Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with early breast cancer.

The European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with early breast cancer were updated and published online in 2023, and adapted, according to previously established standard methodology, to produce the Pan-Asian adapted (PAGA) ESMO consensus guidelines for the management of Asian patients with early breast cancer. The adapted guidelines presented in this manuscript represent the consensus opinions reached by a panel of Asian experts in the treatment of patients with breast cancer representing the oncological societies of China (CSCO), Indonesia (ISHMO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO), co-ordinated by ESMO and KSMO. The voting was based on scientific evidence and was independent of the current treatment practices, drug access restrictions and reimbursement decisions in the different Asian regions represented by the 10 oncological societies. The latter are discussed separately in the manuscript. The aim is to provide guidance for the optimisation and harmonisation of the management of patients with early breast cancer across the different regions of Asia, drawing on the evidence provided by both Western and Asian trials, whilst respecting the differences in screening practices, molecular profiling, as well as the age and stage at presentation. Attention is drawn to the disparity in the drug approvals and reimbursement strategies, between the different regions of Asia.

Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer patients with brain metastases from the randomized DESTINY-Breast03 trial.

BACKGROUND: DESTINY-Breast03 is a randomized, multicenter, open-label, phase III study of trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) previously treated with trastuzumab and a taxane. A statistically significant improvement in progression-free survival (PFS) versus T-DM1 was reported in the primary analysis. Here, we report exploratory efficacy data in patients with and without brain metastases (BMs) at baseline. PATIENTS AND METHODS: Patients were randomly assigned 1 : 1 to receive T-DXd 5.4 mg/kg or T-DM1 3.6 mg/kg. Patients with clinically inactive/asymptomatic BMs were eligible. Lesions were measured as per modified RECIST, version 1.1. Outcomes included PFS by blinded independent central review (BICR), objective response rate (ORR), and intracranial ORR as per BICR. RESULTS: As of 21 May 2021, 43/261 patients randomized to T-DXd and 39/263 patients randomized to T-DM1 had BMs at baseline, as per investigator assessment. Among patients with baseline BMs, 20/43 in the T-DXd arm and 19/39 in the T-DM1 arm had not received prior local BM treatment. For patients with BMs, median PFS was 15.0 months [95% confidence interval (CI) 12.5-22.2 months] for T-DXd versus 3.0 months (95% CI 2.8-5.8 months) for T-DM1; hazard ratio (HR) 0.25 (95% CI 0.13-0.45). For patients without BMs, median PFS was not reached (95% CI 22.4 months-not estimable) for T-DXd versus 7.1 months (95% CI 5.6-9.7 months) for T-DM1; HR 0.30 (95% CI 0.22-0.40). Confirmed systemic ORR was 67.4% for T-DXd versus 20.5% for T-DM1 and 82.1% for T-DXd versus 36.6% for T-DM1 for patients with and without BMs, respectively. Intracranial ORR was 65.7% with T-DXd versus 34.3% with T-DM1. CONCLUSIONS: Patients with HER2-positive mBC whose disease progressed after trastuzumab and a taxane achieved a substantial benefit from treatment with T-DXd compared with T-DM1, including those with baseline BMs.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, staging and treatment of patients with metastatic breast cancer.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, staging and treatment of patients with metastatic breast cancer (MBC) was published in 2021. A special, hybrid guidelines meeting was convened by ESMO and the Korean Society of Medical Oncology (KSMO) in collaboration with nine other Asian national oncology societies in May 2022 in order to adapt the ESMO 2021 guidelines to take into account the differences associated with the treatment of MBC in Asia. These guidelines represent the consensus opinions reached by a panel of Asian experts in the treatment of patients with MBC representing the oncological societies of China (CSCO), India (ISMPO), Indonesia (ISHMO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO). The voting was based on the best available scientific evidence and was independent of drug access or practice restrictions in the different Asian countries. The latter were discussed when appropriate. The aim of these guidelines is to provide guidance for the harmonisation of the management of patients with MBC across the different regions of Asia, drawing from data provided by global and Asian trials whilst at the same time integrating the differences in genetics, demographics and scientific evidence, together with restricted access to certain therapeutic strategies.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with early breast cancer: a KSMO-ESMO initiative endorsed by CSCO, ISMPO, JSMO, MOS, SSO and TOS.

In view of the planned new edition of the most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of primary breast cancer published in 2015, it was decided at the ESMO Asia Meeting in November 2018, by both the ESMO and the Korean Society of Medical Oncology (KSMO), to convene a special face-to-face guidelines meeting in 2019 in Seoul. The aim was to adapt the latest ESMO 2019 guidelines to take into account the ethnic and geographical differences associated with the treatment of early breast cancer in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with early breast cancer representing the oncology societies of Korea (KSMO), China (CSCO), India (ISMPO) Japan (JSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and was independent of both the current treatment practices, and the drug availability and reimbursement situations, in the individual participating Asian countries.

Immune modulation of pathologic complete response after neoadjuvant HER2-directed therapies in the NeoSphere trial.

BACKGROUND: To investigate in the NeoSphere trial the contribution of the immune system to pathologic complete response in the breast (pCRB) after neoadjuvant docetaxel with trastuzumab (TH), pertuzumab (TP), or both (THP), or monoclonal antibodies alone (HP). PATIENTS AND METHODS: Immune gene mRNA expression (n = 350, 83.8%), lymphocyte infiltration (TIL, n = 243, 58.3%), and PDL1 by immunohistochemistry (n = 305, 73.1%) were correlated with pCRB. We studied five selected genes (IFNG, PD1, PDL1, PDL2, CTLA4) and six immune metagenes corresponding to plasma cells (IGG), T cells (CD8A), antigen-presenting cells (MHC2), and to MHC1 genes (MHC1), STAT1 co-expressed genes (STAT1), and interferon-inducible genes (IF-I). Gene expression data from the NOAH trial were used for validation. RESULTS: TIL as continuous variable and PDL1 protein expression were not significantly associated with pCRB. Expression of immune genes/metagenes had different association with pCRB after THP than after other therapies. With THP, higher expression of PD1 and STAT1, or any among PDL1, CTLA4, MHC1, and IF-I were linked with lower pCRB. In the combined TH/TP/HP treatment group, in multivariate analysis, higher expression of PD1, MHC2, and STAT1 were linked with pCRB, and higher PDL1, MHC1, or IF-I to lower pCRB. In the NOAH, a similar association of higher STAT1 with higher pCRB, and higher MHC1 and IF-I with lower pCRB was found for trastuzumab/chemotherapy but not for chemotherapy treatment only. CONCLUSIONS: The immune system modulates response to therapies containing trastuzumab and pertuzumab. Greatest benefit from THP is observed for low expression of some immune markers (i.e. MHC1, CTLA4). The involvement of PDL1 in resistance supports testing combinations of HER2-directed antibodies and immune-checkpoint inhibitors.

Distant metastasis in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) relapses more frequently than hormone receptor-positive subtypes and is often associated with poor outcomes. This retrospective study reviewed the pattern of distant metastasis with regard to survival in patients with TNBC. A total of 205 TNBC patients were analyzed. TNBC patients with lung metastases had the longest median post-metastatic OS (with 95% confidence interval) of 16.6 (10.3-22.9) months, followed by the bone, 16.3 (11.7-20.8) months, the liver, 8.9 (3.5-14.4) months, the pleura, 7.5 (2.8-12.3) months, and the brain, 4.3 (0.6-8.0) months. Kaplan-Meier plots indicated that TNBC patients with metastatic spread to brain, liver, and pleural had poorer post-metastatic OS rate than patients with lung metastases (p = 0.001, 0.004, and 0.029, respectively). Moreover, brain and liver metastases correlated significantly with poorer post-metastatic OS as compared to bone metastasis (p = 0.004 and 0.011, respectively). Route of first metastasis correlated significantly with survival of TNBC patients with brain metastases being the poorest survival indicator, followed by metastases to liver, pleura, bone, and lung.

Modulation of HER2 expression by ferulic acid on human breast cancer MCF7 cells.

BACKGROUND: The molecular mechanisms underlying the mitogenic effect of ferulic acid (FA), an active compound derived from Angelica sinensis, have never been elucidated. It was the aim of this study to investigate the proliferative effect of FA on human breast cancer cell lines and to elucidate its modulation mechanism on HER2 expression in MCF7 line. MATERIALS AND METHODS: By using MCF7 (oestrogen receptor-positive; ER+, HER2-low), BT474 (ER+, HER2-high), MDAMB231 (ER-, HER2-low) and SKBR3 (ER-, HER2-high) human breast cancer cell lines as in vitro models, the mitogenic effects of FA were assessed by trypan blue dye exclusion assay and DNA flow cytometry. Ferulic acid-modulated cell signalling and HER2 gene expression were evaluated in MCF7 line by Western blot and real-time RT-PCR analysis. RESULTS: Ferulic acid ER-dependently stimulated cell proliferation on MCF7 cells in a concentration-dependent manner. The HER2 oncogene (one of the prognostic factors of breast cancer) and ESR1 gene (oestrogen receptor-alpha; ERalpha) transcription were markedly up-regulated by FA treatment. Besides, HER2 signalling and its downstream molecules such as AKT and ERK1/2 were involved in FA-modulated ERalpha and cyclin D1 synthesis. Addition of anti-HER2 antibody, trastuzumab, abrogated FA-enhanced proliferative effect on MCF7 cells, indicated a positive feedback control for the action of HER2 in this setting. The fact that the ER antagonist blocked most of the FA-up-regulated HER2 expression, and that trastuzumab down-regulated ERalpha gene expression, suggested a cross-talk between ERalpha and HER2 signalling on MCF7 cells. CONCLUSION: The authors' conclude that FA causes human breast cancer cell proliferation by up-regulation of HER2 and ERalpha expression.

Polymorphism of estrogen metabolism genes and cataract.

Cataract is the leading cause of visual impairment in older adults in the world. Age-related lens opacities are common and are frequent causes of loss of vision. The incidence of cataract increases significantly with increasing age in women only. The onset coincides with estrogen deficiency that occurs after menopause. Hormone replacement therapy has proven beneficial to selected postmenopausal women. Estrogen effects on biological system are modulated via the estrogen receptors (ER) and/or estrogen metabolites. Although ER have been detected in ocular tissue, whether ER polymorphism is related to cataract is not known at present. The polymorphisms of estrogen metabolizing enzymes are also related to the serum concentration and activity of estrogen. Polymorphism such as cytochrome P450c17 (A2/A2), cytochrome P450c1A (vt/vt) will result in increased formation of catechol estrogen, while people with catechol-O-methyltransferase (COMT) polymorphism COMT (L/L) will have decreased metabolism of catechol estrogen and decreased level of methoxyestradiol. COMT was also involved in tamoxifen metabolism which may further decrease the activity of COMT in breast cancer patients treated with tamoxifen. It is known that a 4-7% increase in cataract was found in tamoxifen-treated breast cancer patients than non-user. The 7.0% COMT (L/L) genotype in general population corresponded well with the 4-7% of cataract formation in tamoxifen-treated breast cancer patients. Our hypothesis is that breast cancer patients with COMT (L/L) genotype may be at increased risk of cataract formation after tamoxifen treatment.

Clinicopathologic and prognostic differences between patients with hepatitis B- and C-related resectable hepatocellular carcinoma.

BACKGROUND AND PURPOSE: Hepatitis B and C viral infections are important factors in the development of hepatocellular carcinoma (HCC). This study examined the clinicopathologic and prognostic differences in patients with hepatitis B- and C-related resectable HCC. METHODS: A total of 270 HCC patients who underwent hepatic resection were enrolled. Among these patients, 211 were positive for hepatitis B surface antigen (HBsAg) and 59 were positive for anti-hepatitis C virus antibody (anti-HCV). The clinical manifestations, pathologic features, and treatment outcomes were compared between the HBsAg-positive and anti-HCV-positive groups. RESULTS: Compared to anti-HCV-positive patients, HBsAg-positive patients were significantly younger, had a higher familial incidence of HCC, larger tumor size, and a higher incidence of multiple tumors. HCC patients who were anti-HCV positive had worse liver function and a higher incidence of history of blood transfusion. DNA flow cytometric analysis revealed significantly more proliferative activity in the non-tumor part of the liver in HBsAg-positive HCC patients. The 1-, 3-, and 5-year overall survival rates of HBsAg-positive patients were 79%, 57%, and 48%, respectively, and for anti-HCV-positive patients were 91%, 75%, and 62%, respectively. HBsAg-positive patients had a significantly lower overall survival rate than anti-HCV-positive patients (p = 0.018). CONCLUSIONS: HBsAg-positive patients with resectable HCC had a less favorable survival rate after tumor resection than anti-HCV-positive HCC patients. This survival difference might have been related to the relatively advanced stage of disease and the higher proliferative activity of the non-tumor part of the liver in HBsAg-positive HCC patients.

Tie-1 tyrosine kinase is an independent prognostic indicator for invasive breast cancer.

Receptor tyrosine kinases are known to be involved in the growth, progression and metastasis of solid tumors. We investigated the relationship between tie-1 expression and progression of invasive ductal breast carcinoma with immunohistochemical analysis. Tie-1 protein was detected in the microvessel endothelial cells and cytoplasm of tumor cells. The tumor size and stage were significantly associated with the expression of tie-1, which portends a worse 5-year disease-free status (39.3% v 59.2%, p = 0.07) and overall survival rate (67.3% v 93%, p = 0.02) than those without tie-1 expression. Multivariate analysis demonstrated that larger tumor size, presence of lymph node metastasis and tie-1 expression were independent prognostic parameters, both in 5-year disease-free survival and overall survival. Patients with lymph node metastases and tie-1 expression had the worst 5-year disease-free survival (0%) and overall survival (42.4%) compared to those without tie-1 expression (50.2%, 85%). In lymph node negative patients, those without tie-1 expression had better 5-year disease-free survival and overall survival (72.9%, 100%) compared to those with tie-1 expression (65.5%, 87.7%). We conclude that tie-1 expression is an independent prognostic factor for invasive ductal breast carcinoma, adversely affecting survival of breast cancer patients with positive nodes to a significant extent.

Sonographic features of breast abscesses with emphasis on "hypoechoic rim" sign.

BACKGROUND: There are only limited reports on the ultrasound (US) features of breast abscess. The purpose of this paper is to review the US features of breast abscess with emphasis on "hypoechoic rim" sign which is more commonly seen in chronic abscess. METHODS: In a period of 10 years, 20,998 patients were referred for breast US examinations. Medical records identified 204 patients in whom breast abscess was diagnosed. All patients were examined using high-resolution real-time US scanners. The initial ultrasound reports and hard copy images were all carefully reviewed. The grading of the echogenicity of the abscess was classified from grade 0 to grade 5. The contours of the lesions were described as smooth, macrolobulated, microlobulated, irregular, zigzag, spiculate or indistinct. The wall thickness was measured to document the presence of "hypoechoic rim" which denoted a wall thickness greater than 2 mm. The associated findings and other acoustic phenomena related to the lesion were recorded. RESULTS: One hundred and thirty-six patients (136/204) having specific aspiration and/or biopsy/histopathological results were included in the study. All of the 136 patients showed abnormal US findings (100%). Most lesions showed grade 1 or grade 2 echogenicity (117, 86%). The contour of the abscess was usually smooth (42, 31%), macrolobulated (42, 31%), or irregular (22, 16%). A hypoechoic rim was noticed in 18 lesions (13%). Focal skin thickening was chiefly noticed in 91% of superficial abscesses (39/43) and 17% of intramammary abscesses (14/84). Diffuse skin thickening was exclusively evident in the breasts coexisting with mastitis. Hypoechoic interstitial streaks were not a common finding (7%), occurring in acute abscesses. The other findings included surrounding hypoechoic amorphous tissue (26%), posterior wall enhancement (71%), distal enhancement (60%) and lateral shadows (57%). CONCLUSIONS: US plays an important role in confirmation of the clinical diagnosis of breast abscess and aids significantly in the management of inflammatory breast diseases. Presence of the hypoechoic rim surrounding a fluid space or a central area of low-level echoes (i.e., grade 1 to grade 3) is indicative of a chronic abscess.

The surgical treatment and prognostic factors of well-differentiated thyroid cancers in Chinese patients: a 20-year experience.

BACKGROUND: Well-differentiated thyroid cancers (WDTC) are usually slow-growing neoplasm with an indolent clinical course. Assessment of treatment modalities for them requires a long-term follow-up in a large population, and is still of much debate. A systematic analysis of the history, prognosis and therapy for this disease in Taiwan is lacking. METHODS: A retrospective analysis of clinical and pathological records was conducted on 488 patients (149 male and 339 female, male: females = 1:2.28) treated for WDTC in the Veterans General Hospital-Taipei from 1971 to 1991 with subsequently follow-up until December 1994 (Mean follow-up: 8.5 years). Factors influencing recurrence, survival and different treatment were analyzed. RESULTS: Papillary thyroid cancer increased obviously as compared to our experience from 1959-1976. Changing tumor behaviors, including increasing female/male ratio, higher percentage of papillary cancer, decreasing primary tumor size and lower distant metastatic rate at the time of initial diagnosis, were noted. Factors influencing survival, as determined by univariate analysis, included age, gender, distant metastasis, extrathyroidal invasion, tumor size, nodal involvement, histological type, extent of surgical therapy and use of postoperative radioactive iodine. Those patients aged more than 45 at initial diagnosis, with primary tumors larger than 4 cm, with extrathyroidal invasion, and with distant metastasis at initial diagnosis were classified as being at high risk. The others were at low risk. Total or near total thyroidectomy (TTx), depending on the judgement of each surgeon, had much higher complication rate than lobectomy with/without isthmusectomy, but offered no benefit effect on disease-free survival or overall survival rates. Postoperative radioactive iodine ablation treatment and thyroxine replacement in suppressive dose after TTX improved survival among high risk patients. Lobectomy with/without isthmusectomy in low risk patients, followed by thyroxine suppression therapy, was adequate to improve the postoperative outcome and with low complication rate. Lymph node resection in patients with clinically palpable nodes improved longterm prognosis. CONCLUSIONS: Changing tumor behavior of WDTC leading to favorable prognosis has been noticed since 1971. Total or near total thyroidectomy is worthwhile in high risk patients with WDTC but does not appear necessary in low-risk patients. Lymph node dissection for metastatic lymph node could improve the survival rate.