Characterization of HER2-low breast cancer in young women with germline BRCA1/2 pathogenetic variants: Results of a large international retrospective cohort study.

BACKGROUND: Breast cancer (BC) in women aged ≤40 years carrying germline pathogenetic variants (PVs) in BRCA1/2 genes is infrequent but often associated with aggressive features. Human epidermal growth factor receptor 2 (HER2)-low-expressing BC has recently emerged as a novel therapeutic target but has not been characterized in this rare patient subset. METHODS: Women aged ≤40 years with newly diagnosed early-stage HER2-negative BC (HER2-0 and HER2-low) and germline BRCA1/2 PVs from 78 health care centers worldwide were retrospectively included. Chi-square test and Student t-test were used to describe variable distribution between HER2-0 and HER2-low. Associations with HER2-low status were assessed with logistic regression. Kaplan-Meier method and Cox regression analysis were used to assess disease-free survival (DFS) and overall survival. Statistical significance was considered for p ≤ .05. RESULTS: Of 3547 included patients, 32.3% had HER2-low BC, representing 46.3% of hormone receptor-positive and 21.3% of triple-negative (TN) tumors. HER2-low vs. HER2-0 BC were more often of grade 1/2 (p < .001), hormone receptor-positive (p < .001), and node-positive (p = .003). BRCA2 PVs were more often associated with HER2-low than BRCA1 PVs (p < .001). HER2-low versus HER2-0 showed better DFS (hazard ratio [HR], 0.86; 95% CI, 0.76-0.97) in the overall population and more favorable DFS (HR, 0.78; 95% CI, 0.64-0.95) and overall survival (HR, 0.65; 95% CI, 0.46-0.93) in the TN subgroup. Luminal A-like tumors in HER2-low (p = .014) and TN and luminal A-like in HER2-0 (p = .019) showed the worst DFS. CONCLUSIONS: In young patients with HER2-negative BC and germline BRCA1/2 PVs, HER2-low disease was less frequent than expected and more frequently linked to BRCA2 PVs and associated with luminal-like disease. HER2-low status was associated with a modestly improved prognosis.

Omission of Axillary Dissection Following Nodal Downstaging With Neoadjuvant Chemotherapy.

Importance: Data on oncological outcomes after omission of axillary lymph node dissection (ALND) in patients with breast cancer that downstages from node positive to negative with neoadjuvant chemotherapy are sparse. Additionally, the best axillary surgical staging technique in this scenario is unknown. Objective: To investigate oncological outcomes after sentinel lymph node biopsy (SLNB) with dual-tracer mapping or targeted axillary dissection (TAD), which combines SLNB with localization and retrieval of the clipped lymph node. Design, Setting, and Participants: In this multicenter retrospective cohort study that was conducted at 25 centers in 11 countries, 1144 patients with consecutive stage II to III biopsy-proven node-positive breast cancer were included between April 2013 and December 2020. The cumulative incidence rates of axillary, locoregional, and any invasive (locoregional or distant) recurrence were determined by competing risk analysis. Exposure: Omission of ALND after SLNB or TAD. Main Outcomes and Measures: The primary end points were the 3-year and 5-year rates of any axillary recurrence. Secondary end points included locoregional recurrence, any invasive (locoregional and distant) recurrence, and the number of lymph nodes removed. Results: A total of 1144 patients (median [IQR] age, 50 [41-59] years; 78 [6.8%] Asian, 105 [9.2%] Black, 102 [8.9%] Hispanic, and 816 [71.0%] White individuals; 666 SLNB [58.2%] and 478 TAD [41.8%]) were included. A total of 1060 patients (93%) had N1 disease, 619 (54%) had ERBB2 (formerly HER2)-positive illness, and 758 (66%) had a breast pathologic complete response. TAD patients were more likely to receive nodal radiation therapy (85% vs 78%; P = .01). The clipped node was successfully retrieved in 97% of TAD cases and 86% of SLNB cases (without localization). The mean (SD) number of sentinel lymph nodes retrieved was 3 (2) vs 4 (2) (P < .001), and the mean (SD) number of total lymph nodes removed was 3.95 (1.97) vs 4.44 (2.04) (P < .001) in the TAD and SLNB groups, respectively. The 5-year rates of any axillary, locoregional, and any invasive recurrence in the entire cohort were 1.0% (95% CI, 0.49%-2.0%), 2.7% (95% CI, 1.6%-4.1%), and 10% (95% CI, 8.3%-13%), respectively. The 3-year cumulative incidence of axillary recurrence did not differ between TAD and SLNB (0.5% vs 0.8%; P = .55). Conclusions and Relevance: The results of this cohort study showed that axillary recurrence was rare in this setting and was not significantly lower after TAD vs SLNB. These results support omission of ALND in this population.

Timing of genetic testing in BRCA1/2 and PALB2-Associated breast cancer: Preoperative result disclosure increases uptake of risk-reducing mastectomy and reduces unnecessary exposure to radiotherapy.

INTRODUCTION: The impact of timing of genetic testing on uptake of risk reducing mastectomy (RRM) in affected female BRCA1/2 or PALB2 carriers remains an area of evolving interest, particularly with the introduction of mainstream genetic testing initiatives. METHODS: Women with stage I-III breast cancer and a confirmed germline pathogenic variant in BRCA1/2 or PALB2 between 2000 and 2023 were identified from an institutional genetics database. Uptake of RRM was evaluated according to disclosure of genetic testing results before or after index surgery for a first diagnosis of breast cancer. RESULTS: The cohort included 287 female BRCA1/2 or PALB2 carriers with a median age of 44 years (IQR, 36-52). Overall, 155 (54 %) carriers received genetic testing results before and 132 (46 %) after index breast surgery. Receipt of genetic testing results before surgery was associated with a higher rate of index bilateral mastectomy (58.7 % vs. 7.6 %, p < 0.001) and a commensurate decrease in adjuvant radiation (41.9 % vs. 74.2 %, p < 0.001). At a median follow up of 4.4 years after genetic testing, 219 (76.3 %) affected carriers had undergone bilateral RRM, including 83.9 % with preoperative knowledge and 67.4 % of patients with postoperative knowledge of their germline pathogenic variant (log rank, p < 0.001). On multivariate regression, disclosure of genetic testing results before index breast surgery was independently associated with long-term uptake of bilateral mastectomy (HR 1.69, 95 % CI 1.21-2.38). CONCLUSION: Genetic testing results delivered prior to index breast surgery increase uptake of bilateral RRM in affected BRCA1/2 and PALB2 carriers. Efforts to mainstream genetic testing would help optimize surgical decision-making.

Oncologic safety of breast conserving surgery after neoadjuvant chemotherapy in patients with multiple ipsilateral breast cancer: A retrospective multi-institutional cohort study.

INTRODUCTION: The recent ACOSOG Z11102 trial demonstrated low recurrence rates with breast conserving surgery (BCS) in women with multiple ipsilateral breast cancers (MIBC). Questions remain regarding the oncologic safety of BCS in women with MIBC receiving neoadjuvant chemotherapy (NAC). METHODS: We conducted a retrospective cohort study of adult patients who underwent BCS following NAC for stage I-III breast cancer from 2012 to 2021 at two academic centers. Descriptive statistics were used to summarize the data and the Kaplan-Meier method was used to provide estimates for recurrence and survival outcomes. MIBC was defined as ≥2 foci of malignancy. RESULTS: A total of 544 patients were included; 29.4% (n = 160) ER+/HER2-, 17.7% (n = 96) ER+/HER2+, 18.2% (n = 99) ER-/HER2+, and 34.7% (n = 189) with ER-/HER2-disease. Overall, 80.5% (n = 438) had unifocal breast cancer while 19.5% (n = 106) had MIBC. Of patients with MIBC, 90.6% (n = 96) had multifocal and 9.4% (n = 10) had multicentric disease. Pathologic complete response was achieved in 41.1% of patients with MIBC versus 41.5% of patients with unifocal disease (p = 0.94). At a median follow-up of 55 months (IQR 32-83); 4.8% of patients in the unifocal group and 4.7% of patients in the MIBC group had had a local recurrence (p = 0.97). There was no difference in 5-year local recurrence-free survival (p = 0.92), recurrence-free survival (p = 0.06), or overall survival (p = 0.07) between the groups. CONCLUSION: In this large cohort of women undergoing BCS post-NAC, there was no significant difference in in breast tumor recurrence or survival outcomes between patients with unifocal disease and those with MIBC.

Preoperative factors that predict pathologic nodal involvement in early-stage HER2+ breast cancer: selecting cT1cN0 patients for treatment with neoadjuvant chemotherapy versus upfront surgery.

PURPOSE: The goal of this study was to identify the preoperative predictors of pathologic nodal metastases (pN+) in cT1cN0 HER2+ breast cancer undergoing upfront surgery. METHODS: We retrospectively reviewed data from women with cT1-T2N0 HER2+ breast cancer treated with neoadjuvant therapy (NAC) or upfront surgery at our institution between 2012 and 2023. Factors associated with management strategy were evaluated, and in those undergoing upfront surgery, univariate analyses were performed to identify the clinicopathologic factors associated with nodal metastases. RESULTS: Overall, 255 women with cT1-T2N0 HER2+ breast cancer met inclusion criteria, including 170 (68.6%) upfront surgery patients and 85 (31.4%) who underwent NAC. The median age at diagnosis was 59 years (range, 27-90 years). Younger age, larger clinical tumor size, high-grade disease, ER-PR-HER2+ subtype, and year of diagnosis after 2019 were significantly associated with receipt of NAC (p < 0.05). In those undergoing upfront surgery, 25.3% were pN+ , including 32.5% of cT1cN0 tumors. Factors associated with nodal involvement included age under 50, larger clinical tumor size, lymphovascular invasion (LVI), multifocality/multicentricity, and abnormal lymph nodes on axillary ultrasound (p < 0.05). In subset analysis of cT1cN0 HER2+ cases, LVI remained the strongest predictor of pN + disease (73.3% vs. 22.6%, p < 0.001). Patients with cT1cN0 HER2+ breast cancer under 50 years had a 47.1% likelihood of pN+ disease. CONCLUSION: Patients with cT1cN0 breast cancer have a 32.5% likelihood of nodal metastases, with higher incidence with younger age, LVI, multifocality/multicentricity, and abnormal axillary ultrasound. The presence of these factors may identify the patients who would benefit from treatment with neoadjuvant chemotherapy.

Counselling Framework for Germline BRCA1/2 and PALB2 Carriers Considering Risk-Reducing Mastectomy.

Female BRCA1/2 and PALB2 germline pathogenic variant carriers have an increased lifetime risk of breast cancer and may wish to consider risk-reducing mastectomy (RRM) for surgical prevention. Quantifying the residual lifetime risk and absolute benefit from RRM requires careful consideration of a patient's age, pathogenic variant, and their personal history of breast or ovarian cancer. Historically, patients have been counselled that RRM does not necessarily prolong survival relative to high-risk surveillance, although recent studies suggest a possible survival benefit of RRM in BRCA1 carriers. The uptake of RRM has increased dramatically over the last several decades yet varies according to sociodemographic factors and geographic region. The increased adoption of nipple-sparing mastectomy techniques, ability to avoid axillary staging, and availability of reconstructive options for most germline pathogenic variant carriers has helped to minimize the morbidity of RRM. Preoperative discussions should include evidence regarding postmastectomy sensation, the potential for supplemental surgery, pregnancy-related chest wall changes, and the need for continued clinical surveillance. Approaches that include sensation preservation and robotic nipple-sparing mastectomy are an area of evolving research that may be more widely adopted in the future.

Unique Challenges in Biomarkers for Psychotic Disorders.

Biomarkers are observations that provide information about the risk of certain conditions (predictive) or their underlying mechanisms (explanatory) [...].

Pregnancy After Breast Cancer in Young BRCA Carriers: An International Hospital-Based Cohort Study.

Importance: Young women with breast cancer who have germline pathogenic variants in BRCA1 or BRCA2 face unique challenges regarding fertility. Previous studies demonstrating the feasibility and safety of pregnancy in breast cancer survivors included limited data regarding BRCA carriers. Objective: To investigate cumulative incidence of pregnancy and disease-free survival in young women who are BRCA carriers. Design, Setting, and Participants: International, multicenter, hospital-based, retrospective cohort study conducted at 78 participating centers worldwide. The study included female participants diagnosed with invasive breast cancer at age 40 years or younger between January 2000 and December 2020 carrying germline pathogenic variants in BRCA1 and/or BRCA2. Last delivery was October 7, 2022; last follow-up was February 20, 2023. Exposure: Pregnancy after breast cancer. Main Outcomes and Measures: Primary end points were cumulative incidence of pregnancy after breast cancer and disease-free survival. Secondary end points were breast cancer-specific survival, overall survival, pregnancy, and fetal and obstetric outcomes. Results: Of 4732 BRCA carriers included, 659 had at least 1 pregnancy after breast cancer and 4073 did not. Median age at diagnosis in the overall cohort was 35 years (IQR, 31-38 years). Cumulative incidence of pregnancy at 10 years was 22% (95% CI, 21%-24%), with a median time from breast cancer diagnosis to conception of 3.5 years (IQR, 2.2-5.3 years). Among the 659 patients who had a pregnancy, 45 (6.9%) and 63 (9.7%) had an induced abortion or a miscarriage, respectively. Of the 517 patients (79.7%) with a completed pregnancy, 406 (91.0%) delivered at term (≥37 weeks) and 54 (10.4%) had twins. Among the 470 infants born with known information on pregnancy complications, 4 (0.9%) had documented congenital anomalies. Median follow-up was 7.8 years (IQR, 4.5-12.6 years). No significant difference in disease-free survival was observed between patients with or without a pregnancy after breast cancer (adjusted hazard ratio, 0.99; 95% CI, 0.81-1.20). Patients who had a pregnancy had significantly better breast cancer-specific survival and overall survival. Conclusions and Relevance: In this global study, 1 in 5 young BRCA carriers conceived within 10 years after breast cancer diagnosis. Pregnancy following breast cancer in BRCA carriers was not associated with decreased disease-free survival. Trial Registration: ClinicalTrials.gov Identifier: NCT03673306.

Awareness and Candidacy for Endocrine Prevention and Risk Reducing Mastectomy in Unaffected High-Risk Women Referred for Breast Cancer Risk Assessment.

INTRODUCTION: Primary prevention of breast cancer in women at elevated risk includes several strategies such as endocrine prevention and risk-reducing mastectomy (RRM). The objective of this study was to evaluate awareness of different preventive strategies across high-risk subgroups. PATIENTS AND METHODS: Women referred for high risk evaluation between 2020 and 2023 completed an initial risk-assessment questionnaire that included questions around perceived lifetime risk and consideration of preventive strategies. One-way analysis of variance (ANOVA) and chi-squared tests were used to compare differences across different high-risk subgroups. RESULTS: 482 women with a median age of 43 years (20-79 years) met inclusion criteria; 183 (38.0%) germline pathogenic variant carriers (GPV), 90 (18.7%) with high-risk lesions (HRL) on breast biopsy, and 209 (43.4%) with strong family history (FH) without a known genetic predisposition. Most high-risk women reported that they had considered increased screening and surveillance (83.7%) and lifestyle strategies (80.6%), while fewer patients had considered RRM (39.8%) and endocrine prevention (27.0%). Prior to initial consultation, RRM was more commonly considered in GPV carriers (59.4%) relative to those with HRL (33.3%) or strong FH (26.3%, p < 0.001). Based on current guidelines, 206 (43%) patients were deemed eligible for endocrine prevention, including 80.5% with HRL and 39.0% with strong FH. Prior consideration of endocrine prevention was highest in patients with HRL and significantly lower in those with strong FH (47.2% HRL versus 31.1% GPV versus 18.7% FH, p = 0.001). CONCLUSIONS: Endocrine prevention is the least considered preventive option for high-risk women, despite eligibility in a significant proportion of those presenting with HRL or strong FH.

Surgical Decision Making in Genetically High-Risk Women: Quantifying Postoperative Complications and Long-Term Risks of Supplemental Surgery After Risk-Reducing Mastectomy.

BACKGROUND: Risk-reducing mastectomy (RRM) helps prevent breast cancer in high-risk women but also carries a risk of unanticipated supplemental surgeries. We sought to determine the likelihood of supplemental surgeries following RRM. METHODS: We performed a retrospective cohort study of female patients with a confirmed germline pathogenic variant (GPV) in a breast cancer susceptibility gene (BRCA1/2, PALB2 and others) who underwent bilateral or contralateral RRM at our institution between 2006 and 2022. Supplemental surgeries were defined as any operation requiring general or local anesthesia performed outside of the initially planned procedure(s). The Kaplan-Meier method was used to estimate the 5-years cumulative incidence of supplemental surgery. RESULTS: Of 560 GPV carriers, RRMs were performed in 258 (46.1%) women. The median age of the cohort was 44 years (interquartile range 37-52 years), with 33 (12.8%) patients undergoing RRM without reconstruction and 225 (87.2%) undergoing RRM with reconstruction. Following surgery, 34 patients (13.2%) developed early (< 30 days) postoperative complications, including infection, hematoma, seroma, loss of the nipple areola complex, flap necrosis, implant exposure and/or prosthesis removal. At a median follow-up of 3.8 years, 94 (36.4%) GPV carriers underwent at least one reoperation. Participants who experienced an early postoperative complication had the highest rate of reoperation (85.3% vs. 29.0%; p < 0.001) and a significantly higher likelihood of multiple additional surgical interventions (41.2% vs. 10.7%; p < 0.001). The 5-years rate of supplemental surgery was 39.2% [95% confidence interval (CI) 32.7-46.5] in the overall cohort and 31.5% (95% CI 24.9-39.3) in patients without an early postoperative complication. CONCLUSIONS: Unanticipated supplemental surgeries occur in 40% of GPV carriers following RRM and in nearly one-third of patients without early postoperative complications.

Best practice & research clinical haematology: Screening for breast cancer in hodgkin lymphoma survivors.

Childhood and young adult survivors of Hodgkin lymphoma are at an elevated risk of developing breast cancer. Breast cancer risk is felt to originate from chest wall radiation exposure prior to the third decade of life, with incidence beginning to rise approximately eight to ten years following Hodgkin lymphoma treatment. Although incidence varies according to age at radiation exposure, dosage, and treatment fields, cohort studies have documented a cumulative incidence of breast cancer of 10-20% by 40 years of age. Women with a history of chest radiation for Hodgkin lymphoma are counselled to begin screening with bilateral breast MRI at 25 years of age, or eight years after radiation, whichever occurs later. Outside of high-risk surveillance, the optimal management approach for women with prior radiation exposure continues to evolve. When diagnosed with breast malignancy, evidence supports consideration of unilateral therapeutic and contralateral prophylactic mastectomy, although breast conserving surgery may be considered following multidisciplinary assessment. This review will address the epidemiology, characteristics, screening and management guidelines, and breast-cancer prevention efforts for Hodgkin lymphoma survivors treated with radiation therapy in adolescence and young adulthood.

Prevalence, time trends, and correlates of major depressive episode and other psychiatric conditions among young people amid major social unrest and COVID-19 in Hong Kong: a representative epidemiological study from 2019 to 2022.

Background: Hong Kong is among the many populations that has experienced the combined impacts of social unrest and the COVID-19 pandemic. Despite concerns about further deteriorations in youth mental health globally, few epidemiological studies have been conducted to examine the prevalence and correlates of major depressive episode (MDE) and other major psychiatric disorders across periods of population-level changes using diagnostic interviews. Methods: We conducted a territory-wide household-based epidemiological study from 2019 to 2022 targeting young people aged 15-24 years. MDE, generalised anxiety disorder (GAD), panic disorder (PD), and bipolar disorder (BD) were assessed using the Composite International Diagnostic Interview-Screening Scales in 3340 young people. Psychotic disorders were assessed by experienced psychiatrists according to the DSM. Help-seeking patterns were also explored. Findings: 16.6% had any mental disorder (13.7% 12-month MDE, 2.3% BD, 2.1% GAD, 1.0% PD, 0.6% psychotic disorder). The prevalence of MDE increased from 13.2% during period 1 (May 2019-June 2020) to 18.1% during period 2 (July-December 2020), followed by 14.0% during period 3 (January-June 2021) and 13.2% during period 4 (July 2021-June 2022). Different stressors uniquely contributed to MDE across periods: social unrest-related stressors during period 1, COVID-19 stressors during period 2, and personal stressors during periods 3-4. Lower resilience, loneliness, frequent nightmares, and childhood adversity were consistently associated with MDE. Compared to other conditions, those with MDE showed the lowest service utilisation rate (16.7%). Perceiving services to "cost too much" and "talked to friends or relatives instead" were among the major reasons for not seeking help. MDE was also significantly associated with poorer functioning and health-related quality of life. Interpretation: MDE can be sensitive to population-level changes, although its persistently elevated prevalence across the study period is of concern. Efforts to mitigate their impacts on youth mental health alongside personal risk factors are needed. Further work is required to increase the availability and acceptability of youth-targeted mental health services. Funding: Food and Health Bureau (HKSAR Government).

Excessive fear of clusters of holes, its interaction with stressful life events and the association with anxiety and depressive symptoms: large epidemiological study of young people in Hong Kong.

BACKGROUND: Excessive and persistent fear of clusters of holes, also known as trypophobia, has been suggested to reflect cortical hyperexcitability and may be associated with mental health risks. No study, however, has yet examined these associations in representative epidemiological samples. AIMS: To examine the prevalence of trypophobia in a population-representative youth sample, its association with mental health and functioning, and its interaction with external stress. METHOD: A total of 2065 young people were consecutively recruited from a household-based epidemiological youth mental health study in Hong Kong. Trypophobia, symptoms of anxiety, depression and stress, and exposure to personal stressors were assessed. Logistic regression was used to assess the relationships between trypophobia and mental health. Potential additive and interaction effects of trypophobia and high stress exposure on mental health were also tested. RESULTS: The prevalence of trypophobia was 17.6%. Trypophobia was significantly associated with severe symptoms of anxiety (odds ratio (OR) = 1.83, 95% CI = 1.32-2.53), depression (OR = 1.78, 95% CI = 1.24-2.56) and stress (OR = 1.68, 95% CI = 1.11-2.53), even when accounting for sociodemographic factors, personal and family psychiatric history, resilience and stress exposure. Dose-response relationships were observed, and trypophobia significantly potentiated the effects of stress exposure on symptom outcomes, particularly for depressive symptoms. Those with trypophobia also showed significantly poorer functioning across domains and poorer health-related quality of life. CONCLUSIONS: Screening for trypophobia in young people may facilitate early risk detection and intervention, particularly among those with recent stress exposure. Nevertheless, the generally small effect sizes suggest that other factors have more prominent roles in determining recent mental health outcomes in population-based samples; these should be explored in future work.

Rumination as a Transdiagnostic Phenomenon in the 21st Century: The Flow Model of Rumination.

Rumination and its related mental phenomena share associated impairments in cognition, such as executive functions and attentional processes across different clinical conditions (e.g., in psychotic disorders). In recent decades, however, the notion of rumination has been increasingly narrowed to the "self-focused" type in depressive disorders. A closer review of the literature shows that rumination may be construed as a broader process characterized by repetitive thoughts about certain mental contents that interfere with one's daily activities, not only limited to those related to "self". A further examination of the construct of rumination beyond the narrowly focused depressive rumination would help expand intervention opportunities for mental disorders in today's context. We first review the development of the clinical construct of rumination with regard to its historical roots and its roles in psychopathology. This builds the foundation for the introduction of the "Flow Model of Rumination (FMR)", which conceptualizes rumination as a disruption of a smooth flow of mental contents in conscious experience that depends on the coordinated interactions between intention, memory, affect, and external events. The conceptual review concludes with a discussion of the impact of rapid technological advances (such as smartphones) on rumination. Particularly in contemporary societies today, a broader consideration of rumination not only from a cognition viewpoint, but also incorporating a human-device interaction perspective, is necessitated. The implications of the FMR in contemporary mental health practice are discussed.

Spurious Autobiographical Memory of Psychosis: A Mechanistic Hypothesis for the Resolution, Persistence, and Recurrence of Positive Symptoms in Psychotic Disorders.

Psychotic disorders are complex disorders with multiple etiologies. While increased dopamine synthesis capacity has been proposed to underlie psychotic episodes, dopamine-independent processes are also involved (less responsive to dopamine receptor-blocking medications). The underlying mechanism(s) of the reduction in antipsychotic responsiveness over time, especially after repeated relapses, remain unclear. Despite the consistent evidence of dopamine overactivity and hippocampal volume loss in schizophrenia, few accounts have been provided based on the interactive effect of dopamine on hippocampal synapse plasticity mediating autobiographical memory processes. The present hypothesis builds upon previous works showing the potential effects of dopamine overactivity on hippocampal-mediated neuroplasticity underlying autobiographical memory, alongside known patterns of autobiographical memory dysfunction in psychosis. We propose that spurious autobiographical memory of psychosis (SAMP) produced during active psychosis may be a key mechanism mediating relapses and treatment non-responsiveness. In a hyperdopaminergic state, SAMP is expected to be generated at an increased rate during active psychosis. Similar to other memories, it will undergo assimilation, accommodation, and extinction processes. However, if SAMP fails to integrate with existing memory, a discontinuity in autobiographical memory may result. Inadequate exposure to normalizing experiences and hyposalience due to overmedication or negative symptoms may also impede the resolution of SAMP. Residual SAMP is hypothesized to increase the propensity for relapse and treatment non-responsiveness. Based on recent findings on the role of dopamine in facilitating hippocampal synapse plasticity and autobiographical memory formation, the SAMP hypothesis is consistent with clinical observations of DUP effects, including the repetition of contents in psychotic relapses as well as the emergence of treatment non-responsiveness after repeated relapses. Clinical implications of the hypothesis highlight the importance of minimizing active psychosis, integrating psychosis memory, avoiding over-medication, and fostering normalizing experiences.

Predictors of nodal metastases in early stage HER2+ breast cancer: Deciding on treatment approach with neoadjuvant chemotherapy vs. upfront surgery.

BACKGROUND: The purpose of this study is to evaluate preoperative predictors of nodal metastases in patients with early-stage, HER2-positive (HER2+) breast cancer. METHODS: The SEER Database was queried to identify women with a first diagnosis of stage I-II (T1-T2) HER2-positive breast cancer treated with upfront surgery in 2018. Multivariable logistic regression was used to identify clinical characteristics independently associated with nodal involvement. RESULTS: Overall, 3333 women with stage I-II HER2+ breast cancer met inclusion criteria and were included in the study. The median age at diagnosis was 59 years (IQR, 51-69 years). Most patients underwent breast-conserving surgery (60.9%), with a median of 3 (IQR 2-4) axillary lymph nodes removed. On final pathology, 762 (22.9%) of T1-T2 HER2+ patients were node positive; 2.7% pN0[i+], 3.7% pN1mi, 15.1% pN1, and 1.4% pN2. Women less than 40 years and those between 40 and 49 years showed the highest proportion of axillary lymph node metastasis, in 33.7% and 30.7% respectively, and declining with age (p < 0.001). Patients with triple-positive breast cancer had the highest rates of nodal involvement (24.8%), compared to 20.7% ER+/PR-/HER2+ and 19.6% of HER2-enriched patients (p = 0.006). On adjusted analysis, age, biologic subtype, tumour size, and type of surgery remained independent predictors of nodal involvement. On subgroup analysis, women under age 50 with T1c HER2-enriched or triple-positive breast cancer had a 33% and 35% incidence of nodal involvement, which declined with age. CONCLUSIONS: The likelihood of pathologic nodal involvement in early-stage HER2+ breast cancer is contingent on age, ER/PR status, and tumour size.