Impact of estrogen receptor (ER) and human epidermal growth factor receptor-2 (HER2) co-expression on breast cancer disease characteristics: implications for tumor biology and research.

ER and HER2 are critical drivers of breast cancer biology and can interact when co-expressed, but less data describe the impact of ER/HER2 co-expression on clinical disease characteristics. We studied the impact of ER and HER2 (co)-expression in a cohort of 1,187 patients with invasive breast cancer and compared disease characteristics among different groups according to ER and HER2 status. Age, tumor size, grade, nodal status, TNM stage, and metastatic sites were compared and significance determined using the appropriate t tests. All p values were two-tailed. Compared to ER-negative/HER2-negative disease as the control group, ER expression was associated with older age, smaller tumors, lower grade, earlier TNM stage, and increased bone involvement in de novo metastasis, while HER2 had no significant impact on these characteristics. ER and HER2 co-expression was associated with lower grade and higher bone involvement in de novo metastasis, reflecting a retained impact for ER. HER2 impact on ER-positive disease was reflected by younger age, higher grade and TNM stage, and increased frequency of visceral involvement in de novo metastasis. Within the ER-positive/HER2-positive group, triple positive breast cancer (ER+/PgR+/HER2+) was associated with younger age compared to ER+/PgR-/HER2+ disease (mean age of 50.8 vs. 56 years, p = 0.0226). PgR was also associated with younger age in ER+/HER2- disease with a mean age of 57.6 years in ER+/PgR+/HER2- disease vs. 63.4 years in ER+/PgR-/HER2- disease (p < 0.0001). In conclusion, ER has a profound impact on breast cancer characteristics, including a retained impact when co-expressed with HER2. Similarly, HER2 dramatically modulates ER-positive breast cancer making it more aggressive. PgR association with young age may be related to hormonal levels of the premenopausal state, with HER2 providing an earlier growth advantage in triple positive disease, suggesting a specific dependence for this subset on high estrogen levels.

Ki-67 Testing in Breast Cancer: Assessing Variability With Scoring Methods and Specimen Types and the Potential Subsequent Impact on Therapy Eligibility.

Abemaciclib was originally FDA approved for patients with ER-positive/HER2-negative breast cancer with Ki-67 expression ≥20%. However, there were no guidelines provided on which specimen to test or which scoring method to use. We performed a comprehensive study evaluating the variation in Ki-67 expression in breast specimens from 50 consecutive patients who could have been eligible for abemaciclib therapy. Three pathologists with breast expertise each performed a blinded review with 3 different manual scoring methods [estimated (EST), unweighted (UNW), and weighted (WT) (WT recommended by the International Ki-67 in Breast Cancer Working Group)]. Quantitative image analysis (QIA) using the HALO platform was also performed. Three different specimen types [core needle biopsy (CNB) (n=63), resection (RES) (n=52), and axillary lymph node metastasis (ALN) (n=50)] were evaluated for each patient. The average Ki-67 for all specimens was 14.68% for EST, 14.46% for UNW, 14.15% for WT, and 11.15% for QIA. For the manual methods, the range between the lowest and highest Ki-67 for each specimen between the 3 pathologists was 8.44 for EST, 5.94 for WT, and 5.93 for UNW. The WT method limited interobserver variability with ICC1=0.959 (EST ICC1=0.922 and UNW=0.949). Using the aforementioned cutoff of Ki-67 ≥20% versus <20% to determine treatment eligibility, the averaged EST method yields 20 of 50 patients (40%) who would have been treatment-eligible, versus 15 (30%) for the UNW, 17 (34%) for the WT, and 12 (24%) for the QIA. There was no statistically significant difference in Ki-67 among the 3 specimen types. The average Ki-67 difference was 4.36 for CNB vs RES, 6.95 for CNB versus ALN, and RES versus ALN (P=0.93, 0.99, and 0.94, respectively). Our study concludes that further refinement in Ki-67 scoring is advisable to reduce clinically significant variation.

Communication with physicians and family about breast Cancer recurrence.

Objective: Adequate physician-patient communication about cancer recurrence is vital to quality of life and to informed decision-making related to survivorship care. The current study was guided by a cognitive-affective framework to examine communication with family and physicians about breast cancer recurrence risk. Methods: A survey of recently-diagnosed, early-stage breast cancer patients in Appalachia investigated physician-patient and familial communication about breast cancer recurrence risk. Results: Over 30% of participants reported not talking to family or physicians about breast cancer recurrence risk. Younger patients reported more conversations, and speaking with physicians was associated with greater perception risk factors associated with recurrence risk. Greater worry about recurrence was associated with more communication with family and plans to talk to family, physicians, and friends about recurrence risk in the future. Conclusion: Additional supports for patients and physicians are needed to improve understanding of breast cancer recurrence risk and risk factors for recurrence. Innovation: Family communication about breast cancer recurrence risk is understudied. The combination of physician and family communication adds novelty to our analysis.

Phase Ib study of HSP90 inhibitor, onalespib (AT13387), in combination with paclitaxel in patients with advanced triple-negative breast cancer.

Background: Heat shock protein 90 (HSP90) is a molecular chaperone required for stabilization of client proteins over-activated in triple-negative breast cancer (TNBC). Over-expression of HSP90 client proteins has been implicated in paclitaxel resistance. Onalespib (AT13387) is a potent inhibitor of HSP90 that could improve paclitaxel efficacy when administered in combination. Design: This phase Ib trial administered onalespib with paclitaxel in patients with advanced TNBC to assess safety and establish a recommended phase II dose (RP2D). Objectives: The primary objectives were determining the dose-limiting toxicities and maximum tolerated dose of combination therapy. Secondary objectives included pharmacokinetic (PK) analysis and determination of overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS). Methods: Patients with advanced TNBC were treated with standard dose intravenous paclitaxel in combination with intravenous onalespib at doses ranging from 120 to 260 mg/m2 administered on days 1, 8, and 15 of a 28-day cycle using a standard 3 + 3 design. A total of 15 patients were enrolled to dose expansion cohort at RP2D to confirm safety profile. Results: Thirty-one patients were enrolled in the study, of which over 90% had received prior taxane therapy. Paclitaxel was given for metastatic disease in 23% of patients. Adverse events (AEs) included anemia (grade 3: 20%), lymphopenia (grade 3: 17%), and neutropenia (grade 3: 33%, grade 4: 4%). The most frequent grade ⩾3 non-hematologic AE was diarrhea (7%). The established RP2D was 260 mg/m2 onalespib when given with paclitaxel at 80 mg/m2. PK analysis revealed a modest drug interaction profile for onalespib in the combination regimen. ORR was 20%. Three patients achieved complete responses, all of whom had received prior taxane therapy. Median DOR was 5.6 months; median PFS was 2.9 months. Conclusion: Combination treatment with onalespib and paclitaxel had an acceptable toxicity profile and RP2D was determined to be 260 mg/m2 of onalespib. Combination therapy showed antitumor activity in patients with advanced TNBC. Trial registration: Onalespib and paclitaxel in treating patients with advanced TNBC https://clinicaltrials.gov/ct2/show/NCT02474173.

Phase 1b study of HSP90 inhibitor called onalespib in combination with paclitaxel in patients with advanced triple-negative breast cancer This Phase 1b study demonstrated that treatment with a combination of onalespib and paclitaxel was reasonably well tolerated by most patients. Onalespib at 260 mg/m² given intravenously on days 1, 8 and 15 on 28-day cycles in combination with standard dose and schedule of paclitaxel was established as the recommended phase 2 dose for further clinical development. Despite minor drug-drug interactions between these 2 agents, onalespib did not alter paclitaxel exposure and paclitaxel did not affect exposure to onalespib. While onalespib with paclitaxel combination therapy did not yield durable objective responses or prolonged progression-free survival, there were several patients with long-lasting benefit from this combination including patients who previously experienced progression on taxane therapy.

Plasma TNF-α and Soluble TNF Receptor Levels after Doxorubicin with or without Co-Administration of Mesna-A Randomized, Cross-Over Clinical Study.

PURPOSE: Chemotherapy-induced cognitive impairment (CICI) is a common sequelae of cancer therapy. Recent preclinical observations have suggested that CICI can be mediated by chemotherapy-induced plasma protein oxidation, which triggers TNF-α mediated CNS damage. This study evaluated sodium-2-mercaptoethane sulfonate (Mesna) co-administration with doxorubicin to reduce doxorubicin-induced plasma protein oxidation and resultant cascade of TNF-α, soluble TNF receptor levels and related cytokines. METHODS: Thirty-two evaluable patients were randomized using a crossover design to receive mesna or saline in either the first or second cycle of doxorubicin in the context of a standard chemotherapy regimen for either non-Hodgkin lymphoma or breast cancer. Mesna (360 mg/m2) or saline administration occurred 15 minutes prior and three hours post doxorubicin. Pre-treatment and post-treatment measurements of oxidative stress, TNF-α and related cytokines were evaluated during the two experimental cycles of chemotherapy. RESULTS: Co-administration of mesna with chemotherapy reduced post-treatment levels of TNF-related cytokines and TNF-receptor 1 (TNFR1) and TNF-receptor 2 (TNFR2) (p = 0.05 and p = 0.002, respectively). Patients with the highest pre-treatment levels of each cytokine and its receptors were the most likely to benefit from mesna co-administration. CONCLUSIONS: The extracellular anti-oxidant mesna, when co-administered during a single cycle of doxorubicin, reduced levels of TNF-α and its receptors after that cycle of therapy, demonstrating for the first time a clinical interaction between mesna and doxorubicin, drugs often coincidentally co-administered in multi-agent regimens. These findings support further investigation to determine whether rationally-timed mesna co-administration with redox active chemotherapy may prevent or reduce the cascade of events that lead to CICI. TRIAL REGISTRATION: clinicaltrials.gov NCT01205503.

A Narrative Review of the Confluence of Breast Cancer and Low-wage Employment and Its Impact on Receipt of Guideline-recommended Treatment.

Breast cancer is the leading cause of cancer among women in the United States, costing the healthcare system, employers, and society billions of dollars each year. Despite improvements in screening and treatment, significant breast cancer treatment and survivorship disparities exist among various groups of women. One variable that has not been explored extensively as a possible contributor to breast cancer treatment disparities is employment. This is concerning, given the changing economic and employment trends in the United States favoring low-wage employment. Currently, one-quarter to one-third of all US workers are considered to be working poor, and women are disproportionally represented in this group. Characteristics of low-wage work-limited paid time off, minimal health benefits, schedule inflexibility, and economic insecurity-may become even more significant in the event of a breast cancer diagnosis. To date, there has been limited research into how job conditions inherent to low-wage work may influence working poor survivors' receipt of guideline-recommended breast cancer treatment. Therefore, the purpose of this narrative review was to critically examine the current literature to further our understanding of how employment context may impact treatment decisions and adherence-and therefore receipt of guideline-recommended care-among newly diagnosed, working poor breast cancer survivors. After undertaking a comprehensive review, we failed to identify any published literature that explicitly addressed low-wage employment and receipt of guideline-recommended breast cancer treatment. Four articles reported circumstances where women delayed, missed, or quit treatments due to work interference, or alternatively, developed strategies that allowed them to continue to work and obtain their breast cancer treatment concurrent with medical and economic challenges. An additional five articles, while focused on other cancer and employment outcomes, described the need for increased patient-provider communication about the influence of work on treatment decisions and the development of alternative treatment plans. Due to the paucity of research in this area, future policy, practice, and research efforts should focus on the employment context of working poor breast cancer survivors as a potential contributor to cancer disparities. Engagement of women, employers, oncology providers, healthcare systems, and interdisciplinary researchers is warranted to improve cancer outcomes among this disparate population of working women.

SINOPSIS: El cáncer de mama es la principal causa de cáncer entre la mujeres en los Estados Unidos, que cuesta al sistema sanitario, a los empleadores y a la sociedad miles de millones de dólares cada año. A pesar de las mejoras en cuanto a detección y tratamiento, existen importantes desigualdades en el tratamiento del cáncer de mama y en la supervivencia entre diversos grupos de mujeres. Una variable que no se ha investigado en profundidad como posible factor que contribuye a las desigualdades en el tratamiento del cáncer de mama es el empleo. Es algo que resulta preocupante teniendo en cuenta el cambio en las tendencias económicas y laborales en los Estados Unidos, que favorece el empleo de baja remuneración. En la actualidad se considera que entre la cuarta y la tercera parte de todos los trabajadores estadounidenses son trabajadores pobres, y en este grupo las mujeres se encuentran representadas de manera desproporcionada. Las características del trabajo de baja remuneración (limitación del tiempo libre remunerado, prestaciones sanitarias mínimas, falta de flexibilidad en los horarios e inseguridad económica) pueden adquirir una importancia aún mayor en el caso de un diagnóstico de cáncer de mama. Hasta la fecha se ha llevado a cabo una investigación limitada en torno a cómo las condiciones laborales inherentes al trabajo de baja remuneración influyen sobre la recepción por las supervivientes que son trabajadoras pobres del tratamiento del cáncer de mama recomendado por las directrices. Por esa razón, el objetivo de esa revisión narrativa consistió en examinar con un punto de vista crítico la bibliografía actual para profundizar en nuestra comprensión sobre cómo el contexto laboral puede afectar a las decisiones en cuanto a tratamiento y al cumplimiento de este ­y por consiguiente a la recepción de la atención recomendada por las directrices­entre las supervivientes de cáncer de mama recientemente diagnosticadas que son trabajadoras pobres. Tras una exhaustiva revisión no fuimos capaces de identificar ninguna publicación que abordase explícitamente el empleo de baja remuneración y la recepción del tratamiento del cáncer de mama recomendado por las directrices. En cuatro artículos se informaba de circunstancias en que determinadas mujeres retrasaron, omitieron o abandonaron su tratamiento debido a la interferencia del trabajo o, alternativamente, desarrollaron estrategias que les permitían seguir trabajando y recibir su tratamiento para el cáncer de mama simultáneamente con los retos médicos y económicos. En otros cinco artículos, aunque se centraban en otros resultados en cuanto al cáncer y al empleo, se describía la necesidad de aumentar la comunicación entre pacientes y médicos en torno a la influencia del trabajo en las decisiones sobre el tratamiento y en la elaboración de planes alternativos de tratamiento. Debido a la falta de suficiente investigación en este ámbito, los esfuerzos políticos, prácticos y de investigación futuros se deberían centrar en el contexto laboral de las supervivientes de cáncer de mama que son trabajadoras pobres como posible factor que contribuye a las desigualdades en cuanto al cáncer. Está garantizado que la implicación de mujeres, emplead-ores, servicios de oncología, sistemas sanitarios e investigadores interdisciplinarios ha de mejorar los resultados del cáncer entre esta desigual población de mujeres trabajadoras.

Iron deficiency anemia.

The prevalence of iron deficiency anemia is 2 percent in adult men, 9 to 12 percent in non-Hispanic white women, and nearly 20 percent in black and Mexican-American women. Nine percent of patients older than 65 years with iron deficiency anemia have a gastrointestinal cancer when evaluated. The U.S. Preventive Services Task Force currently recommends screening for iron deficiency anemia in pregnant women but not in other groups. Routine iron supplementation is recommended for high-risk infants six to 12 months of age. Iron deficiency anemia is classically described as a microcytic anemia. The differential diagnosis includes thalassemia, sideroblastic anemias, some types of anemia of chronic disease, and lead poisoning. Serum ferritin is the preferred initial diagnostic test. Total iron-binding capacity, transferrin saturation, serum iron, and serum transferrin receptor levels may be helpful if the ferritin level is between 46 and 99 ng per mL (46 and 99 mcg per L); bone marrow biopsy may be necessary in these patients for a definitive diagnosis. In children, adolescents, and women of reproductive age, a trial of iron is a reasonable approach if the review of symptoms, history, and physical examination are negative; however, the hemoglobin should be checked at one month. If there is not a 1 to 2 g per dL (10 to 20 g per L) increase in the hemoglobin level in that time, possibilities include malabsorption of oral iron, continued bleeding, or unknown lesion. For other patients, an endoscopic evaluation is recommended beginning with colonoscopy if the patient is older than 50.