Phase II study of a trastuzumab biosimilar in combination with paclitaxel for HER2-positive recurrent or metastatic urothelial carcinoma: KCSG GU18-18.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2) is a widely explored therapeutic target in solid tumors. We evaluated the efficacy and safety of trastuzumab-pkrb, a biosimilar of trastuzumab, in combination with paclitaxel, in HER2-positive recurrent or metastatic urothelial carcinoma (UC). PATIENTS AND METHODS: We enrolled 27 patients; they were administered a loading dose of 8 mg/kg trastuzumab-pkrb on day 1, followed by 6 mg/kg and 175 mg/m2 paclitaxel on day 1 every 3 weeks, intravenously. All patients received six cycles of the combination treatment and continued to receive trastuzumab-pkrb maintenance until disease progression, unacceptable toxicity, or for up to 2 years. HER2 positivity (based on immunohistochemistry analysis) was determined according to the 2013 American Society of Clinical Oncology /College of American Pathologists HER2 testing guidelines. The primary endpoint was objective response rate (ORR); the secondary endpoints were overall survival (OS), progression-free survival (PFS), and safety. RESULTS: Twenty-six patients were evaluated via primary endpoint analysis. The ORR was 48.1% (1 complete and 12 partial responses) and the duration of response was 6.9 months [95% confidence interval (CI) 4.4-9.3 months]. With a median follow-up of 10.5 months, the median PFS and OS were 8.4 months (95% CI 6.2-8.8 months) and 13.5 months (95% CI 9.8 months-not reached), respectively. The most common treatment-related adverse event (TRAE) of any grade was peripheral neuropathy (88.9%). The most common grade 3/4 TRAEs were neutropenia (25.9%), thrombocytopenia (7.4%), and anemia (7.4%). CONCLUSIONS: Trastuzumab-pkrb plus paclitaxel demonstrates promising efficacy with manageable toxicity profiles in patients with HER2-positive recurrent or metastatic UC.

The value of breast MRI for BI-RADS category 4B mammographic microcalcification: based on the 5th edition of BI-RADS.

AIM: To investigate whether magnetic resonance imaging (MRI) can improve the positive predictive value (PPV) for Breast Imaging-Reporting and Data System (BI-RADS) category 4B mammographic microcalcification. MATERIALS AND METHODS: One hundred and eight consecutive patients with BI-RADS category 4B microcalcification without mass on mammography underwent breast MRI and subsequent histopathological confirmation between January 2009 and December 2015. Mammography and MRI findings were reviewed retrospectively, and imaging features were analysed according to the 5th edition of BI-RADS. The PPV of each descriptor was analysed to identify subgroups in which PPV could be improved by the addition of MRI. RESULTS: When the criteria of presence of enhancement on MRI was applied to category 4B microcalcification, PPV increased from 0.38 (41 of 108) to 0.82 (37 of 45) and reduced benign biopsy results by 88% (59 of 67). Four ductal carcinoma in situ lesions were missed. For amorphous microcalcification with regional or grouped distribution, MRI images increased PPV without missing malignancy. CONCLUSION: Breast MRI has the potential to improve PPV for category 4B mammographic microcalcification by reducing false-positive findings. If amorphous microcalcification with regional or grouped distribution on mammography shows no enhancement on MRI, follow-up could be considered rather than immediate biopsy. In addition, breast MRI might have the potential to guide the best site to biopsy in category 4B microcalcification.

Pretreatment MRI features associated with diagnostic accuracy of post-treatment MRI after neoadjuvant chemotherapy.

AIM: To investigate whether pretreatment magnetic resonance imaging (MRI) features are associated with diagnostic accuracy of post-treatment MRI for predicting pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) in patients with breast cancer. MATERIALS AND METHODS: From January 2005 and December 2016, 221 consecutive patients (mean age, 50 years; range, 20-81 years) who had undergone NAC, breast MRI before and after NAC, and surgery for invasive breast cancer were enrolled. Pretreatment and post-treatment MRI images were reviewed. Radiological complete response (rCR) was defined as the absence of both early and late enhancement on MRI after NAC. The association of pretreatment MRI features and post-treatment MRI diagnostic accuracy was assessed by using logistic regression analysis. RESULTS: Among 221 patients, 60 (27.1%) underwent pCR after NAC. The diagnostic accuracy of post-treatment MRI was 84.2% (186/221). False-positive diagnosis occurred in 21 cases and false-negative diagnosis occurred in 14 cases. Of pretreatment features, the presence of peritumoural oedema (odds ratio, 3; 95% confidence interval [CI]: 1.1, 8.0; p=0.03) and HER2 (human epidermal growth factor receptor 2)-positive status (odds ratio, 3.4; 95% CI: 1.2, 9.9; p=0.02) were significantly associated with false-positive MRI results. Dense fibroglandular tissue (odds ratio, 10.8; 95% CI: 1.1, 105.2; p=0.04), presence of rim enhancement (odds ratio, 7.5; 95% CI: 1.2, 38.3; p=0.02) and oestrogen receptor (ER)-positive status (odds ratio, 6.3; 95% CI: 1.2, 32.5; p=0.03) were significantly associated with false-negative MRI results. CONCLUSION: Pretreatment MRI features and cancer subtypes may be associated with diagnostic accuracy of post-treatment MRI after NAC in patients with breast cancer.

Complex chromosomal rearrangements by single catastrophic pathogenesis in NUT midline carcinoma.

Background: Nuclear protein in testis (NUT) midline carcinoma (NMC) is a rare aggressive malignancy often occurring in the tissues of midline anatomical structures. Except for the pathognomonic BRD3/4-NUT rearrangement, the comprehensive landscape of genomic alterations in NMCs has been unexplored. Patients and methods: We investigated three NMC cases, including two newly diagnosed NMC patients in Seoul National University Hospital, and a previously reported cell line (Ty-82). Whole-genome and transcriptome sequencing were carried out for these cases, and findings were validated by multiplex fluorescence in situ hybridization and using individual fluorescence probes. Results: Here, we present the first integrative analysis of whole-genome sequencing, transcriptome sequencing and cytogenetic characterization of NUT midline carcinomas. By whole-genome sequencing, we identified a remarkably similar pattern of highly complex genomic rearrangements (previously denominated as chromoplexy) involving the BRD3/4-NUT oncogenic rearrangements in two newly diagnosed NMC cases. Transcriptome sequencing revealed that these complex rearrangements were transcribed as very simple BRD3/4-NUT fusion transcripts. In Ty-82 cells, we also identified a complex genomic rearrangement involving the BRD4-NUT rearrangement underlying the simple t(15;19) karyotype. Careful inspections of rearrangement breakpoints indicated that these rearrangements were likely attributable to single catastrophic events. Although the NMC genomes had >3000 somatic point mutations, canonical oncogenes or tumor suppressor genes were rarely affected, indicating that they were largely passenger events. Mutational signature analysis showed predominant molecular clock-like signatures in all three cases (accounting for 54%-75% of all base substitutions), suggesting that NMCs may arise from actively proliferating normal cells. Conclusion: Taken together, our findings suggest that a single catastrophic event in proliferating normal cells could be sufficient for neoplastic transformation into NMCs.

Comparison of Cancer Yields and Diagnostic Performance of Screening Mammography vs. Supplemental Screening Ultrasound in 4394 Women with Average Risk for Breast Cancer.

PURPOSE: The effectiveness of supplemental screening ultrasound (US) was investigated in women ≥ 40 years at average risk for breast cancer regardless of breast parenchymal density. A total of 4394 women at average risk and having previously undergone screening mammography were classified as the mammography group.  MATERIALS AND METHODS: Of 4394 women, 2005 underwent screening US after a final assessment of category 1 or 2 on screening mammography, and were categorized as the US group. Category 0, 4, and 5 on mammography and 3, 4, and 5 on US were defined as positive. The cancer yields per 1000 women and diagnostic performance of two groups were compared. RESULTS: The total cancer and invasive cancer yields for the mammography group were 3.0 (95 % confidence interval 1.6, 5.1) and 2.0 (95 % CI, 0.9, 3.9) per 1000 women, higher than the US values of 2.0 (0.5, 5.1) and 1.0 (0.1, 3.6), not statistically significant. The specificity, accuracy, and positive predictive value (PPV) for mammography were 88.90 % (87.93, 89.81), 88.85 % (87.88, 89.76), and 2.61 % (1.39, 4.41), significantly higher than the US values of 69.07 % (66.99, 71.09), 69.13 % (67.05, 71.15), and 0.64 % (0.18, 1.64). The short-term follow-up rate of mammography was 5.51 % (4.85, 6.22), significantly lower than the rate of 26.58 (24.66, 28.58) for US.  CONCLUSION: Supplemental screening US in mammographically negative breasts can find additional carcinomas in women at average risk but is not as effective as screening mammography because of the lower cancer yield, invasive cancer yield, specificity, accuracy, PPV and a high short-term follow-up rate.

A risk-adapted approach using US features and FNA results in the management of thyroid incidentalomas identified by 18F-FDG PET.

PURPOSE: To assess the risk of malignancy of thyroid incidentalomas found on 18F-FDG PET/CT by US features and cytologic results, and to evaluate the clinical usage of a combination of US features and cytology for post-FNA management of thyroid incidentalomas on 18F-FDG PET/CT. MATERIALS AND METHODS: From September 2006 to December 2008, 132 patients with 134 thyroid incidentalomas detected on 18F-FDG PET/CT who had undergone US and US-FNA were included in this study. We evaluated the malignancy rate of thyroid incidentalomas in different subgroups subdivided by US features and US-FNA cytology results. Several variables were compared between the benign and malignant group. RESULTS: The risk of malignancy was 58.2 % (78/132) in thyroid incidentalomas on 18F-FDG PET/CT. Age, gender, and tumor size were not significantly different between the malignant and benign group.  Malignancy rate of thyroid incidentalomas was significantly higher in the suspicious malignant (88.9 %) than in the probably benign group (11.3 %) on US (p < 0.001). Malignancy rates were high in thyroid nodules with "malignancy", "suspicious for malignancy", or "follicular neoplasm" on cytologic results, regardless of US features. However, malignancy rates of thyroid incidentalomas with "unsatisfactory" or "benign" results on cytology were higher in the suspicious malignant (75 %, 12.5 %, respectively) than in the probably benign (0 %) group on US.  CONCLUSIONS: This study demonstrated that the risk of malignancy was high in thyroid incidentalomas on 18F-FDG PET/CT even without suspicious US features. However, there was no malignancy in nodules with no suspicious US features and benign cytology. Based on these results, we concluded that US may not replace FNA in the diagnosis of PET incidentalomas, and that a follow-up may be considered of thyroid incidentalomas with benign cytology and no suspicious US features.

The diagnosis of non-malignant papillary lesions of the breast: comparison of ultrasound-guided automated gun biopsy and vacuum-assisted removal.

AIM: To compare the histological upgrade rate of ultrasound (US)-guided vacuum-assisted removal (VAR) and US-14 G-automated core needle biopsy (ACNB) in the diagnosis of papillary breast lesions. MATERIALS AND METHODS: Two hundred and seventy-one biopsies of 230 papillary lesions were examined, which underwent subsequent surgical excision or long-term follow-up after US-ACNB (n = 206) or US-VAR (n = 65). The false-negative and atypical papilloma underestimation rate were compared between the ACNB and VAR groups. Patient and lesion characteristics were collected. The histological upgrade rates of the diagnosis were estimated and compared. RESULTS: Out of 271 papillary lesions, 195 (80.0%) were benign, 21 (7.7%) were atypical, and 55 (20.3%) were malignant. There were no false negatives or underestimated atypical papillomas in the VAR group. However, in the ACNB group, the false-negative rate was 7.6% (12 of 157 benign papillomas, 95% CI; 4.4-12.9%, p = 0.039) and the atypical papilloma underestimation rate was 33% (five of 15 atypical papillomas, 95% CI; 15.2-58.3%, p = 0.135). The histological upgrade rates of the diagnosis for papillary breast lesions were 0% for the VAR (0 of 66) group and 10.2% for the ACNB (21 of 206) group before adjusting for the population (p = 0.003). CONCLUSIONS: ACNB was associated with significantly higher false-negative and histological upgrade rates of diagnosis for papillary breast lesions than VAR.

Zooming method (x 2.0) of digital mammography vs digital magnification view (x 1.8) in full-field digital mammography for the diagnosis of microcalcifications.

The purpose of this study was to determine whether the interpretation of microcalcifications assessed on images zoomed (x 2.0) from digital mammograms is at least equivalent to that from digital magnification mammography (x 1.8) with respect to diagnostic accuracy and image quality. Three radiologists with different levels of experience in mammography reviewed each full-field digital mammography reader set for 185 patients with pathologically proven microcalcification clusters, which consisted of digital magnification mammograms (MAGs) with a magnification factor of 1.8 and images zoomed from mammograms (ZOOM) with a zoom factor of 2.0. Each radiologist rated their suspicion of breast cancer in microcalcific lesions using a six-point scale and the image quality and their confidence in the decisions using a five-point scale. Results were analysed according to display methods using areas under the receiver operating characteristic curves (A(z) value) for ZOOM and MAGs to interpret microcalcifications, and the Wilcoxon matched pairs signed rank test for image quality and confidence levels. There was no statistically significant difference in the level of suspicion of breast cancer between the ZOOM and MAG groups (A(z) = 0.8680 for ZOOM; A(z) = 0.8682 for MAG; p = 0.9897). However, MAG images were significantly better than ZOOM images in terms of visual imaging quality (p < 0.001), and the confidence level with MAG was better than with ZOOM (p < 0.001). In conclusion, the performance of radiologists in the diagnosis of microcalcifications using ZOOM was similar to that using MAGs, although image quality and confidence levels were better using MAGs.

Diagnosis of breast cancer at dynamic MRI in patients with breast augmentation by paraffin or silicone injection.

AIM: To determine the diagnostic performance of dynamic magnetic resonance imaging (MRI) for breast cancer in breasts augmented with liquid paraffin or silicone injection. MATERIALS AND METHODS: Among 62 patients with breast augmentation by liquid paraffin or silicone injection who had undergone dynamic breast MRI at our institution, 27 women, who had pathological diagnosis or at least 1-year MRI follow-up, were included in this retrospective study and their MRI images were reviewed. For enhancing lesions on MRI, the morphological features, enhancement kinetics, and BI-RADS assessment category were analysed. The lesion characteristics at MRI were correlated with the final diagnosis based on the histopathological result or at least 1-year MRI follow-up. RESULTS: Of the 27 patients, 17 enhancing lesions in 13 patients were found on MRI. All six lesions that were confirmed as malignancy showed suspicious morphological findings and type 2 or 3 enhancement kinetics, assigned to BI-RADS category 4 or 5. Of the remaining 11 benign lesions, 10 showed benign-favouring morphological findings, and all showed type 1 enhancement kinetics, assigned to BI-RADS category 2 or 4. CONCLUSION: In patients with breasts injected with foreign material, MRI was used to successfully diagnose malignant breast lesions and could be the diagnostic method of choice. Analysis of the morphological and kinetic features at MRI in conjunction with clinical findings is essential.