Managing menopause after cancer.

Globally, 9 million women are diagnosed with cancer each year. Breast cancer is the most commonly diagnosed cancer worldwide, followed by colorectal cancer in high-income countries and cervical cancer in low-income countries. Survival from cancer is improving and more women are experiencing long-term effects of cancer treatment, such as premature ovarian insufficiency or early menopause. Managing menopausal symptoms after cancer can be challenging, and more severe than at natural menopause. Menopausal symptoms can extend beyond hot flushes and night sweats (vasomotor symptoms). Treatment-induced symptoms might include sexual dysfunction and impairment of sleep, mood, and quality of life. In the long term, premature ovarian insufficiency might increase the risk of chronic conditions such as osteoporosis and cardiovascular disease. Diagnosing menopause after cancer can be challenging as menopausal symptoms can overlap with other common symptoms in patients with cancer, such as fatigue and sexual dysfunction. Menopausal hormone therapy is an effective treatment for vasomotor symptoms and seems to be safe for many patients with cancer. When hormone therapy is contraindicated or avoided, emerging evidence supports the efficacy of non-pharmacological and non-hormonal treatments, although most evidence is based on women older than 50 years with breast cancer. Vaginal oestrogen seems safe for most patients with genitourinary symptoms, but there are few non-hormonal options. Many patients have inadequate centralised care for managing menopausal symptoms after cancer treatment, and more information is needed about cost-effective and patient-focused models of care for this growing population.

Association of area- and volumetric-mammographic density and breast cancer risk in women of Asian descent: a case control study.

BACKGROUND: Mammographic density (MD) has been shown to be a strong and independent risk factor for breast cancer in women of European and Asian descent. However, the majority of Asian studies to date have used BI-RADS as the scoring method and none have evaluated area and volumetric densities in the same cohort of women. This study aims to compare the association of MD measured by two automated methods with the risk of breast cancer in Asian women, and to investigate if the association is different for premenopausal and postmenopausal women. METHODS: In this case-control study of 531 cases and 2297 controls, we evaluated the association of area-based MD measures and volumetric-based MD measures with breast cancer risk in Asian women using conditional logistic regression analysis, adjusting for relevant confounders. The corresponding association by menopausal status were assessed using unconditional logistic regression. RESULTS: We found that both area and volume-based MD measures were associated with breast cancer risk. Strongest associations were observed for percent densities (OR (95% CI) was 2.06 (1.42-2.99) for percent dense area and 2.21 (1.44-3.39) for percent dense volume, comparing women in highest density quartile with those in the lowest quartile). The corresponding associations were significant in postmenopausal but not premenopausal women (premenopausal versus postmenopausal were 1.59 (0.95-2.67) and 1.89 (1.22-2.96) for percent dense area and 1.24 (0.70-2.22) and 1.96 (1.19-3.27) for percent dense volume). However, the odds ratios were not statistically different by menopausal status [p difference = 0.782 for percent dense area and 0.486 for percent dense volume]. CONCLUSIONS: This study confirms the associations of mammographic density measured by both area and volumetric methods and breast cancer risk in Asian women. Stronger associations were observed for percent dense area and percent dense volume, and strongest effects were seen in postmenopausal individuals.

Clustering of HR + /HER2- breast cancer in an Asian cohort is driven by immune phenotypes.

Breast cancer exhibits significant heterogeneity, manifesting in various subtypes that are critical in guiding treatment decisions. This study aimed to investigate the existence of distinct subtypes of breast cancer within the Asian population, by analysing the transcriptomic profiles of 934 breast cancer patients from a Malaysian cohort. Our findings reveal that the HR + /HER2- breast cancer samples display a distinct clustering pattern based on immune phenotypes, rather than conforming to the conventional luminal A-luminal B paradigm previously reported in breast cancers from women of European descent. This suggests that the activation of the immune system may play a more important role in Asian HR + /HER2- breast cancer than has been previously recognized. Analysis of somatic mutations by whole exome sequencing showed that counter-intuitively, the cluster of HR + /HER2- samples exhibiting higher immune scores was associated with lower tumour mutational burden, lower homologous recombination deficiency scores, and fewer copy number aberrations, implicating the involvement of non-canonical tumour immune pathways. Further investigations are warranted to determine the underlying mechanisms of these pathways, with the potential to develop innovative immunotherapeutic approaches tailored to this specific patient population.

Consensus Guidelines on Human Epidermal Growth Factor Receptor 2 (HER2)-Low Testing in Breast Cancer in Malaysia.

Breast cancer is one of the most common cancers in Malaysia. Recently, a new nomenclature was introduced for breast cancers with human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) 1+, or 2+ with negative in situ hybridization (ISH), i.e., HER2-low breast cancer. In current clinical practice, these breast cancers are reported as HER2-negative. Clinical trials have shown that HER2-low breast cancer benefits from targeted therapy with anti-HER2 antibody-drug conjugates. Unfortunately, various challenges and obstacles are faced by local pathologists in HER2 testing, which may jeopardize the standard of care for patients with HER2-low breast cancer. This consensus guideline aims to elucidate standard practices pertaining to HER2 testing and HER2-low interpretation in Malaysia. Topics discussed among a panel of local experts include tissue sampling and handling, assay and antibody selection, result interpretation and reporting, and quality assurance. Practice recommendations made in this consensus guideline reflect current international guidelines and, where appropriate, adapted to the Malaysian landscape.

Trends in Presentation, Management, and Survival of Women With Breast Cancer in a Multiethnic, Middle-Income Asian Setting.

PURPOSE: Granular data on breast cancer (BC) are pertinent for surveillance, planning, and monitoring of cancer care delivery. We determined the trends in clinical presentation, management, and survival of women with BC in a multiethnic middle-income Asian setting over 15 years. METHODS: Data of 7,478 Malaysian women newly diagnosed with invasive BC between 2005 and 2019 from three hospital-based cancer registries were included. Trends in demographic, tumor, and treatment characteristics were compared across period 1 (P1): 2005-2009, period 2 (P2): 2010-2014, and period 3 (P3): 2015-2019. Overall survival and net survival were determined. RESULTS: More women in P3 than P1 were older than 60 years at diagnosis. Only a marginal increase in proportion of women with stage I disease was observed (23.7% v 27.2% in P1 and P3, respectively, P = .004). Nonetheless, patients were increasingly presenting with smaller tumors, fewer axillary node involvement, well-differentiated tumors, and hormone receptor expression in recent times. Proportion of women with human epidermal growth factor receptor 2 (HER2)-overexpressed tumors significantly decreased. Among indicated patients, receipt of anticancer therapies was somewhat similar over the calendar periods, except for neoadjuvant chemotherapy and anti-HER2 therapy, where increases in administration were noted. Significant improvements in survival were observed over the 15 years, particularly for HER2-overexpressed BCs. CONCLUSION: Although the improvements in BC survival that we have observed validate ongoing cancer control efforts and treatment advances, study findings suggest that more could be done for earlier detection and improved access to effective therapies in our settings.

Gene expression signature for predicting homologous recombination deficiency in triple-negative breast cancer.

Triple-negative breast cancers (TNBCs) are a subset of breast cancers that have remained difficult to treat. A proportion of TNBCs arising in non-carriers of BRCA pathogenic variants have genomic features that are similar to BRCA carriers and may also benefit from PARP inhibitor treatment. Using genomic data from 129 TNBC samples from the Malaysian Breast Cancer (MyBrCa) cohort, we developed a gene expression-based machine learning classifier for homologous recombination deficiency (HRD) in TNBCs. The classifier identified samples with HRD mutational signature at an AUROC of 0.93 in MyBrCa validation datasets and 0.84 in TCGA TNBCs. Additionally, the classifier strongly segregated HRD-associated genomic features in TNBCs from TCGA, METABRIC, and ICGC. Thus, our gene expression classifier may identify triple-negative breast cancer patients with homologous recombination deficiency, suggesting an alternative method to identify individuals who may benefit from treatment with PARP inhibitors or platinum chemotherapy.

Feasibility of monitoring Global Breast Cancer Initiative Framework key performance indicators in 21 Asian National Cancer Centers Alliance member countries.

Background: The Global Breast Cancer Initiative (GBCI) Framework, launched by the World Health Organisation (WHO) in 2023, emphasises assessing, strengthening, and scaling up services for the early detection and management of breast cancer. This study aims to determine the feasibility of monitoring the status of breast cancer control in the 21 Asian National Cancer Centers Alliance (ANCCA) countries based on the three GBCI Framework key performance indicators (KPIs): stage at diagnosis, time to diagnosis, and treatment completion. Methods: We reviewed published literature on breast cancer control among 21 ANCCA countries from May to July 2023 to establish data availability and compiled the latest descriptive statistics and sources of the indicators using a standardised data collection form. We performed bivariate Pearson's correlation analysis to measure the strength of correlation between stage at diagnosis, mortality and survival rates, and universal health coverage. Findings: Only 12 (57%) ANCCA member countries published national cancer registry reports on breast cancer age-standardised incidence rate (ASIR) and age-standardised mortality rate (ASMR). Indonesia, Myanmar, and Nepal had provincial data and others relied on WHO's Global Cancer Observatory (GLOBOCAN) estimates. GLOBOCAN data differed from the reported national statistics by 5-10% in Bhutan, Indonesia, Iran, the Republic of Korea, Singapore, and Thailand and >10% in China, India, Malaysia, Mongolia, and Sri Lanka. The proportion of patients diagnosed in stages I and II strongly correlated with the five-year survival rate and with the universal health coverage (UHC) index. Three countries (14%) reported national data with >60% of invasive breast cancer patients diagnosed at stages I and II, and a five-year survival rate of >80%. Over 60% of the ANCCA countries had no published national data on breast cancer staging, the time interval from presentation to diagnosis, and diagnosis to treatment. Five (24%) countries reported data on treatment completion. The definition of delayed diagnosis and treatment completion varied across countries. Interpretation: GBCI's Pillar 1 KPI correlates strongly with five-year survival rate and with the UHC index. Most ANCCA countries lacked national data on cancer staging, timely diagnosis, and treatment completion KPIs. While institutional-level data were available in some countries, they may not represent the nationwide status. Strengthening cancer surveillance is crucial for effective breast cancer control. The GBCI Framework indicators warrant more detailed definitions for standardised data collection. Surrogate indicators which are measurable and manageable in country-specific settings, could be considered for monitoring GBCI indicators. Ensuring UHC and addressing health inequalities are essential to early diagnosis and treatment of breast cancer. Funding: Funding for this research article's processing fee (APC) will be provided by the affiliated institution to support the open-access publication of this work. The funding body is not involved in the study design; collection, management, analysis and interpretation of data; or the decision to submit for publication. The funding body will be informed of any planned publications, and documentation provided.

Age-specific breast and ovarian cancer risks associated with germline BRCA1 or BRCA2 pathogenic variants - an Asian study of 572 families.

Background: Clinical management of Asian BRCA1 and BRCA2 pathogenic variants (PV) carriers remains challenging due to imprecise age-specific breast (BC) and ovarian cancer (OC) risks estimates. We aimed to refine these estimates using six multi-ethnic studies in Asia. Methods: Data were collected on 271 BRCA1 and 301 BRCA2 families from Malaysia and Singapore, ascertained through population/hospital-based case-series (88%) and genetic clinics (12%). Age-specific cancer risks were estimated using a modified segregation analysis method, adjusted for ascertainment. Findings: BC and OC relative risks (RRs) varied across age groups for both BRCA1 and BRCA2. The age-specific RR estimates were similar across ethnicities and country of residence. For BRCA1 carriers of Malay, Indian and Chinese ancestry born between 1950 and 1959 in Malaysia, the cumulative risk (95% CI) of BC by age 80 was 40% (36%-44%), 49% (44%-53%) and 55% (51%-60%), respectively. The corresponding estimates for BRCA2 were 29% (26-32%), 36% (33%-40%) and 42% (38%-45%). The corresponding cumulative BC risks for Singapore residents from the same birth cohort, where the underlying population cancer incidences are higher compared to Malaysia, were higher, varying by ancestry group between 57 and 61% for BRCA1, and between 43 and 47% for BRCA2 carriers. The cumulative risk of OC by age 80 was 31% (27-36%) for BRCA1 and 12% (10%-15%) for BRCA2 carriers in Malaysia born between 1950 and 1959; and 42% (34-50%) for BRCA1 and 20% (14-27%) for BRCA2 carriers of the same birth cohort in Singapore. There was evidence of increased BC and OC risks for women from >1960 birth cohorts (p-value = 3.6 × 10-5 for BRCA1 and 0.018 for BRCA2). Interpretation: The absolute age-specific cancer risks of Asian carriers vary depending on the underlying population-specific cancer incidences, and hence should be customised to allow for more accurate cancer risk management. Funding: Wellcome Trust [grant no: v203477/Z/16/Z]; CRUK (PPRPGM-Nov20∖100002).