Real-World Analysis of the Clinical and Economic Impact of the 21-Gene Recurrence Score (RS) in Invasive Lobular Early-Stage Breast Carcinoma in Ireland.

Background: This study, using real-world data, assesses the impact of RS testing on treatment pathways and the associated economic consequences of such testing. This paper pertains to lobular breast cancer. Methods: A retrospective, observational study was undertaken between 2011 and 2019 on a cross-section of hormone receptor-positive (HR+), HER2-negative, lymph node-negative, early-stage breast cancer patients. All patients had ILC and had RS testing in Ireland. The patient population is representative of the national population. Patients were classified as low (RS ≤ 25) or high (RS > 25) risk. Patients aged ≤50 were stratified as low (RS 0-15), intermediate (RS 16-25), or high risk (RS > 25). Results: A total of 168 patients were included, most of whom had grade 2 (G2) tumors (n = 154, 92%). Overall, 155 patients (92.3%) had low RS (≤25), 12 (7.1%) had high RS (>25), and 1 (0.6%) had unknown RS status. In 29 (17.5%) patients aged ≤50 at diagnosis, RS was ≤15 in 16 (55%), 16-20 in 6 (21%), 21-25 in 5 (17%), >25 in 1 (3.5%), and unknown in 1 (3.5%). Post RS testing, 126 patients (78%) had a change in chemotherapy recommendation; all to hormone therapy. In total, only 35 patients (22%) received chemotherapy. RS testing achieved a 75% reduction in chemotherapy use, resulting in savings of €921,543.84 in treatment costs, and net savings of €387,283.84. Conclusions: The use of this test resulted in a 75% reduction in chemotherapy and a significant cost savings in our publicly funded health system.

Real-world outcomes and toxicity of adjuvant chemotherapy in NSCLC: a single-center experience.

Aim: Adjuvant chemotherapy in NSCLC is associated with modest benefits and significant toxicity. We sought to evaluate the toxicity of adjuvant chemotherapy and disease-specific outcomes in a real-world population. Methods: We performed a retrospective analysis of patients undergoing adjuvant chemotherapy for NSCLC in an Irish center over a 7-year period. We described treatment-associated toxicity, recurrence-free survival and overall survival. Results: 62 patients underwent adjuvant chemotherapy. Treatment-associated hospitalisation occurred in 29% of patients. Relapse was recorded in 56% of patients and median recurrence-free survival was 27 months. Conclusion: High rates of disease recurrence and treatment-associated morbidity were observed in patients receiving adjuvant chemotherapy for NSCLC. Novel therapeutic strategies are required to improve outcomes in this population.

Early NSCLC is primarily managed with lung cancer surgery. Chemotherapy is offered to some patients with early NSCLC after surgery depending on the size of the tumor and lymph node involvement. The benefit of post-surgery (adjuvant) chemotherapy in reducing the chance of cancer recurrence has been shown to be relatively small in previous studies. Large studies of post-surgery chemotherapy in NSCLC have included limited numbers of older patients, and patients with significant medical issues. This study looked to evaluate the safety and treatment-associated side effects of adjuvant chemotherapy in a group of patients more reflective of everyday clinical practice, and to assess the rates of cancer recurrence in these patients. In our study of 62 patients who underwent adjuvant chemotherapy for NSCLC, nearly 1 in 3 patients required hospital admission due to treatment-associated side effects. Almost 40% of patients experienced significant blood test abnormalities (including anaemia, reduced platelets, and reduced white blood cells). Approximately 1 in 4 patients required a reduction in the doses of their treatment due to treatment-associated side effects. More than half of the patients in our study experienced a recurrence of their cancer. Our study demonstrates the significant side effects associated with adjuvant chemotherapy in NSCLC and highlights the need for better-tolerated treatment strategies to reduce cancer recurrence in early NSCLC.

Timing of high-dose methotrexate CNS prophylaxis in DLBCL: a multicenter international analysis of 1384 patients.

Prophylactic high-dose methotrexate (HD-MTX) is often used for diffuse large B-cell lymphoma (DLBCL) patients at high risk of central nervous system (CNS) relapse, despite limited evidence demonstrating efficacy or the optimal delivery method. We conducted a retrospective, international analysis of 1384 patients receiving HD-MTX CNS prophylaxis either intercalated (i-HD-MTX) (n = 749) or at the end (n = 635) of R-CHOP/R-CHOP-like therapy (EOT). There were 78 CNS relapses (3-year rate 5.7%), with no difference between i-HD-MTX and EOT: 5.7% vs 5.8%, P = .98; 3-year difference: 0.04% (-2.0% to 3.1%). Conclusions were unchanged on adjusting for baseline prognostic factors or on 6-month landmark analysis (n = 1253). In patients with a high CNS international prognostic index (n = 600), the 3-year CNS relapse rate was 9.1%, with no difference between i-HD-MTX and EOT. On multivariable analysis, increasing age and renal/adrenal involvement were the only independent risk factors for CNS relapse. Concurrent intrathecal prophylaxis was not associated with a reduction in CNS relapse. R-CHOP delays of ≥7 days were significantly increased with i-HD-MTX vs EOT, with 308 of 1573 (19.6%) i-HD-MTX treatments resulting in a delay to subsequent R-CHOP (median 8 days). Increased risk of delay occurred in older patients when delivery was later than day 10 in the R-CHOP cycle. In summary, we found no evidence that EOT delivery increases CNS relapse risk vs i-HD-MTX. Findings in high-risk subgroups were unchanged. Rates of CNS relapse in this HD-MTX-treated cohort were similar to comparable cohorts receiving infrequent CNS prophylaxis. If HD-MTX is still considered for certain high-risk patients, delivery could be deferred until R-CHOP completion.

Spotlight on International Quality: COVID-19 and Its Impact on Quality Improvement in Cancer Care.

This report from ASCO's International Quality Steering Group summarizes early learnings on how the COVID-19 pandemic and its stresses have disproportionately affected cancer care delivery and its delivery systems across the world. This article shares perspectives from eight different countries, including Austria, Brazil, Ghana, Honduras, Ireland, the Philippines, South Africa, and the United Arab Emirates, which provide insight to their unique issues, challenges, and barriers to quality improvement in cancer care during the pandemic. These perspectives shed light on some key recommendations applicable on a global scale and focus on access to care, importance of expanding and developing new treatments for both COVID-19 and cancer, access to telemedicine, collecting and using COVID-19 and cancer registry data, establishing measures and guidelines to further enhance quality of care, and expanding communication among governments, health care systems, and health care providers. The impact of the COVID-19 pandemic on cancer care and quality improvement has been and will continue to be felt across the globe, but this report aims to share these experiences and learnings and to assist ASCO's international members and our global fight against the pandemic and cancer.

Combined, patient-level, analysis of two randomised trials evaluating the addition of denosumab to standard first-line chemotherapy in advanced NSCLC - The ETOP/EORTC SPLENDOUR and AMGEN-249 trials.

INTRODUCTION: The efficacy of adding denosumab to standard first-line chemotherapy for advanced NSCLC patients has been evaluated in two separate randomised trials (SPLENDOUR and AMGEN-249). In this pooled analysis, we will assess the combination-treatment effect in the largest available population, in order to conclude about the potential impact of denosumab in NSCLC. METHODS: Both trials included in this combined analysis, were randomised (SPLENDOUR 1:1, AMGEN-249 2:1) multi-centre trials stratified by histology, bone metastasis, geographical region and for SPLENDOUR only, ECOG PS. Cox proportional hazards models, were used to assess the treatment effect with respect to overall survival (OS; primary endpoint) and progression-free survival (PFS; secondary endpoint). Heterogeneity between trials was assessed, and subgroup analyses were performed. RESULTS: The pooled analysis was based on 740 randomised patients (SPLENDOUR:514; AMGEN-249:226), with 407 patients in the chemotherapy-denosumab arm and 333 in the chemotherapy-alone arm. In the chemotherapy-denosumab arm, at a median follow-up of 22.0 months, 277 (68.1%) deaths were reported with median OS 9.2 months (95%CI:[8.0-10.7]), while in the chemotherapy-alone arm, with similar median follow-up of 20.3 months, 230 (69.1%) deaths with median OS 9.9 months (95%CI:[8.2-11.2]). No significant denosumab effect was found (HR = 0.98; 95%CI:[0.82-1.18]; P = 0.85). Among subgroups, interaction was found between treatment and histology subtypes (P = 0.020), with a statistically significant benefit in the squamous group (HR = 0.70; 95%CI:[0.49-0.98]; P = 0.038), from 7.6 to 9.0 months median OS. With respect to PFS, 363 (89.2%) and 298 (89.5%) events were reported in the chemotherapy-denosumab and chemotherapy-alone arms, respectively, with corresponding medians 4.8 months (95%CI:[4.4-5.3]) and 4.9 months (95%CI:[4.3-5.4]). HR for PFS was 0.97(95%CI:[0.83-1.15]; P = 0.76), indicating that no significant denosumab benefit existed for PFS. CONCLUSION: In this pooled analysis, no statistically significant improvement was shown in PFS/OS with the combination of denosumab and chemotherapy for advanced NSCLC and no meaningful benefit in any of the subgroups.

Pregnancy-associated breast cancer: evaluating maternal and foetal outcomes. A national study.

PURPOSE: Pregnancy-associated breast cancer (PABC) is defined as breast cancer diagnosed during the gestational period (gp-PABC) or in the first postpartum year (pp-PABC). Despite its infrequent occurrence, the incidence of PABC appears to be rising due to the increasing propensity for women to delay childbirth. We have established the first retrospective registry study of PABC in Ireland to examine specific clinicopathological characteristics, treatments, and maternal and foetal outcomes. METHODS: This was a national, multi-site, retrospective observational study, including PABC patients treated in 12 oncology institutions from August 2001 to January 2020. Data extracted included information on patient demographics, tumour biology, staging, treatments, and maternal/foetal outcomes. Survival data for an age-matched breast cancer population over a similar time period was obtained from the National Cancer Registry of Ireland (NCRI). Standard biostatistical methods were used for analyses. RESULTS: We identified 155 patients-71 (46%) were gp-PABC and 84 (54%) were pp-PABC. The median age was 36 years. Forty-four patients (28%) presented with Stage III disease and 25 (16%) had metastatic disease at diagnosis. High rates of triple-negative (25%) and HER2+ (30%) breast cancer were observed. We observed an inferior 5-year overall survival (OS) rate in our PABC cohort compared to an age-matched breast cancer population in both Stage I-III (77.6% vs 90.9%) and Stage IV disease (18% vs 38.3%). There was a low rate (3%) of foetal complications. CONCLUSION: PABC patients may have poorer survival outcomes. Further prospective data are needed to optimise management of these patients.

Potentially inappropriate medication (PIM) use and severe drug interactions (SDIs) in older adults with cancer.

BACKGROUND: Older adults with cancer frequently have other co-morbidities requiring prescription pharmacotherapy. The objectives of this study were to identify the prevalence of potentially inappropriate medications (PIMs), severe drug interactions (SDIs) and associated risk factors in these patients. MATERIALS AND METHODS: This twelve-month prospective observation study was conducted at an Irish Hospital. PIMs were identified in older adults (≥65 years) using STOPP and OncPal criteria; potential SDIs using Stockley's interaction checker. RESULTS: We enrolled 186 patients; mean age 72.5(SD5.7) years, 46.2% female, mean co-morbidities 7.5(SD3.4), median medications 7(IQR4-9). Polypharmacy (≥6 medications) and major polypharmacy (≥11 medications) were identified in 60.8% and 17.7% respectively. STOPP PIMs were observed in 73.1%; median 2(IQR1-3). The most common PIM identified was any drug prescribed beyond the recommended duration (46.5%). For each additional prescription, the odds of receiving a STOPP PIM increased by 79.2% (OR 1.792, 95% CI 1.459-2.02). Potential SDIs were identified in 50.5% participants. The most common were beta-blocker/alpha-blocker (6.5%), selective-serotonin re-uptake inhibitor (SSRI)/proton pump inhibitor (PPI) (5.9%) and SSRI/Aspirin (4.8%). For each additional prescription, the odds of an SDI increased by 50.8% (OR 1.508, 95% CI 1.288-1.764). Seventy-seven (41.4%) participants died within six months of enrolment. OncPal PIMs were observed in 81.8% of this cohort, median 2(IQR1-3). The most common OncPal PIM was statin therapy (38%). For each additional prescription, the odds of receiving an OncPal PIM increased by 38.2%, (OR 1.382, 95% CI 1.080-1.767). CONCLUSIONS: PIMs and SDIs are common in this population. Comprehensive specialist evaluation of medications by a geriatrician may identify PIMs thereby reducing related adverse outcomes such as SDIs.

Assessing the Quality of Care Delivered to Transgender and Gender Diverse Patients with Cancer in Ireland: A Case Series.

INTRODUCTION: "Transgender" and "gender diverse" are umbrella terms encompassing those whose gender identities or expressions differ from those typically associated with the sex they were assigned at birth. There is scant global information on cancer incidence, outcome, and mortality for this cohort. This group may present with advanced cancer, have mistrust in health care services and report anxiety and depression at higher frequencies, a finding often seen in marginalized groups because of minority stress. MATERIALS AND METHODS: Medical oncologists were contacted by secure email to identify patients who self-identify as transgender and gender diverse in three Irish hospitals. Five patients were identified. A retrospective chart review was conducted and a pseudonymized patient survey was distributed. RESULTS: All patients included in our chart review (n = 5) were diagnosed with advanced disease on initial diagnosis. Two patients identified as men, two as women, and one as a transwoman. Two of five patients' health record charts reflected a name or gender change. Three patients had gender transitioning treatment postponed. Assessing comorbidities, it was seen that four patients required psychiatry input. Predominant issues noted in our patient survey by the two respondents (n = 2) were "mis-gendering," lack of a gender-neutral hospital environment, lack of inclusion in cancer groups, and barriers in changing name and/or sex on hospital records. CONCLUSION: Components of care requiring revision include patient accessible pathways to change names and gender on health records, earlier access to psychological support and targeted screening and support groups. Resources for hospital staff to improve awareness of correct terminology and to provide gender neutral facilities are worthwhile. IMPLICATIONS FOR PRACTICE: The implications for practice on an international level include patient-friendly pathways for changing hospital name and gender so that patients may feel comfortable using wristbands. The need for international screening guidelines for transgender patients and national transgender cancer support groups is highlighted. On a day-to-day level for providers, the correct use of pronouns makes a big difference to patients. Asking about preferred pronoun on first visit and noting on patient's file is worthwhile. It is important for providers to know that increased psychological support should be offered early on first clinic visit and engaged with as necessary when patient has a history of anxiety or depression. Providers should discuss openly that some gender transitioning treatment will be postponed because of cancer care and refer to both the physical and psychological sequelae of this. Asking transgender patients which room or bathroom they would prefer when rooms are gendered is essential.

Efficacy and tolerability of metronomic chemotherapy in patients with metastatic breast cancer - an international experience in West Sweden and in the South of Ireland.

INTRODUCTION: Metronomic chemotherapy (MCT) is the continuous administration of low dose chemotherapy. It has significant clinical efficacy with minimal toxicity as compared to conventional chemotherapy regimens. Thus represents an attractive treatment modality in selected patients with advanced breast cancer. METHODS: Patients who received MCT in the form of Capecitabine/Cyclophosphamide for the treatment of advanced breast cancer between May 2014 and October 2018 in Sahlgrenska University Hospital in Sweden and in Cork University Hospital, University Hospital Kerry and the South Infirmary-Victoria University Hospital in Ireland were identified. Medical records were retrospectively reviewed to collect data. All survival analyses were described by Kaplan-Meier curves and analysed with log-rank tests. The primary end-point was time on treatment, used as a surrogate marker for efficacy. RESULTS: 148 patients were identified (84 - Sweden, 64 - Ireland), with a median age of 64.2 (range 31-89). The overall mean time on treatment for all patients in both countries is 9.05 months (range 0.36 - 67.21). In patients with bone only disease the mean time on treatment was 10.1 months (range 0.7 - 67.2), compared to patients with visceral disease of 8.91 months (range 0.36 - 39.77). Treatment was ended in the majority of patients because of progression of disease, representing 108 patients (72.9%). CONCLUSION: This is an observational, retrospective study demonstrating the real world effectiveness of MCT in the treatment of advanced breast cancer. In this cohort of unselected pre-treated patients, the efficacy of MCT was comparable with the survival outcomes of landmark clinical trials.

European practice patterns and barriers to smoking cessation after a cancer diagnosis in the setting of curative versus palliative cancer treatment.

BACKGROUND: Smoking cessation after a cancer diagnosis is associated with improved overall survival. Few studies have reported oncologists' cessation practice patterns, but differences between the curative and palliative settings have not been described. We aimed to study the oncologist's perceptions on patients' tobacco use, current practices and barriers to providing smoking cessation support, while distinguishing between treatment with curative (C) and palliative (P) intent. METHODS: In 2019, an online 34-item survey was sent to approximately 6235 oncologists from 16 European countries. Responses were descriptively reported and compared by treatment setting. RESULTS: Responses from 544 oncologists were included. Oncologists appeared to favour addressing tobacco in the curative setting more than in the palliative setting. Oncologists believe that continued smoking impacts treatment outcomes (C: 94%, P: 74%) and that cessation support should be standard cancer care (C: 95%, P: 63%). Most routinely assess tobacco use (C: 93%, P: 78%) and advise patients to stop using tobacco (C: 88%, P: 54%), but only 24% (P)-39% (C) routinely discuss medication options, and only 18% (P)-31% (C) provide cessation support. Hesitation to remove a pleasurable habit (C: 13%, P: 43%) and disbelieve on smoking affecting outcomes (C: 3%, P: 14%) were disparate barriers between the curative and palliative settings (p < 0.001), but dominant barriers of time, resources, education and patient resistance were similar between settings. CONCLUSION: Oncologists appear to favour addressing tobacco use more in the curative setting; however, they discuss medication options and/or provide cessation support in a minority of cases. All patients who report current smoking should have access to evidence-based smoking cessation support, also patients treated with palliative intent given their increasing survival.

Survival of childhood and adolescent/young adult (AYA) cancer patients in Ireland during 1994-2013: comparisons by age.

BACKGROUND: Some studies indicate that survival of adolescents and young adults (AYA) with cancer may be inferior to that of younger children with similar cancers, possibly related (in part) to differences in access to centralized or standardized treatment. AIMS: This study aims to evaluate differences in survival for AYA patients when compared with paediatric patients treated in Ireland over a 20-year time period. METHODS: This study compares relative survival for patients diagnosed in Ireland at ages 0-15 (paediatric group) and 16-24 (AYA group) during 1994-2013, followed to the end of 2014, for cancers defined by the International Classification of Childhood Cancer (ICCC) (Third Edition) group or subgroup. Five-year relative survival estimates, and excess hazard ratios (EHR) comparing excess mortality associated with a cancer diagnosis among AYA with that in the paediatric group, are presented. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. RESULTS: Significantly higher excess mortality was found for AYA with leukaemias, lymphomas, astrocytomas, malignant bone tumours, and Ewing and related bone sarcomas, soft tissue sarcomas and 'other/unspecified' epithelial cancers, rhabdomyosarcomas, and 'other and unspecified' carcinomas. In contrast, lower excess mortality was found in the AYA group for all cancers and intracranial/intraspinal tumours, and for gliomas other than astrocytomas or ependymomas. Comparing 1994-2003 and 2004-2013 cohorts, age-related survival differences narrowed for lymphoid leukaemias, but widened for all cancers combined and intracranial/intraspinal tumours combined. Centralization of services varied depending upon cancer subtype, with leukaemias, CNS tumours and bone sarcomas most centralized. Within these, improvements in survival for leukaemias and CNS tumours have been seen for the AYA population. CONCLUSIONS: Reasons for age-related survival differences, and differences in time-trend by age group, are not clear. The significant narrowing of survival differences by age in more recent years for lymphoid leukaemias reflects a more marked recent increase in survival among AYA. More work is required to explain and improve other age-related survival differences.

Adverse Drug Reactions in an Oncological Population: Prevalence, Predictability, and Preventability.

BACKGROUND: Our goal was to determine (a) the prevalence of multimorbidity and polypharmacy in patients with cancer and (b) the prevalence, predictability, and preventability of adverse drug reactions (ADRs) causing/contributing to hospitalization. MATERIALS AND METHODS: We conducted a 12-month prospective observational study of patients aged ≥16 years admitted to an oncology center. Older adults were aged ≥70 years. RESULTS: We enrolled 350 patients: 52.3% (n = 183) female, mean age 63.6 years (SD 12.1), 36.6% (n = 121) aged ≥70 years. Multimorbidity (≥2 conditions) was identified in 96.9%; 68% had ≥5 conditions. The median number of medications was 6 (interquartile range [IQR] 4-8); 47% were prescribed ≥6 medications and 11.4% ≥11 medications. Older adults had higher numbers of comorbid conditions (7 [IQR 5-10] vs. 5 [IQR 3-7]) and were prescribed more medications (median 7 [IQR 4-9] vs. 4 [IQR 2-7]). ADRs caused/contributed to hospitalization in 21.5% (n = 75): 35.8% (n = 72) of emergency admissions and 4.7% (n = 3) of elective admissions. The most common ADRs were neutropenia with infection (25.3%), dyspepsia/nausea/vomiting (20%), and constipation (20%). Causative medications included systemic anticancer therapies (SACTs; 53.3%), opioids (17.3%), corticosteroids (6.7%), and nonsteroidal anti-inflammatory drugs (5.3%). ADR prevalence was similar in older and younger adults secondary to SACTs (8.3% vs. 13.1%), non-cancer medications (10.7% vs. 8.3%), and both (0% vs. 1.3%). ADRs were predictable in 89.3% (n = 67), definitely avoidable in 29.3% (n = 22), and possibly avoidable in 33.3% (n = 25). No association was identified between ADRs and age, gender, daily medication number, length of stay, or death. No ADR predictor variables were identified by logistic regression. CONCLUSION: More than 21% of admissions to an oncology service are ADR-related. ADRs are caused by both SACTs and non-cancer-specific medications. The majority are predictable; ≥60% may be preventable. Patients with cancer have high levels of multimorbidity and polypharmacy, which require vigilance for related adverse outcomes. IMPLICATIONS FOR PRACTICE: A diagnosis of cancer often occurs in patients with multimorbidity and polypharmacy. Cancer can cause an altered physiological environment, placing patients at risk of drug-drug interactions, drug-disease interactions, and adverse drug reactions (ADRs). This study identified that ADRs caused or contributed to one in five hospital admissions of patients with cancer. ADRs were caused by systemic anticancer therapies (SACTs) in 53.3% of cases and non-cancer medications in 45.4% of cases, and a combination of both in 1.3%. ADRs occurred in similar frequencies in older and younger patients secondary to SACTs (8.3% vs. 13.1%, p = .295), non-SACTs (10.7% vs. 8.3%, p = .107), and a combination of both (0% vs. 1.3%, p = .240). The majority of ADRs were predictable (89.3%) and potentially preventable (62.6%). These findings support the need for increased awareness of medication-related adversity in patients with cancer and interventions to minimize their occurrence, thus supporting the American Society of Clinical Oncology guidelines that recommend adults ≥65 years of age receiving chemotherapy have geriatric assessment to identify medical and medication issues.

Co-occurrence of EGFR sensitising and resistance mutations at diagnosis in NSCLC.

BACKGROUND: De novo epidermal growth factor receptor (EGFR) resistance mutations in tyrosine kinase inhibitor-naïve patients are rare when assessed by standard genotyping methods. METHODS: Patients with EGFR mutations were identified using PCR-based fragment length analysis, mass spectrometry-based genotyping (Sequenom), and Sanger sequencing. RESULTS: From 2008 to 2015, we observed de novo EGFR resistance mutations in 12.8 patients who received an EGFR TKI with an overall response rate of 25%, median PFS 24 months, and median OS 34 months. Five patients (63%) received erlotinib in the first-line setting with a 60% disease control rate (DCR) and a median duration of response of 6 months (range 4-45 months). Three (37%) received cytotoxic chemotherapy in the first-line setting with 67% DCR and a median duration of response of 11 months (range 10-12 months). In patients with de novo EGFR T790M mutations, 50% (2/4) had stable disease with one patient having an ongoing response to erlotinib of over 96 months. In patients with de novo EGFR S768I mutations who received erlotinib, 50% (2/4) have ongoing partial responses at 30 and 6 months. CONCLUSION: This is the largest Irish review of de novo synchronous EGFR mutations. The incidence of co-occurring EGFR mutations in our cohort of non-small cell lung carcinoma (NSCLCA) is 1% on routine assays. Erlotinib appears to have activity in this cohort in both in the first- and second-line setting. De novo S768I and T790M represent distinct clinical entities. For de novo T790M mutations cytotoxic chemotherapy may still be considered first line. For de novo S768I mutations, erlotinib appears to be a reasonable therapeutic option.

Evaluation of Discordance in Primary Tumor and Lymph Node Response After Neoadjuvant Therapy in Breast Cancer.

BACKGROUND: Neoadjuvant therapy (NAT) offers a unique opportunity to assess tumor response to systemic agents. However, a discrepancy may exist between the response of the primary tumor and involved nodes. We report on the frequency of response discordance after NAT in breast cancer. PATIENTS AND METHODS: All consecutive node-positive patients receiving NAT in our department from 2009 to 2014 were identified. Patient demographics, and radiologic and pathologic features were tabulated. Tumor response was estimated by magnetic resonance imaging of the breast. Lymph node (LN) response was estimated from pathologic treatment response measurements. Statistical analysis was performed. RESULTS: A total of 108 node-positive patients treated with NAT were eligible for inclusion. Median age was 51.73 years (range, 20-87 years). All patients underwent axillary clearance, and 62% underwent mastectomy. A 40% mean reduction in tumor size was observed. Statistically, a positive correlation between tumor and LN response after NAT was observed (Spearman correlation coefficient, r = 0.46, P < .001). Complete pathologic response was observed in 17 patients (15.7%). However, 21 patients experienced complete LN response, with only 81% of these patients (n = 17) experiencing a complete response in tumor also. A complete response was observed in tumor in 20 patients, and this predicted complete nodal response in 85% of cases (n = 17). Fifteen percent of primary tumors with complete pathologic response had persistently positive LNs. CONCLUSION: A significant discordance exists between the primary tumor and LN response, representing a concern for the lack of response of occult regional or systemic metastases due to potential biologic heterogeneity.

Phase II Study of Alemtuzumab (CAMPATH-1) in Patients with HTLV-1-Associated Adult T-cell Leukemia/lymphoma.

PURPOSE: Therapeutic regimens for adult T-cell leukemia/lymphoma (ATL) are limited with unsatisfactory results, thereby warranting development of novel therapies. This study investigated antitumor activity and toxicity of alemtuzumab with regard to response, duration of response, progression-free survival, and overall survival in patients with human T-cell lymphotropic virus-1 (HTLV-1)-associated ATL. EXPERIMENTAL DESIGN: Twenty-nine patients with chronic, acute, and lymphomatous types of ATL were enrolled in a single-institution, nonrandomized, open-label phase II trial wherein patients received intravenous alemtuzumab 30 mg three times weekly for a maximum of 12 weeks. RESULTS: Twenty-nine patients were evaluable for response and toxicity. The overall objective response was 15 of 29 patients [95% confidence interval (CI), 32.5%-70.6%]. The 15 patients who responded manifested a median time to response of 1.1 months. Median response duration was 1.4 months for the whole group and 14.5 months among responders. Median progression-free survival was 2.0 months. Median overall survival was 5.9 months. The most common adverse events were 2 with vasovagal episodes (7%) and 3 with hypotensive episodes (10%), leukopenia (41%) grade 3 and (17%) grade 4, lymphocytopenia (59%) grade 3, neutropenia (31%) grade 3, anemia (24%), and thrombocytopenia (10%). All patients developed cytomegalovirus antigenemia (CMV). Three were symptomatic and all responded to antiviral therapy. Grade 3 or 4 infections were reported in 4 (14%) of patients. CONCLUSIONS: Alemtuzumab induced responses in patients with acute HTLV-1-associated ATL with acceptable toxicity, but with short duration of responses. These studies support inclusion of alemtuzumab in novel multidrug therapies for ATL. Clin Cancer Res; 23(1); 35-42. ©2016 AACR.

90Y-daclizumab, an anti-CD25 monoclonal antibody, provided responses in 50% of patients with relapsed Hodgkin's lymphoma.

Despite significant advances in the treatment of Hodgkin's lymphoma (HL), a significant proportion of patients will not respond or will subsequently relapse. We identified CD25, the IL-2 receptor alpha subunit, as a favorable target for systemic radioimmunotherapy of HL. The scientific basis for the clinical trial was that, although most normal cells with exception of Treg cells do not express CD25, it is expressed by a minority of Reed-Sternberg cells and by most polyclonal T cells rosetting around Reed-Sternberg cells. Forty-six patients with refractory and relapsed HL were evaluated with up to seven i.v. infusions of the radiolabeled anti-CD25 antibody (90)Y-daclizumab. (90)Y provides strong ß emissions that kill tumor cells at a distance by a crossfire effect. In 46 evaluable HL patients treated with (90)Y-daclizumab there were 14 complete responses and nine partial responses; 14 patients had stable disease, and nine progressed. Responses were observed both in patients whose Reed-Sternberg cells expressed CD25 and in those whose neoplastic cells were CD25(-) provided that associated rosetting T cells expressed CD25. As assessed using phosphorylated H2AX (γ-H2AX) as a bioindicator of the effects of radiation exposure, predominantly nonmalignant cells in the tumor microenvironment manifested DNA damage, as reflected by increased expression of γ-H2AX. Toxicities were transient bone-marrow suppression and myelodysplastic syndrome in six patients who had not been evaluated with bone-marrow karyotype analyses before therapy. In conclusion, repeated (90)Y-daclizumab infusions directed predominantly toward nonmalignant T cells rosetting around Reed-Sternberg cells provided meaningful therapy for select HL patients.

18F-fluorodeoxyglucose Positron Emission Tomography in Kaposi Sarcoma Herpesvirus-Associated Multicentric Castleman Disease: Correlation With Activity, Severity, Inflammatory and Virologic Parameters.

BACKGROUND: Kaposi sarcoma herpesvirus (KSHV)-associated multicentric Castleman disease (MCD) is a lymphoproliferative inflammatory disorder commonly associated with human immunodeficiency virus (HIV). Its presentation may be difficult to distinguish from HIV and its complications, including lymphoma. Novel imaging strategies could address these problems. METHODS: We prospectively characterized (18)F-fluorodeoxyglucose positron emission tomography (PET) findings in 27 patients with KSHV-MCD. Patients were imaged with disease activity and at remission with scans evaluated blind to clinical status. Symptoms, C-reactive protein level, and HIV and KSHV loads were assessed in relation to imaging findings. RESULTS: KSHV-MCD activity was associated with hypermetabolic symmetric lymphadenopathy (median maximal standardized uptake value [SUVmax], 6.0; range, 2.0-8.0) and splenomegaly (3.4; 1.2-11.0), with increased metabolism also noted in the marrow (2.1; range, 1.0-3.5) and salivary glands (3.0; range, 2.0-6.0). The (18)F-fluorodeoxyglucose PET abnormalities improved at remission, with significant SUVmax decreases in the lymph nodes (P = .004), spleen (P = .008), marrow (P = .004), and salivary glands (P = .004). Nodal SUVmax correlated with symptom severity (P = .005), C-reactive protein level (R = 0.62; P = .004), and KSHV load (R = 0.54; P = .02) but not HIV load (P = .52). CONCLUSIONS: KSHV-MCD activity is associated with (18)F-FDG PET abnormalities of the lymph nodes, spleen, marrow, and salivary glands. These findings have clinical implications for the diagnosis and monitoring of KSHV-MCD and shed light on its pathobiologic mechanism.

Rituximab plus liposomal doxorubicin in HIV-infected patients with KSHV-associated multicentric Castleman disease.

Kaposi sarcoma (KS) herpesvirus-associated multicentric Castleman disease (KSHV-MCD) is a lymphoproliferative disorder, most commonly seen in HIV-infected patients, that has a high mortality if untreated. Concurrent KS is common. Although rituximab has reported activity in KSHV-MCD, its use is often associated with KS progression. Within a natural history study of KSHV-MCD, we prospectively evaluated rituximab 375 mg/m(2) combined with liposomal doxorubicin 20 mg/m(2) (R-Dox) every 3 weeks in 17 patients. Patients received a median of 4 cycles (range 3-9). All received antiretroviral therapy, 11 received consolidation interferon-α, and 6 received consolidation high-dose zidovudine with valganciclovir. Using NCI KSHV-MCD response criteria, major clinical and biochemical responses were attained in 94% and 88% of patients, respectively. With a median 58 months' potential follow-up, 3-year event-free survival was 69% and 3-year overall survival was 81%. During R-Dox therapy, cutaneous KS developed in 1 patient, whereas 5 of 6 patients with it had clinical improvement. R-Dox was associated with significant improvement in anemia and hypoalbuminemia. KSHV viral load, KSHV viral interleukin-6, C-reactive protein, human interleukin-6, and serum immunoglobulin free light chains decreased with therapy. R-Dox is effective in symptomatic KSHV-MCD and may be useful in patients with concurrent KS. This trial was registered at www.clinicaltrials.gov as #NCT00092222.

Human and viral interleukin-6 and other cytokines in Kaposi sarcoma herpesvirus-associated multicentric Castleman disease.

Kaposi sarcoma herpesvirus (KSHV)-associated multicentric Castleman disease (MCD) is a polyclonal B-cell lymphoproliferative disorder. Human (h) IL-6 and a KSHV-encoded homolog, viral IL-6, have been hypothesized to contribute to its pathogenesis, but their relative contributions to disease activity is not well understood. We prospectively characterized KSHV viral load (VL), viral (v) and hIL-6, and other cytokines during KSHV-MCD flare and remission in 21 patients with 34 flares and 20 remissions. KSHV-VL, vIL-6, hIL-6, IL-10, and to a lesser extent TNF-α, and IL-1ß were each elevated during initial flares compared with remission. Flares fell into 3 distinct IL-6 profiles: those associated with elevations of vIL6-only (2 flares, 6%), hIL-6 elevations only (17 flares, 50%), and elevations in both hIL-6 and vIL-6 (13 flares, 38%). Compared with hIL-6-only flares, flares with elevated hIL-6 plus vIL-6 exhibited higher C-reactive protein (CRP) (P = .0009); worse hyponatremia (P = .02); higher KSHV VL (P = .016), and higher IL-10 (P = .012). This analysis shows vIL-6 and hIL-6 can independently or together lead to KSHV-MCD flares, and suggests that vIL-6 and hIL-6 may jointly contribute to disease severity. These findings have implications for the development of novel KSHV-MCD therapies targeting IL-6 and its downstream signaling. This trial was registered at clinicaltrials.gov as #NCT099073.