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Pooja Advani,1 Lauren Cornell,2 Saranya Chumsri,1 Alvaro Moreno-Aspitia1 1Division of Hematology and Oncology, 2Department of Internal Medicine, Mayo Clinic, Jacksonville, FL, USA Abstract: Human epidermal growth factor receptor 2 (HER2) is a tyrosine kinase transmembrane receptor that is overexpressed on the surface of 15%–20% of breast tumors and has been associated with poor prognosis. Consistently improved pathologic response and survival rates have been demonstrated with use of trastuzumab in combination with standard chemotherapy in both early and advanced breast cancer. However, resistance to trastuzumab may pose a major problem in the effective treatment of HER2-positive breast cancer. Dual HER2 blockade, using agents that work in a complimentary fashion to trastuzumab, has more recently been explored to evade resistance in both the preoperative (neoadjuvant) and adjuvant settings. Increased effectiveness of dual anti-HER2 agents over single blockade has been recently reported in clinical studies. Pertuzumab in combination with trastuzumab and taxane is currently approved in the metastatic and neoadjuvant treatment of HER2-positive breast cancer. Various biomarkers have also been investigated to identify subsets of patients with HER2-positive tumors who would likely respond best to these targeted therapy combinations. In this article, available trial data regarding efficacy and toxicity of treatment with combination HER2 agents in the neoadjuvant and adjuvant setting have been reviewed, and relevant correlative biomarker data from these trials have been discussed. Keywords: HER2, dual blockade, neoadjuvant, adjuvant, breast cancer, trastuzumab

Saranya Chumsri Department of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, USA Abstract: Aromatase is an enzyme that converts testosterones to estrogens. Inhibition of this enzyme has been shown to have several clinical utilities in breast cancer. Currently, there are three aromatase inhibitors (AIs) in clinical use, namely anastrozole, letrozole, and exemestane. AIs have been used in various clinical settings for breast cancer, ranging from chemoprevention in breast cancer to treating breast cancer in both early stage in the adjuvant setting and metastatic disease. This article reviews mechanism of action, AI classification, and clinical utilities of AIs in various clinical settings in the context of breast cancer. Keywords: aromatase inhibitor, endocrine therapy, breast cancer

Abstract Context. - Myeloid sarcoma (MS) is a neoplasm of immature granulocytes, monocytes, or both involving any extramedullary site. The correct diagnosis of MS is important for adequate therapy, which is often delayed because of a high misdiagnosis rate. Objective. - To evaluate the lineage differentiation of neoplastic cells in MS by immunohistochemistry, and to correlate the results with clinicopathologic findings and cytogenetic studies. Design. - Histologic and immunohistochemical examinations were performed on formalin-fixed paraffin-embedded tissue samples from 13 cases of MS. They were classified according to the World Health Organization criteria. Chromosomal analysis data were available in 11 cases. Clinical, pathological, and cytogenetic findings were analyzed. Results. - The study included six male and seven female patients with an age range of 25 to 72 years (mean, 49.3 years) and a male to female ratio of 1:1.2. MS de novo occurred in 4/13 (31%) of cases examined. The most sensitive immunohistochemical markers were CD43 and lysozyme present in all cases with MS (13/13, 100%). All de novo MS showed a normal karyotype, monoblastic differentiation, and lack of CD34. The most common chromosomal abnormalities in MS associated with a hematopoietic disorder were trisomy 8 and inv(16) (2/11, 18%). Conclusion. - An immunohistochemical panel including CD43, lysozyme, myeloperoxidase (MPO), CD68 (or CD163), CD117, CD3 and CD20 can successfully identify the vast majority of MS variants in formalin-fixed paraffin-embedded tissue sections. The present report expands the spectrum of our knowledge showing that de novo MS has frequent monoblastic differentiation and frequently carries a normal karyotype.

Introduction: The most practical approach to assessment of medication adherence in clinical practice is via patient self-reporting, which can be measured using the 8-item Morisky Medication Adherence Scale (MMAS). The 8-item MMAS was developed from a previously validated 4-item scale by supplementing additional items measuring specific medication-taking behaviors to better capture barriers surrounding adherence behavior and has been determined to have better reliability than 4-item scale. Validated medication adherence surveys such as an 8-item MMAS, are untested in oncology, but have been validated in HTN, HIV, DM and other disorders in the setting of multiple chronic medications. Thus this study will serve as a pilot study of the MMAS in the oncology population. Methods: This is a prospective study conducted at the University of Maryland Greenebaum Cancer Center (UMGCC). The primary objective was to identify the adherence level (high, medium, low) to adjuvant (AI) in early stage (1-3) breast cancer (BC) patients in order to identify predictors of adherence. Subjects were stratified according to duration of therapy with AI (≤ 2 yrs or >2 yrs) at the time of the survey. The secondary objective was to identify baseline predictors for adherence. Patients received a maximum 8 points for maximum adherence to medication treatment or high adherence, 6-7 points for medium adherence and < 6 points for low adherence. Eligibility: Adult females, postmenopausal, signed consent, hormone receptor-positive BC (ER and/or PR >=1%), pathologically confirmed Stage 1-3 BC, completed surgery, adjuvant chemotherapy, and/or radiation therapy, and were recommended by their medical oncologist to take adjuvant AI for 5 years. Pts received a prescription for adjuvant AIs (anastrozole, letrozole or exemestane) after completion of adjuvant chemotherapy. Results: Patient characteristics: 73 BC pts were sequentially accrued so far at the UMGCC and filled out the self-reported questionnaire; Causcasian-62%, African American (AAF)- 37%, Asian-1%, median age at diagnosis-54 (range33-84); stage 1-36%, stage 2-47%, stage 3-17%; mastectomy-61%; lumpectomy-39%; local radiation therapy 62%; ER+ 95%; PR+ 78%, HER2+ 17 %; tumor type ductal-75%; lobular-20%; mixed ductal/lobular-5%; tumor grade-1-46%, 2-41%,3-12%; adjuvant chemotherapy- 63%. Educational level- N/A- 3%, 2 years. Univariable regression models for continuous predictors and rxc contingency tables for categorical ones revealed that the adherence to AI therapy is not affected by age, marital status, education, prior cancer therapy, tumor stage, and concurrent medication. However, there was a trend for better adherence to AI therapy in Caucasian women vs. AAF (p = 0.013). The study is ongoing. [ABSTRACT FROM AUTHOR]

Background: Dual anti-human epidermal growth factor receptor 2 (HER2) blockade has improved the outcomes of patients with early and metastatic HER2-positive breast cancer. Here we present the final 10-year analysis of the ALTTO trial., Patients and Methods: The ALTTO trial (NCT00490139) is a prospective randomized, phase III, open-label, multicenter study that investigated the role of adjuvant chemotherapy and trastuzumab alone, in combination or sequentially with lapatinib. The primary endpoint was disease-free survival (DFS) and secondary endpoints included overall survival (OS), time to distant recurrence and safety., Results: Overall, 6281 patients with HER2-positive early breast cancer were included in the final efficacy analysis in three treatment groups: trastuzumab (T), lapatinib + trastuzumab (L + T) and trastuzumab followed by lapatinib (T→L). Baseline characteristics were well balanced between groups. At a median follow-up of 9.8 years, the addition of lapatinib to trastuzumab and chemotherapy did not significantly improve DFS nor OS. The 10-year DFS was 77% in T, 79% in L + T and 79% in T→L, and the 10-year OS was 87%, 89% and 89%, respectively. The incidence of any cardiac event was low and similar in the three treatment groups., Conclusions: With a longer follow-up, no significant improvement was observed in DFS in patients treated with dual anti-HER2 blockade with lapatinib + trastuzumab compared to trastuzumab alone. The 10-year survival rates for the combination group are consistent with other studies that have explored dual anti-HER2 therapy., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Anti-Müllerian hormone (AMH) serves as an indirect marker for predicting primordial follicles that are representative of ovarian reserve. In this study the possibility of using AMH and age to predict the ovarian reserve in domestic cats. Ovaries and blood were collected from 30 cats undergoing routine ovariohysterectomy. The animals were divided into three age groups: prepubertal (<4 mo, n = 10), adult (1-5 y, n = 10), and senior (>5 y, n = 10). Blood was collected at surgery for serum AMH measurements using the AMH Gen II ELISA kit. The intra-assay coefficient of variation (CV) and inter-assay CV were 3.56 % and 7.68 %, respectively. One side of the ovary was processed to determine AMH localization using immunohistochemistry and for a histological count of follicles, which is the gold standard. The expression of AMH protein was quantified from the contralateral ovary by Western blot analysis. Primordial follicles exhibited the most pronounced inverse relationship with age (rho = -0.779, P < 0.05), followed by a positive association with serum AMH concentration (rho = 0.490, P < 0.05), indicating that both age and AMH are potential markers indicative of primordial follicles. Furthermore, secondary (rho = 0.651, P < 0.05) and small antral follicles (rho = 0.648, P < 0.05) were identified as the major sources of circulating AMH, as indicated by the stronger correlation with serum AMH concentrations compared with primary follicles. However, there was no significant correlation between the expression of AMH protein and other factors, including age, primordial follicles, primary follicles, secondary follicles, small antral follicles, and serum AMH concentration. A model for predicting primordial follicle number using serum AMH concentration (AIC = 672.66, P < 0.05) and age (AIC = 668.93, P < 0.05) was established. In conclusion, both serum AMH concentration and age may serve as comparable markers of ovarian reserve in domestic cats. Moreover, AMH is particularly useful in situations where age information is not available., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The Clinical Treatment Score post-5 years (CTS5) is a risk stratification tool used to determine the risk of late recurrence in hormone receptor-positive (HR+), HER2-negative breast cancer (BC). Limited data exist on its use in HR+, HER2-positive (HER2+) BC., Patients and Methods: CTS5 was evaluated in HR+, HER2+ BC in the North Central Cancer Treatment Group (NCCTG) N9831 (Alliance) and NSABP B-31 (NRG) trials., Results: A total of 1,862 patients with HR+, HER2+ BC without recurrence 5 years after enrollment were included. Overall, the CTS5 score was significantly associated with recurrence-free survival (RFS), with a hazard ratio (HR) of 1.35 (95% CI, 1.12-1.63; P=.002), but did not reach statistical significance in patients who received trastuzumab (n=829; HR, 1.29; 95% CI, 0.98-1.71; P=.07). CTS5 risk category was not significantly associated with RFS. In patients who received trastuzumab, other variables used in CTS5, including patient age and tumor size, were not significantly associated with RFS. N3 was significantly associated with worse outcomes (HR, 1.86; 95% CI, 1.09-3.17; P=.02) compared with N0-N1. Paradoxically, higher tumor grade was associated with better outcomes after 5 years in the multivariate analysis (HR, 0.71; 95% CI, 0.50-1.00; P=.05). The incidence of recurrences or deaths between years 5 to 10 was 10.6% in the CTS5 low-risk category, 5.6% in the intermediate-risk category, and 9.8% in the high-risk category., Conclusions: The CTS5 model does not accurately predict the risk of late recurrence in HR+, HER2+ BC treated with adjuvant trastuzumab in the N9831 and B-31 trials. This study underlines the need to develop a new prognostic model to better delineate the risk of late recurrence in patients with HR+, HER2+ BC receiving adjuvant trastuzumab., Clinicaltrials: gov identifiers: NCT00005970 (NCCTG N9831) and NCT00004067 (NRG/NSABP B-31).