple-negative and HER2 + breast cancer patients.

Comparison of GenesWell BCT Score With Oncotype DX Recurrence Score for Risk Classification in Asian Women With Hormone Receptor-Positive, HER2-Negative Early Breast Cancer.

Introduction: The GenesWell Breast Cancer Test (BCT) is a recently developed multigene assay that predicts the risk of distant recurrence in patients with early breast cancer. Here, we analyzed the concordance of the BCT score with the Oncotype DX recurrence score (RS) for risk stratification in Asian patients with pN0-N1, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Methods: Formalin-fixed, paraffin-embedded breast cancer tissues previously analyzed using the Oncotype DX test were assessed using the GenesWell BCT test. The risk stratification by the two tests was then compared. Results: A total of 771 patients from five institutions in Korea were analyzed. According to the BCT score, 527 (68.4%) patients were classified as low risk, and 244 (31.6%) as high risk. Meanwhile, 134 (17.4%), 516 (66.9%), and 121 (15.7%) patients were categorized into the low-, intermediate-, and high-risk groups, respectively, according to the RS ranges used in the TAILORx. The BCT high-risk group was significantly associated with advanced lymph node status, whereas no association between RS risk groups and nodal status was observed. The concordance between the two risk stratification methods in the overall population was 71.9% when the RS low-risk, and intermediate-risk groups were combined into one group. However, poor concordance was observed in patients aged ≤50 years and in those with lymph node-positive breast cancer. Conclusions: The concordance between the BCT score and RS was low in women aged ≤50 years or with lymph node-positive breast cancer. Further studies are necessary to identify more accurate tests for predicting prognosis and chemotherapy benefit in this subpopulation.

Somatic evolution and global expansion of an ancient transmissible cancer lineage.

The canine transmissible venereal tumor (CTVT) is a cancer lineage that arose several millennia ago and survives by "metastasizing" between hosts through cell transfer. The somatic mutations in this cancer record its phylogeography and evolutionary history. We constructed a time-resolved phylogeny from 546 CTVT exomes and describe the lineage's worldwide expansion. Examining variation in mutational exposure, we identify a highly context-specific mutational process that operated early in the cancer's evolution but subsequently vanished, correlate ultraviolet-light mutagenesis with tumor latitude, and describe tumors with heritable hyperactivity of an endogenous mutational process. CTVT displays little evidence of ongoing positive selection, and negative selection is detectable only in essential genes. We illustrate how long-lived clonal organisms capture changing mutagenic environments, and reveal that neutral genetic drift is the dominant feature of long-term cancer evolution.

Rapid histologic diagnosis using quick fluorescence staining and tissue confocal microscopy.

With the development of advanced and minimally invasive surgical techniques, and in view of the functional and cosmetic aspects, the need for rapid and accurate diagnosis during surgery is increasing. This study was conducted to develop a tissue diagnosis method using confocal microscopy after simple tissue staining that does not require freezing and slicing. At present, fluorescence staining with confocal microscopy is not generalized for real-time diagnosis during surgery. In this paper, we propose a fluorescence staining method using Hoechst 33342 and Eosin that does not require tissue freezing and slicing. The proposed method can be used as part of a rapid tissue diagnosis method that is suitable for use in the operating room, although further research is required before it can be applied in clinical practice.

The evolutionary history of dogs in the Americas.

Dogs were present in the Americas before the arrival of European colonists, but the origin and fate of these precontact dogs are largely unknown. We sequenced 71 mitochondrial and 7 nuclear genomes from ancient North American and Siberian dogs from time frames spanning ~9000 years. Our analysis indicates that American dogs were not derived from North American wolves. Instead, American dogs form a monophyletic lineage that likely originated in Siberia and dispersed into the Americas alongside people. After the arrival of Europeans, native American dogs almost completely disappeared, leaving a minimal genetic legacy in modern dog populations. The closest detectable extant lineage to precontact American dogs is the canine transmissible venereal tumor, a contagious cancer clone derived from an individual dog that lived up to 8000 years ago.

Magnetic Resonance Imaging (MRI) Assessment of Residual Breast Cancer After Neoadjuvant Chemotherapy: Relevance to Tumor Subtypes and MRI Interpretation Threshold.

PURPOSE: To investigate the diagnostic performance of magnetic resonance imaging (MRI) for predicting pathologic complete response after neoadjuvant chemotherapy (NAC) depending on subtypes of breast cancer using different interpretation thresholds of MRI negativity. PATIENTS AND METHODS: A total of 353 women with breast cancer who had undergone NAC were included. Pathologic examination after complete surgical excision was the reference standard. Tumors were divided into 4 subtypes on the basis of expression of hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2). Tumor enhancement was assessed on early and late phases of MRI. MRI negativity was divided into radiologic complete response (rCR, complete absence of enhancement on both early and late phases) and near-rCR (no discernible early enhancement but observed late enhancement). RESULTS: Ninety (25.5%) of 353 patients experienced pathologic complete response. When analyzing the data of all patients, sensitivity of MRI was higher for rCR versus near-rCR (97.72% vs. 90.49%, P < .0001), whereas specificity was lower for rCR versus near-rCR (44.44% vs. 72.22%, P < .0001). Accuracy was equivalent (84.14% vs. 85.84%). In HR-HER2+ tumors, 100% sensitivity and negative predictive value were achieved by assessing early enhancement only. In HR+HER2- tumors, sensitivity of MRI was higher for rCR versus near-rCR (96.12% vs. 86.82%, P = .0005). CONCLUSION: Diagnostic performance of MRI after NAC differs in accordance with the subtypes and threshold of MRI negativity. MRI assessment with consideration of tumor subtypes is required, along with standardization of MRI interpretation criteria in the NAC setting.

CKAP2 (cytoskeleton-associated protein2) is a new prognostic marker in HER2-negative luminal type breast cancer.

BACKGROUND: Recently, we reported cytoskeleton-associated protein2 (CKAP2) as a possible new prognostic breast cancer marker. However, it has not yet been applied in clinic. Therefore, clinical significance of CKAP2 was evaluated in comparison with that of Ki-67 in a cohort of breast cancer patients, and the expression difference was analyzed in cell cycle-arrested cancer and fibroblast cells. METHODS: A total of 579 early breast cancer patients who underwent surgery at the National Cancer Center Hospital in Korea between 2001 and 2005 were accrued. CKAP2-positive cell count (CPCC) and Ki-67 labeling index (Ki-67LI) were evaluated by immunohistochemcal staining. The immunocytochemical staining patterns of CKAP2 and Ki-67 were analyzed in HeLa and human fibroblast cells after synchronization by double thymidine block. RESULTS: Although there was a significant correlation (R = 0.754, P < 0.001) between CPCC and Ki-67LI, only CPCC was correlated with DFS in overall population (HR, 2.029; 95% CI, 1.012-4.068; P = 0.046) and HER2-negative luminal subgroup (HR, 3.984; 95% CI, 1.350-11.762; P = 0.012) by multivariate analysis. In immunocytochemical staining, more than 50% of serum-starved or non-mitotic cell phase HeLa cells were positive for Ki-67, in comparison to the low CKAP2-positivity, which might explain the prognostic difference between CPCC and Ki-67LI. CONCLUSIONS: The current study showed that CPCC but not Ki-67LI is an independent prognostic indicator in early breast cancer, more specifically in HER2-negative luminal breast cancer. The difference between two markers may be related to the lower background expression of CKAP2 in cancer cells.

High volumetric breast density predicts risk for breast cancer in postmenopausal, but not premenopausal, Korean Women.

PURPOSE: We investigated the association between mammographic breast density and breast cancer risk in Korean women according to menopausal status and breast cancer subtypes. METHODS: We enrolled 677 patients diagnosed with breast cancer and 1,307 healthy controls who participated in screening mammography at the National Cancer Center. Breast density was estimated using volumetric breast composition measurement. RESULTS: Of the total population, 1,156 (58.3 %) women were postmenopausal. The risk of breast cancer increased progressively with the increment of volumetric density grade (VDG) in postmenopausal women (p < 0.001). High breast density (VDG 4) was significantly associated with breast cancer compared with low breast density (VDG 1/2) regardless of body mass index. However, the association with parity and history of hormone replacement therapy (HRT) was only found in those with ≥2 children and those not receiving HRT. Breast density was positively associated with breast cancer risk regardless of histologic grade, tumor size, lymph node involvement, Ki67 index, and hormone receptor status. The association was more prominent in human epidermal growth factor receptor 2 (HER2)-positive tumors (VDG 1/2 vs. VDG 4 for HER2 normal, odds ratio [OR] 2.21, 95 % confidence interval [CI] 1.28-3.83, p < 0.001; for HER2 positive, OR 8.63, 95 % CI 3.26-22.83, p = 0.001; P heterogeneity = 0.030). However, no significant association was found between breast density and breast cancer risk in premenopausal women except for those with large-sized tumors (>2 cm) and a Ki67 index >15 %. CONCLUSION: High volumetric breast density is significantly associated with the risk of breast cancer in postmenopausal women; however, these relationships were not found in premenopausal women.

Predicting nonsentinel lymph node metastasis using lymphoscintigraphy in patients with breast cancer.

UNLABELLED: Several models for predicting the likelihood of nonsentinel lymph node (NSLN) metastasis using histopathologic parameters in sentinel-positive breast cancer patients have been proposed. In this study, we established a new model that uses sentinel lymphoscintigraphic findings and histopathologic parameters as covariates and assessed its predictive performance. METHODS: The analysis included breast cancer patients (n = 301 women) who underwent sentinel lymphoscintigraphy (SLS) using (99m)Tc-labeled human serum albumin, had sentinel lymph node biopsy results positive for metastasis, and subsequently underwent complete axillary lymph node dissection. First, we devised a grading system relating SLS patterns to the risk of NSLN metastasis positivity. Second, we developed a multivariate logistic regression model for the prediction of NSLN metastasis using the SLS pattern and histopathologic parameters as covariates and compared its performance with that of the extensively validated Memorial Sloan-Kettering Cancer Center model using receiver-operating-characteristic curve analysis. RESULTS: The SLS visual grade was strongly correlated with the presence of NSLN metastases. A well-calibrated prediction model for NSLN metastasis was constructed using SLS grade and histopathologic findings. The mean area under the curve of our model was 0.812, which is significantly greater than that of the Memorial Sloan-Kettering Cancer Center model (P < 0.001). A nomogram was drawn to facilitate the application of our model. CONCLUSION: SLS can aid in predicting NSLN metastasis in patients with breast cancer. Our model performed better than did established prediction models.

Potential antitumor effects of nitrogen-containing bisphosphonate in hormone receptor negative breast cancer patients with bone metastases.

BACKGROUND: This retrospective study evaluated, according to hormone receptor status, the antitumor effects of bisphosphonate especially on survival and disease progression in breast cancer patients with metastatic bone disease. METHODS: Of 317 patients with initial bone metastasis and known breast cancer subtypes, 230 patients (72.6%) had hormone receptor (HR) positive tumors, and 87 patients (27.4%) had HR negative tumors. We assessed the primary outcome of overall survival (OS), after adjusting for other factors, comparing a group that received bisphosphonates (BPs) with a group that did not receive it. RESULTS: 87.8% of HR positive and 69.0% of HR negative patients received BPs with a median number of 17.7 cycles. Although BPs treatment made no survival benefit in HR positive group, HR negative patients showed a significant prolonged survival when they received BPs treatment (hazard ratio = 0.56 [95% CI 0.34 to 0.91], P = 0.019). In multivariate analysis, disease free interval > 2 years (P = 0.036), a sum of metastatic sites < 3 (P = 0.034), and BP treatments (P = 0.007) were significant factors for survival in HR negative patients. CONCLUSION: Bisphosphonate treatment can result in a survival benefit in metastatic breast cancer patients with HR negative tumors.

Different susceptibility of increased DNMT1 expression by exposure to tobacco smoke according to histology in primary non-small cell lung cancer.

PURPOSE: DNA methyltransferase 1 (DNMT1) is known to play an important role in the development of cancers. However, the underlying mechanisms responsible for the altered expression of DNMT1 in non-small cell lung cancers (NSCLCs) remain to be elucidated. METHODS: We investigated the relationships of mRNA expression levels of DNMT1 to the altered expression of retinoblastoma (Rb) and p53 and to the clinicopathological variables in 153 NSCLCs. The expression of DNMT1 was determined by quantitative real-time PCR, and the altered expressions of p53 and Rb were assessed by immunohistochemistry. RESULTS: The increased expression of DNMT1 was found in 47 (31%) of 153 NSCLC patients examined. The prevalence of increased DNMT1 expression was significantly different between adenocarcinoma and squamous cell carcinoma (42% vs. 19%, respectively; P = 0.004). Patients who had smoked more than 65 packyears showed a 4.17 times [95% confidence interval (CI) = 1.17-69.49; P = 0.007] higher risk of increased DNMT1 expression compared to those who had smoked less than 45 packyears in adenocarcinoma. The expressions of Rb and p53 proteins were not associated with the increased expression of DNMT1 in 153 NSCLCs (P = 0.18 and 0.54, respectively). CONCLUSIONS: The present study suggests that the susceptibility of increased DNMT1 expression by exposure to tobacco smoke may be different according to histologic subtypes in NSCLC.

Renal cell carcinoma in South Korea: a multicenter study.

The incidence of renal cell carcinoma (RCC) in South Korea is steadily becoming similar to that in Western countries. This study summarizes the results of a 3-year multicenter survey of RCC in South Korea, conducted by the Korean Genitourinary Pathology Study Group. A total of 795 cases of RCC were collected from 20 institutes between 1995 and 1997, including 686 clear cell RCCs (86.3%), 58 papillary RCCS (7.30%), 49 chromphobe RCCs (6.16%), and 2 collecting duct RCCs (0.25%). At least 5 years of follow-up was available for 627 clear cell, 54 papillary, and 49 chromophobe RCCs. All subtypes presented most frequently with stage T3aN0M0 at the time of operation, and papillary RCCs demonstrated more frequent lymph node metastasis. Overall survival was not significantly related to the histological subtype (clear cell vs papillary, P = 0.8651; clear cell vs chromophobe, P = 0.0584; papillary vs chromophobe, P = 0.0743). For clear cell RCCs, statistically significant associations were found between overall survival and sex (P = 0.0153), multiplicity (P = 0.0461), necrosis (P = 0.0191), age, sarcomatoid change, TNM stage, nuclear grade, and modality of treatment (all P <0.0001). Overall survival was significantly associated with tumor size (P = 0.0307), nuclear grade (P = 0.0235), multiplicity, sarcomatoid change, and TNM stage (all P <0.0001) for papillary RCCs and with the presence of sarcomatoid change (P = 0.0281), nuclear grade (P = 0.0015), treatment modality (P = 0.0328), and TNM stage (P <0.0001) for chromophobe RCCs. Age (P = 0.0125), nodal stage (P = 0.0010), and treatment modality (P = 0.0001) were significant independent prognostic indicators for clear cell RCC on multivariate analysis. This is the first multicenter study of RCC in South Korea, demonstrating the general patterns and prognostic factors of Korean RCCs.