bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I trial of panobinostat with ipilimumab in advanced melanoma.
Authors: Khushalani Nikhil I. , Markowitz Joseph , Eroglu Zeynep , Giuroiu Iulia , Ladanova Viktoriya , Reiersen Pamela , Rich Jeani , Thapa Ram , Schell Michael J. , Sotomayor Eduardo M. , Weber Jeffrey S.
Published: September 2018

9547

Background: Immune checkpoint blockade is standard therapy for advanced melanoma (MEL), yet not all patients (pts) benefit. Panobinostat (PAN), a pan inhibitor of class I, II, and IV histone deacetylases (HDAC) is immunomodulatory, decreases tumor associated inhibitory cytokines and inhibition of effector T-cells. This dose finding study aimed to determine the safety and efficacy of escalating doses of PAN combined with ipilimumab (IPI) in advanced MEL. Methods: Eligible pts with unresectable stage 3/4 MEL, up to 3 prior lines of therapy, and adequate laboratory values were treated with oral PAN 5mg thrice weekly (TIW) plus IPI at 3mg/kg IV every 3 weeks X 4 doses, followed by maintenance PAN until progression or intolerance. Using a modified Ji design, PAN dose escalation by 5mg was planned in 3-12 pt cohorts up to a maximum dose of 20mg TIW, without intra-pt dose escalation. Dose limiting toxicity (DLT) was assessed up to day 84 from start of therapy. Results: Seventeen pts (M/F: 13/4), median age 66 yrs (48, 80) were treated with a median of 4 cycles of IPI (1,4). Of 6 pts treated at PAN 5mg TIW, there was one DLT (G3 hydronephrosis). Eleven pts received PAN 10mg TIW; of 9 evaluable for DLT, there were 3 DLTs (G3 rash, G3 diarrhea, G4 thrombocytopenia) preventing further dose escalation. Other G3 toxicities included anemia, hypophysitis, diarrhea, fatigue (all n = 2); rash, colitis, nausea, dehydration, dizziness, hypotension, ↑ lipase, ↓ sodium, & ↑ glucose (all n = 1). Three pts had previous anti-PD1 therapy. The response rate was 12% (2 PRs) with 35% stable disease. One pt remains on PAN > 24m since start of therapy. Median progression free- and overall survival was 2.23m (95% CI,1.57, 5.8) and 20.97m (95% CI, 8.97, NR) respectively. Biomarker analysis from peripheral blood and limited tumor biopsies pre-and on treatment examining immunoregulatory markers, including EOMES promoter acetylation in T-cells from PAN are ongoing. Conclusions: At tolerated doses, PAN does not appear to increase response to standard IPI in advanced MEL. Biomarker analyses will inform if immunomodulation by PAM improves efficacy of IPI. Combinations with selective HDAC inhibitors may be more appropriate for future study. Supported by grant P50 CA168536, Moffitt Skin Cancer SPORE. Clinical trial information: NCT02032810.
Surveillance imaging with FDG-PET/CT in the post-operative follow-up of stage 3 melanoma.
Authors: Sayers Louise , Lewin Jeremy Howard , Kee Damien , Walpole Imogen , Sanelli Alexandra , Herschtal Alan , Spillane John , Gyorki David E. , Speakman David , Estall Vanessa , Donahoe Simon , Pohl Miklos , Pope Kathy , Chua Margaret , Sandhu Shahneen Kaur , McArthur Grant A. , McCormack Christopher , Henderson Michael A. , Hicks Rodney J , Shackleton Mark J.
Published: September 2018

9563

Background: With the evolving treatment landscape in metastatic melanoma, approaches to disease surveillance post resection in stage 3 disease requires reconsideration. We previously reported the outcomes of sub-stage-specific schedules of combined fluorodeoxyglucose-positron emission and computerized tomography (PET/CT) surveillance at high risk of relapse following surgery. The aim of this study was to provide an update on our surveillance protocol with an extended sample size and longer duration of follow-up. Methods: From 2009, patients with AJCC stage 3 melanoma underwent PET/CT scans according to pre-specified schedules based on Bayesian probabilities of sub-stage-specific relapse. Schedules were stage 3A: 6, 18 mo; stage 3B: 6, 12, 18, 24, 36, 48, 60 months; stage 3C: 6, 12, 18, 24, 36 months. Contingency tables were used to evaluate the sensitivity, specificity and predictive values of these schedules. Results: In total, 171 patients (3A: 34; 3B: 93; 3C:44) underwent 553 PET/CT scans with a median follow up of 47 months. Relapses were identified in 65 (38%) patients of which (72%) were asymptomatic at the time of radiologically documented relapse. False positive results occurred in 8%. The positive predictive value (PPV) of an individual scan for diagnosing true recurrence was 77% (64-87%). Negative scans at 6 months had negative predictive values (NPV) between 57% in Stage 3A to 69% in Stage 3B for relapse. Sensitivity and specificity of the overall approach of sub-stage-specific PET/CT surveillance for detecting disease relapse were 70% and 89%, respectively. Evaluable predictive values for detecting disease relapse were: stage 3A: PPV:56%, NPV:76%; 3B: PPV 83%, NPV 86%; stage 3C: PPV 84%, NPV 84%. 32 of 65 patients (49%; 3A: 1; 3B: 7; 3C: 2) underwent resection of relapsed disease and 10 of these patients remained free of disease with a median follow-up of 24 months. Conclusions: Sub-stage-specific PET/CT is effective in detecting asymptomatic recurrence in stage 3 melanoma, and is associated with a high rate of disease resection at relapse.
Clinicopathologic features and survival in immunocompromised vs. immunocompetent patients with Merkel cell carcinoma: An exploratory analysis of a series of consecutive patients.
Authors: Del Rosario Michael , Anderson Eric , Lu Yani , Farrell Stephanie , Plaxe Steven C. , Dasanu Constantin
Published: September 2018

9568

Background: Clinicopathologic characteristics and outcomes between immunocompromised and immunocompetent Merkel cell carcinoma (MCC) patients may differ. Methods: With approval of IRB, we conducted retrospective analysis in 40 consecutive patients with MCC treated at our institution in 2006-2016. 10 patients were immunocompromised and 30 immunocompetent. Immunosuppressed patients included patients with organ transplantation (n = 3), chronic lympocytic leukemia (n = 2), metastatic skin cancer post chemotherapy (n = 1), rheumatoid arthritis on azathioprine (n = 1), myasthenia gravis on mycophenolate mofetil (n = 1), follicular lymphoma post chemotherapy (n = 1) and human immunodeficiency virus infection (n = 1). Clinicopathologic features, therapy and survival were compared between two cohorts. Significance of associations was assessed via Fishers' exact test. Survival analysis was performed via Cox proportional model and 95% confidence intervals (CI). Results: Compared to immunocompetent MCC patients, the immunocompromised had an absolute male predominance (100% vs. 67%; p < 0.01), more TNM stage III disease (40% vs. 33%; p = 0.021) but less lymphovascular invasion (30% vs. 7%; p < 0.01). They received more chemotherapy (50% vs. 30%; p < 0.01) and radiation therapy (80% vs 57%; p < 0.01). Survival was worse in immunocompromised subjects (average time to death 290.13 days vs. 618.2 days (p < 0.001), and they were 5 times more likely to die (RR = 5.01, 95% CI = 1.49-16.86). Conclusions: Immunocompromised MCC patients displayed significantly shorter survival than their immunocompetent counterparts. They were all male, with more advanced disease but less lymphovascular invasion. They received more chemo- and radiotherapy presumably due to a more advanced stage. As our study is limited by sample size, larger studies are needed to confirm the significance of our findings.
Performance of a 31-gene expression profile (GEP) test for metastatic risk prediction in cutaneous melanomas (CM) of the head and neck.
Authors: Vetto John T. , Leachman Sancy Ann , Middlebrook Brooke , Covington Kyle R. , Wayne Jeffrey D. , Gerami Pedram , Zager Jonathan S.
Published: September 2018

9576

Background: Accurate prognostication of distant metastatic risk using sentinel lymph node (SLN) biopsy for CM can be challenging in melanomas of the head and neck due to a higher false negative rate compared to other anatomical areas. A GEP signature that predicts metastatic risk based on primary tumor biology, providing a binary outcome of Class 1 (low risk of metastasis) or Class 2 (high risk), was previously described. The prognostic capabilities of the GEP independently and in combination with SLN status in a cohort of patients with primary head and neck CM are assessed here. Methods: All samples and clinical data were collected under an IRB-approved multicenter protocol. qPCR analysis was used to assess expression of the gene signature (Class 1 vs. Class 2). Distant metastasis-free survival (DMFS) and melanoma-specific survival (MSS) were assessed. Results: 157 subjects with primary CMs in the head and neck region were identified. 110 of 157 subjects had a SLN biopsy performed. Median age was 65 years (range 25-89) and median Breslow depth was 1.6 mm (range 0.2-15.0 mm). In 71 SLN-negative patients, 18 of 27 (67%) distant metastatic events were GEP Class 2. Overall, 73% (47 of 64) distant metastases, and 88% (22 of 25) deaths due to CM were called Class 2. By comparison, sensitivities for DMFS and MSS were 41% (26 of 64) and 52% (13 of 25), respectively, using SLN biopsy alone, and increased to 80% (51 of 64) and 88% (22 of 25), respectively, when combining the SLN status and GEP class. Kaplan-Meier 5-year DMFS and MSS rates based on SLN status alone or in combination with GEP are shown in the table. Conclusions: These data support the ability of the GEP test to accurately identify low- and high-risk cases of head and neck melanoma. The results strongly support the role of GEP testing to enhance current staging by better predicting the risk of distant metastasis and death for patients with melanoma in an anatomic region that is associated with a higher SLN biopsy false negative rate. [Table: see text]
Neoadjuvant ipilimumab + nivolumab (IPI+NIVO) in palpable stage III melanoma: Updated data from the OpACIN trial and first immunological analyses.
Authors: Rozeman Elisa A. , Blank Christian U. , Van Akkooi Alexander Christopher Jonathan , Kvistborg Pia , Fanchi Lorenzo , Van Thienen Johannes V. , Stegenga Bauke , Lamon Brian , Haanen John B. A. G. , Schumacher Ton
Published: September 2018

9586

Background: The combination of IPI+NIVO induces high response rates and improved overall survival in late stage melanoma. T cell checkpoint inhibition is of greatest value at the moment of TCR triggering and therefore dependent on the amount of antigen present, indicating that adjuvant immunotherapy may work most efficiently, when initiated prior to surgery. Methods: Two-arm Phase 1b feasibility trial of 20 high risk AJCC stage IIIB and IIIC melanoma patients with palpable nodal disease receiving the combination of IPI 3mg/kg and NIVO 1mg/kg, either adjuvant four courses after surgery, or split two courses neo-adjuvant and two courses adjuvant. Results: In this update all 20 patients are evaluable. Neo-adjuvant application of IPI+NIVO was feasible and no surgery-associated adverse events were attributed to (neo-)adjuvant therapy. 18/20 patients had to stop early due to grade 3/4 toxicities. Neo-adjuvant IPI+NIVO reduced tumor load in 8/10 patients (3 pCR, 4 near-pCRs [minimal remaining micrometastases], 1 pPR [75% reduction], 1 SD and 1 PD). To date, after a median follow-up of 45 weeks (range 13-74), none of the responders in the neoadjuvant arm has relapsed. Relapse was observed for both non-responders within the neo-adjuvant arm and for 3 patients within the adjuvant arm. TCR sequencing and MHC tetramer-based analysis to compare the induction and expansion of tumor (neo-)antigen-specific T cell responses between both treatment arms are underway and will be presented. Conclusions: The combination of IPI+NIVO in the (neo-)adjuvant treatment setting for high risk stage III melanoma patients is feasible and induces very frequent responses. At the same time, severe grade 3/4 toxicity is more frequent than expected from stage IV melanoma patient study data. These results indicate that IPI+NIVO is a promising combination for neo-adjuvant treatment in stage III melanoma. Adjusted combination schemes are currently tested in the phase 2 OpACIN-neo trial, with the aim of reducing toxicity while preserving efficacy. Clinical trial information: NCT02437279.
Relapse-free survial and target identification to enhance response with neoadjuvant and adjuvant dabrafenib + trametinib (D+T) treatment compared to standard-of-care (SOC) surgery in patients (pts) with high-risk resectable BRAF-mutant metastatic melanoma.
Authors: Wargo Jennifer Ann , Amaria Rodabe Navroze , Prieto Peter A. , Andrews Miles Cameron , Tetzlaff Michael T. , Futreal Phillip Andrew , Hwu Patrick , Hwu Wen-Jen , Glitza Isabella Claudia , Tawbi Hussein Abdul-Hassan , Cormier Janice N. , Lee Jeffrey Edwin , Patel Sapna Pradyuman , Simpson Lauren , Burton Elizabeth M. , Bassett Roland L. , Ross Merrick I. , Gershenwald Jeffrey E. , Davies Michael A. , Woodman Scott Eric
Published: September 2018

9587

Background: Targeted and immune therapies have dramatically improved outcomes in stage IV metastatic melanoma pts. These agents are now being tested in earlier-stage disease. SOC surgery for high-risk resectable melanoma (AJCC stage IIIB/IIIC), with or without adjuvant therapy, is associated with a high risk of relapse (~70%). We hypothesized that neoadjuvant (neo) + adjuvant treatment with D+T improves RFS in these pts. Longitudinally collected biospecimens from pts receiving this treatment were analyzed to identify candidate strategies to further improve outcomes. Methods: A prospective single-institution randomized clinical trial (NCT02231775) was conducted in BRAF-mutant pts with resectable Stage IIIB/C or oligometastatic stage IV melanoma. Pts were randomized 1:2 to SOC (Arm A) versus neo + adjuvant D+T (Arm B; 8 wks neo + 44 wks adjuvant). The primary endpoint was RFS. Tumor biopsies were collected at baseline, week 3, and at surgery for molecular and immune profiling (whole exome sequencing, gene expression profiling, IHC, flow cytometry). Results: 21 of a planned 84 patients were enrolled (Arm A = 7, Arm B = 14). Arms were well balanced for standard prognostic factors, and toxicity was manageable. RECIST response rate with neo D+T was 77%, and the pathologic complete response rate (pCR) was 58%. First interim analysis revealed significantly improved RFS in the D+T arm over SOC (HR 62.5, p < 0.0001), leading to early closure to enrollment. Pts with a pCR at surgery had significantly improved RFS versus pts without pCR (p = 0.04) on neo D+T. Tumor profiling revealed incomplete MAPK pathway blockade and higher levels of CD8+ T cells expressing immunomodulators Tim-3 and Lag-3 in pts who did not achieve a pCR. Conclusions: Neo + adjuvant D+T is associated with a high pCR rate and markedly improved RFS over SOC in pts with high-risk resectable BRAF-mutant metastatic melanoma. pCR at surgery is associated with improved RFS. Tumor analyses reveal candidate targets for testing in future trials to enhance responses to neo D+T. Clinical trial information: NCT02231775.
Financial toxicity and cancer-related distress among melanoma survivors.
Authors: Buzaglo Joanne S , Miller Melissa F , Zaleta Alexandra K , Johnson Jamese , Gupta Niraj K.
Published: September 2018

9588

Background: Melanoma survivors are at risk for significant financial burden due to cancer care and out of pocket costs. We explored 1) the financial impact of melanoma and its relationship to cancer-related distress, and 2) survivors’ experiences discussing financial burden with their health care team. Methods: Of 110 melanoma survivors enrolled in the Cancer Support Community’s online Cancer Experience Registry, 56 completed questions about financial impact of cancer and cost of care communication. Participants rated concern (0 = not at all; 4 = very seriously) about 27 items encompassing psychological, emotional, physical and practical concerns; items were summed into a total distress score (mean = 33, SD = 21, range 0-88). Financial impact and overall distress were examined via regression analysis. Results: Participants were 71% female, 89% Caucasian, median age 54, and median time since diagnosis 2.5 years. Total annual income: 34% < $60K; 46% $60K+; 20% not reported. 24% spent $101-250/month on melanoma out of pocket costs; 20% spent $251-500; and 24% spent ≥$500. The top concern was health insurance/money worries (69% moderately to very seriously concerned). Due to medical costs, 57% depleted their savings, 20% borrowed against or used retirement money, 20% used pharmaceutical assistance programs, 13% skipped medicine dosages at least sometimes, and 17% postponed filling prescriptions. Only 28% reported that their health care team spoke to them about cost of care, and 28% were asked about financial distress; 42% desired financial assistance. Financial impact was associated with an increase in overall distress for those with income < $60K (p < .05; interaction p < 0.05). Conclusions: Substantial proportions of melanoma survivors experience financial burden that can impact quality of life, particularly lower income individuals. Although oncologists are encouraged to discuss treatment costs, most patients report they have not had these discussions with providers. These results support the development/evaluation of interventions to enhance doctor-patient communication, and financial counseling to minimize financial burden of melanoma and the risks it can confer for quality of life, course of cancer care, and health outcomes.
Whole genome and RNA sequencing reveal the distinct genomic landscape of acral melanoma.
Authors: Kong Yan , Chi Zhihong , Si Lu , Sheng Xinan , Cui Chuanliang , Dai Jie , Ma Meng , Wu Xiaowen , Tang Huan , Yu Jiayi , Yan Junya , Yu Huan , Xu Tianxiao , Guo Jun
Published: September 2018

9589

Background: Acral melanoma is a common subtype of melanoma in Asians with extremely poor prognosis, and therapy strategy has not been clearly established for acral melanoma. The aim of this study is to perform genomic and RNA profiling of acral melanoma to obtain the comprehensive genomic view of this subtype of melanoma. Methods: Genomic DNA was extracted with Qiagen DNeasy Blood or Tissue Kit . DNA libraries were prepared using a CancerPROTM-P88 BOX library Prep kit and sequencing was performed using the Illumina HiSeq X10. RNA was isolated with Qiagen RNeasy mini-spin column. cDNA was synthesized from total RNA using the SuperScript III first-strand synthesis system . RNA libraries were prepared using the NEBNext Ultra II Directional RNA Library Prep Kit and sequencing was performed using the Illumina HiSeq X10. Results: To obtain a comprehensive genomic and functional genomic view of acral melanoma, we sequenced the genomes of 14 acral melanoma and transcriptomes of 11 of these melanoma samples. We found a new mutation in the V28 codon of BRAF in three patients. Furthermore, we identified recurrent non-synonymous single nucleotide variants in previously described oncogene NRAS, as well as in genes encoding keratin associated proteins (KRTAP4-7, KRTAP4-5) and mucin (MUC2, MUC21). Notably, a recurrent noncoding hotspot mutation was discovered in 4 of 11 cases. By analyzing the RNA sequencing data, we found significant divergence on transcriptome between patients with or without ulcer. In total, we identified 201 genes were significantly up-regulated and 386 genes significantly down-regulated in acral melanoma patients with ulcer. Differentially expressed genes were enriched in pathways associated with cancers, melanogenesis, cell death signaling, skin diseases, etc. Conclusions: Our study reveals potentially different driver mutations and distinct transcriptome in acral melanoma patients compared with cutaneous melanoma patients and sheds lights to the further personalized medicine for acral melanoma patients.
Adherence to tamoxifen in Mexican young women with breast cancer.
Authors: Villarreal-Garza Cynthia Mayte , Martinez-Cannon Bertha Alejandra , Castro-Sanchez Andrea , Platas Alejandra , Fonseca Alan , Vega Yoatzin , Barragan-Carrillo Regina , Mohar Alejandro , Bargallo-Rocha Enrique , Bojoquez-Velazquez Karen
Published: September 2018

e12003

Background: Young age has been associated with significantly increased risk of breast cancer (BC) death among women with luminal BC. One contributing factor might be the low rate of tamoxifen (TMX) adherence previously reported in this young group. Given that in Mexico a disproportionate rate of BC is diagnosed among YW, information regarding TMX adherence is particularly relevant. Our study's aim was to report TMX adherence in Mexican YW and its associated determinants. Methods: Consecutive patients ≤40y at diagnosis at the National Cancer Institute in Mexico City, under TMX treatment, completed a multiple-choice survey regarding the use and attitudes about hormonal therapy and adherence. Data of TMX disposal was collected from the pharmacy’s records, and the medication possession ratio (MPR) was calculated; an MPR ≥80% was considered adherent. Results: 135 YW with a median age at diagnosis of 35.7y (24-40) were included. 77% were undergraduate, 28% unpaired and 33% childless. Median follow-up was 26 months. 95% of patients reported a regular TMX intake: 70% did not miss any doses, while 25% missed 1-6 doses a month. Only 45% considered that the information received regarding TMX therapy was sufficient and for 37% was incomprehensive. 43% thought TMX significantly reduced their recurrence-risk and 60% strongly believed that they needed to be on TMX treatment. 73% of women reported adverse effects, being menopausal symptoms the most frequent, but only 27% were worried about the treatment long-term effects. From the 99 patients with a pharmacy record, 73% had an MPR > 80%. No significant factor was statistically associated with TMX adherence. Conclusions: Although Mexican YW and pharmacy data surprisingly sustained higher rates of TMX adherence compared to previous data, still a significant proportion of patients were non-adherent. Two-thirds of our patients reported having adverse effects, which might contribute to late TMX discontinuation. Since the newer recommendations of double hormonal blockade could lead to higher withdrawal rates of endocrine therapy in YW, adherence should be emphasized and closely monitored. Accordingly, hormonal treatment adherence should be a key component in the medical assessment of young luminal BC patients.
Ki 67 analysis and prognostic factors in women with luminal breast cancer.
Authors: Vissotto Eduardo De Figueiredo , da Costa Alexandre Andre Balieiro Anastácio , Boente Leonardo de Azevedo , Ricardo Eliza Dalsasso , Costa Felipe D'Almeida
Published: September 2018

e12024

Background: After screening became available for most women, breast cancer is diagnosed mainly in early stage. The decision to offer adjuvant chemotherapy to patients with luminal breast cancer is not easy and the knowledge of prognostic factors is mandatory. Ki 67 plays an important role in this context, especially in patients who do not have access to genetic signatures. Nevertheless, data available about the optimal cutoff of Ki 67 to predict luminal B subtype is still controversial. Methods: We evaluated Ki 67 and other clinical-pathological factors of women with non-metastatic hormone-positive breast cancer in a major oncologic hospital. The objective was to determine the impact of Ki 67 on the disease free survival (DFS) and the optimal cutoff. This is a retrospective cohort of patients of the AC Camargo Cancer Center between January 2007 and January 2009 selected by a random sample of convenience. Ki 67 analysis was performed through tissue-microarray (TMA). Log rank test and Cox regression were used to test the prognostic value of each variable for DFS. The optimal Ki 67 cutoff was defined plotting a curve for the hazard ratios for each Ki67 cutoff point tested and their 95% confidence intervals. Results: We evaluated 195 patients with a median follow up of 58 months. The optimal cutoff of Ki 67 was 23% for DFS (HR 3,78; CI 95% 1,3 – 10,76; p 0,012). The cutoffs of 20%, 30%, 40% and 50% were also statistically significant. The kappa concordance index between TMA and whole tissue sections was 0,567 (CI 95% 0,268-0,866; p = 0,003). Other poor prognosis factors on the surgical samples were higher histologic grade, presence of vascular-lymphatic invasion and mythotic index superior to 10 mytoses per high powerfield. On the biopsy samples, inflammatory infiltrate absent or low was found to be a poor prognostic factor Conclusions: Analysis of Ki 67 in women with non-metastatic hormone-positive breast cancer is a prognostic factor for DFS, with different cutoffs. This may suggest that Ki 67 should be considered as a continuous variable rather than a dichotomized value. Analysis of others clinical-pathological factors are still important for therapeutical decision.
A comparison of genomic assays in determining risk of late recurrence and benefit of extended endocrine therapy (EET).
Authors: Raque Kathleen , Rico Lina Marie , Yu Eddy , Carter W. Bradford , Frazier Thomas G.
Published: September 2018

e12045

Background: Breast cancer patients who are ER positive, lymph node negative have the best overall prognosis. However 50% of recurrences occur after 5 years. The Breast Cancer Index (BCI) is a gene expression-based biomarker that provides an individual risk of distant recurrence and benefit of EET based on a continuous risk model. (1) The BCI may help with clinical decisions regarding EET since prolonged therapy may have an increase in side effects including uterine cancer, DVT, myalgias and bone loss. The OncotypeDX is a 21 gene assay that predicts recurrence with a recurrence score. A recent study by Wolmark et al. evaluated the use of quantitative Estrogen Receptor Index (ESRI) combined with RS and found that RS was prognostic in patients with higher quantitative ESRI, suggesting EET be used for patients with intermediate and high RS with ESR1 expression > 9.1. (2) Methods: 20 patients, ER positive, node negative who had the BCI and ONC-DX performed were evaluated in this retrospective IRB approved review. Results: Using ESRI alone 85% of patients would be recommended to continue an additional 5 years of EET. Using BCI this number was reduced to 35%. Conclusions: Comparing both the risk of recurrence and benefit of ETT, ESRI and BCI were concordant only 37.5% of the time. The cost of extended adjuvant therapy with Anastrazole ($190/mos x 60 mos = $11,400) or Tamoxifen ($50/mos x 60 mos = $ 3,000) would have resulted in a cost savings of $79,800 (Anastrazole) or $21,000 (Tamoxifen) for this small group of patients. Utilization of the BCI (cost $ 3416.00) may be a cost effective and accurate genomic approach in determining the use of EET and avoiding concomitant side effects.
Early breast cancer in elderly patients: Characteristics, therapy, and long-term outcome.
Authors: Gal Omer , Ishai Yael , Hendler Daniel , Neiman Victoria , Zoref Dalia , Brenner Baruch , Yerushalmi Rinat
Published: September 2018

e12046

Background: The number of older adults diagnosed with breast cancer and the number of breast cancer survivors is on the rise. The majority of women with breast cancer are diagnosed with an early stage (non-metastatic) potentially curable disease. However, data regarding breast cancer characteristics, treatment, and survival for elderly women are sparse. Methods: We retrospectively reviewed all women with invasive, non-metastatic breast cancer treated in our tertiary medical cancer center from January 2004 to December 2007. Patients were divided into 2 groups: those aged 65-75 years and those aged >75 years. Data on tumor characteristics, treatment modalities, and outcome were retrieved from the patient computerized medical files and compared between the groups. Results: The study group comprised 390 patients. Of them, 252 were aged 65-75 years, and 138 were aged >75 years. Patients were followed for a median of 10.6 years.Tumor characteristics were similar in both groups, although older patients had larger tumors at diagnosis. Patients aged >75 years underwent more mastectomies, but were less likely to receive axillary surgery or adjuvant systemic therapy. When grouped according to subtype (luminal, Her-2+, triple-negative), an independent effect on recurrence rate and overall survival (OS) for both age and subtype was observed with the worst outcome in the women with triple-negative disease aged >75 years, and best outcome in the women with Her-2 positive aged 65-75 years (p=0.16 for recurrence, p <0.001 for OS). The median OS for the follow-up period was 10.3 years for women aged 65-75 years and 8.0 years for women aged >75 years. The disease-free survival rate after 8 years of follow-up was 88% for the younger women and 85% for those aged >75 years (p=0.27). Conclusions: The current study reveals the physicians' approach in treating breast cancer in the elderly age groups. It demonstrates the impact of both age and tumor subtype on recurrence rates and OS. Triple-negative disease had the worst outcome in both age groups. Physicians should be aware of the impact of the different breast subtypes on outcome in the older patients subgroup and consider treatment based on the individual patient comorbidities and life expectancy.
Incidence of esophageal and head and neck cancers among breast cancer survivors in the United States.
Authors: Dollar Krista , Tyker Albina , Simpson Matthew , Adjei Boakye Eric , Dombrowski John J. , Varvares Mark A , Osazuwa-Peters Nosayaba
Published: September 2018

e12054

Background: Late sequelae of breast cancer therapies potentially impact morbidity and mortality with increasing numbers of survivors. Radiation exposure has been linked to increased incidence of second primary cancers (SPC). However, to date, there is limited literature describing incidence of head and neck (HN) and esophageal cancers in patients with an index breast cancer (BC). This study aimed to describe the incidence of esophageal and HN cancers following breast cancer diagnosis. Methods: Standardized incidence ratios (SIRs) were calculated using the Surveillance, Epidemiology, and End Results (SEER) 9 database for BC patients diagnosed from 1973-2013. SIRs compared incidence of HN and esophageal cancer after an initial BC diagnosis to the general population. HN included oral cavity, pharynx, and larynx. BC patients were grouped into those who received radiotherapy for their breast cancer (n = 216,045) and those who did not (n = 289,596). SIRs were calculated in 5-year intervals. SEER does not contain information on chemotherapy. Results: Less than 1% of BC patients developed HN (0.3%) or esophageal cancers (0.1%), irrespective of radiation treatment. However, among patients with an index BC who received radiation therapy, there was significant but small increased incidence of HN and esophageal cancers five to nine years following treatment (HN SIR: 1.22; 95% CI, 1.04-1.43 and esophagus SIR: 1.44; 95% CI, 1.09-1.87). Esophageal cancer incidence continued to increase through 15 years of follow-up, however incidence of HN was not significant beyond ten years after the index BC diagnosis and radiation treatment. Conclusions: Compared to the general population, breast cancer patients have elevated incidence of HN and esophageal cancers detected five to nine years after receiving radiation treatment, but only the incidence of second primary esophageal cancer remains elevated at 15 years. These findings warrant further investigations of breast cancer radiation and future malignancies.
Bone health management in early breast cancer patients: An Italian osteoncology center experience.
Authors: Recine Federica , Bongiovanni Alberto , Fausti Valentina , Mercatali Laura , Riva Nada , Calpona Sebastiano , Faedi Marina , De Vita Alessandro , Liverani Chiara , Spadazzi Chiara , Miserocchi Giacomo , Foca Flavia , Vespignani Roberto , Rocca Andrea , Amadori Dino , Ibrahim Toni
Published: September 2018

e12055

Background: Bone health evaluation is important for the optimal management of early stage breast cancer (BC) both in post and pre-menopausal setting. Adjuvant endocrine therapy (ET), including luteinizing hormone-releasing hormone (LHRH) analogues with tamoxifen (TAM) and aromatase inhibitors (AI), may affect bone health resulting in a reduction of the bone mineral density (BMD), leading to an increased risk of bone fractures. The objective of this observational study performed at an Italian Osteoncology Center was to evaluate the prevalence of vertebral fractures in pre and post women with BC treated with adjuvant ET. Methods: Data on patients (pts) with early BC were collected from 2011 to 2016 in a single Institution. We investigated the prevalence of vertebral fractures in pre and post pts treated with ET and other potential independent risk factors associated to bone fractures. To evaluate association with bone fractures and clinical factors, univariate logistic models were carried out. P-value of less than 0.05 was considered significant. Results: A total of 1,165 women with early pre and post-menopausal BC were evaluated; for 702 (60.2%) pts treated with ET was available a X-Ray of the spine and they were included in the analysis. The median age was 61 year-old (31-86 y). A total of 124 were pre-menopausal and 578 were post-menopausal pts. Frequency of bone fractures was 17.6% in post-menopausal and, among them, the major risk of bone fractures was associated with AI treatment (OR:4.37, p:0.005); in pre-menopausal pts bone fractures incidence was 6.4% and the major risk was associated to LHRH+AI treatment (OR:2.18, p:0.307). Higher risk of bone fractures was associated with presence of back-pain (OR:1.81, p:0.006), a lower BMD (OR:2.91, p: < 0.001 for pts with BMD≤2.5) and lower level of Vitamin D (OR:2.06, p:0.030 for pts with ≤10) in univariate analysis. Further analysis are ongoing. Conclusions: This Italian experience confirms the importance of bone health evaluation in order to prevent bone fractures in the management of pre and post-menopausal early BC treated with ET.
Impact of the Prosigna (PAM50) assay on adjuvant clinical decision making in patients with early stage breast cancer: Results of a prospective multicenter public program.
Authors: Rodriguez Cesar Augusto , Garcia-Muñoz Maria , Sancho Magdalena , Garcia-Gonzalez Maria , Delgado Carlota , Soto de Prado Diego , Álvarez José V. , Bayona Cristina , Alés-Martínez José E. , Gallegos Isabel , Puertas Álvarez Javier , García-Palomo Andres , Arevalo Estefania , Condori Eliza , Gómez Asunción , Lozano Rebeca , de la Fuente Natalia , Cruz Juan J.
Published: September 2018

e12062

Background: Prosigna is a standardized test based on the PAM50 gene signature which provides information on intrinsic subtype and risk of recurrence (ROR) score predicting 10y recurrence probability (NanoString Technologies, Inc., Seattle, WA). We evaluated Prosigna’s impact on adjuvant treatment decision beyond immunohistochemistry (IHC) testing. Methods: 125 pre- and postmenopausal EBC patients with ER+, HER2-, pT1-T2 pN0/pN1mi were enrolled (12 centers; 8/2015-11/2016). FFPE specimens were centrally analyzed using Prosigna to classify patients according to the intrinsic tumor subtype and ROR score. The primary endpoint was the impact of the Prosigna test on adjuvant treatment decision. Results: 64% of tumors were classified by PAM50 as Lum A, 35% as Lum B, 0% Basal, 1% HER2-E. The intrinsic subtype concordance between immunohistochemistry (IHC) and Prosigna (n = 119) was 61.3%. In Lum B tumors by IHC the discordance rate was the highest (48% were reclassified as Lum A by Prosigna) as shown in the Table. ROR risk groups were as follows: ROR low (54; 43%), ROR interm. (38; 30%), and ROR high (33; 27%). Prosigna results led to a treatment recommendation change in 49 (39%) patients. In the 76 (61%) cases with the initial recommendation of Hormonal Therapy (HT) alone the final decision changed to chemotherapy (CT)+HT (CHT) in 24 (32%) patients. In the 49 (39%) cases in which the initial recommendation was CHT the final decision changed to HT in 25 (51%) patients. Among the 38 patients with Prosigna intermediate risk, 21 (55%) were allocated to HT. Conclusions: In this prospective decision impact study, Prosigna results led to a 39% change in adjuvant therapy indication. Patients with initial indication of CHT were changed to HT alone in > 50% of cases. Thus, Prosigna results influenced the treatment decisions and reinforced its clinical utility in real-world settings. The intrinsic subtype classification based on IHC didn’t show to be an adequate surrogate for the genomic subtypes as determined by Prosigna. [Table: see text]
Negative predictive value of ipsilateral axillary ultrasound in the pre-operative assessment of invasive breast cancer.
Authors: Ameri Bita , Kanesa-Thasan Riti , Abu-Khalaf Maysa M. , Berger Adam C. , Eisenberg Tara , Lazar Melissa A. , Sevrukov Alexander , Tsangaris Theodore N. , Wasti Nylah , Wilkes Annina , Willis Alliric Isaac , Zorn Lisa , Hsu Elizabeth
Published: September 2018

e12080

Objective: To determine if a negative preoperative axillary ultrasound predicts a negative sentinel lymph node biopsy at surgery. Background: Axillary lymph node involvement is an important prognostic indicator in patients with breast cancer. Sentinel lymph node biopsy (SLNB) is currently the gold standard for determining the presence or absence of axillary metastases. Pre-operative axillary ultrasound is often used to evaluate axillary lymph node status prior to surgery and SLNB. Although there are no established guidelines on when preoperative axillary ultrasound is performed, at our institution we evaluate the axilla when invasive breast cancer is suspected. This study evaluated the negative predictive value (NPV) of axillary ultrasound compared to the pathology results of SLNB. Methods: In this single-center IRB-approved retrospective study, 3 years of breast imaging data (2014-2016) were reviewed. 137 patients had pathology verified invasive breast cancer with negative preoperative axillary ultrasound and subsequent SLNB. All patients had clinically negative axillae. Based upon the pathology results of SLNB, the negative predictive value of preoperative axillary ultrasound was calculated. Negative axillary ultrasound is defined as the absence of morphologically abnormal lymph nodes on imaging. A lymph node is considered morphologically normal when there is preserved fatty hilum and a uniform cortex measuring 3 mm or less. Results: Out of 137 patients with invasive breast cancer who had negative preoperative axillary ultrasound, 122 had negative SLNB results and 15 had positive SLNB results. Preoperative axillary ultrasound demonstrated a NPV of 89.1% for the detection of axillary metastatic disease at the time of SLNB. Conclusions: Negative axillary ultrasound excluded axillary metastatic disease in 89.1% of patients. This data suggests that negative axillary ultrasound may have a role in the setting of failed SLNB (no lymph nodes found at the time of surgery) in deciding whether to pursue axillary dissection.
Dedicated breast PET to improve clinical diagnosis of breast cancer: Initial evaluation.
Authors: Masumoto Norio , Kadoya Takayuki , Fujiwara Makoto , Murakami Chika , Yoshikawa Toru , Handa Yoshinori , Amioka Ai , Gohda Noriko , Kono Miho , Sasada Shinsuke , Kajitani Keiko , Emi Akiko , Haruta Rumi , Kataoka Tsuyoshi , Okada Morihito
Published: September 2018

e12097

Background: Unlike whole body (WB) 18F-fluorodeoxyglucose (FDG) PET, dedicated breast PET (DBPET) enables detailed high-resolution images within the breast and quantitative assessment using SUV. We aimed to determine whether DBPET can detect ductal carcinoma in situ (DCIS) and predict the malignancy and neoplastic progress of invasive breast cancer. Methods: We investigated 155 consecutive patients with breast cancer who underwent concurrent DB– and WB– PET (Elmammo®) between January and November 2016. All DB– and WB– PET images were quantified based on standard uptake values (SUV). We also assessed 12 patients with ring-like uptake (RU) without central FDG accumulation in invasive breast cancers on DBPET images. Results: The SUV (means ± SD) determined from DB– and WB– PET images of breast cancer were 8.2 ± 7.7 and 3.1 ± 3.3 respectively. We detected DCIS in DB- and WB– PET images from 22 (84.7%) and 15 (57.6%) of 26 among the 155 patients, respectively (p = 0.003). The SUV on WB– PET images was significantly higher for NG3 than for NG1-2 (p = 0.004), and for high (≥ 20%) than low ( < 20%) Ki67 (p = 0.003), and significantly lower for Luminal A than Luminal B, HER2 and triple-negative cancer (p < 0.05 for all three). The SUV for NG (p = 0.002), Ki67 (p = 0.001) and the luminal (p < 0.05) type also significantly differed in DBPET images. RU without central FDG accumulation was evident in DbPET images of 12 patients, all of whom had Ki67 ≥ 20 (p = 0.0001), two had NG1-2 and 10 had NG3 (p = 0.005), one had clinical T1, 11 had T2 (p = 0.0004), five had clinical N0 and seven had N1 (p = 0.03). RU was associated with high-grade malignancy and neoplastic progress. Conclusions: The detection rate of DBPET was excellent for DCIS. The RU on DBPET offers predictive value for high-grade malignancy and the neoplastic progress of invasive breast cancer. Thus, DBPET might help to determine therapeutic strategies.
64Cu-DOTA-trastuzumab PET/CT to predict response to ado-trastuzumab emtansine (TDM1) in HER2-positive metastatic breast cancer.
Authors: Mortimer Joanne E. , Bading James R. , Frankel Paul Henry , Gidwaney Rita , Park John , Tumyan Lusine , Parayno Maria , Poku Kofi , Colcher David
Published: September 2018

e12525

Background: Having demonstrated that 64Cu-DOTA trastuzumab is an effective PET imaging agent for HER2 positive (HER2+) breast cancer, we now evaluate the methodology for prediction of response and benefit from TDM1 in women with metastatic disease. Methods: Patients eligible to receive TDM1 as therapy were chosen on the basis of biopsy confirmed HER2+ disease, and at least 1 site of metastasis ≥ 2.0 cm outside the biopsy site. Pretreatment staging included 18F-FDG PET/CT. Prior to injection of 64Cu-DOTA-trastuzumab, patients received 45 mg of cold trastuzumab to reduce liver uptake. PET-CT scans were obtained at 16-28 h (Day1) and 39-49 h (Day 2) over fields of view chosen in reference to the 18F-FDG scans. TDM1 (3.6 mg/kg) was administered every 3 weeks. Restaging 18F-FDG PET/CT was performed every 2 cycles, and response to therapy was determined by PERCIST (solid tumor) criteria. Radiolabel uptake was measured in terms of maximum voxel, standardized uptake value (SUVmax). Results: Ten women between the ages of 48-83 years old (median 55 years) qualified for study, and have been evaluated for response; 4 continue on TDM1 with treatment durations of 3-27 months.Three were trastuzumab-naïve, while 7 had received trastuzumab-containing chemotherapy 3 wks to 55 mo prior to study entry. HER2 was positive by ImmunoHistoChemistry, IHC (3+) in 5 patients, and by FISH testing in the other 5 (3 were 2+ by IHC; 1 was 1+, and 1 was indeterminate). Complete or partial metabolic response was observed in 5 patients. Median Day 2 SUVmax for 64Cu-DOTA trastuzumab was 9.3 g/ml in responding patients, and 4.6 g/ml in non-responders ( P= 0.03). Progression-free survival was longer for patients with higher SUVmax, with a hazard ratio of 0.73 (95% confidence interval 0.46-1.16) for each 1 unit increase in SUVmax. This was not statistically significant, although we can select a threshold SUVmaxfor which the effect is significant even for this small study. Further data is required to confirm such a threshold effect. Conclusions: 64Cu-DOTA-trastuzumab PET imaging predicts benefit from TDM1 in women with biopsy-confirmed HER2+ metastatic disease. Supported by NCI Clinical trial information: NCT02827877.
Real-world dosing patterns of everolimus-based lines of therapy among post-menopausal women with hormone receptor-positive and human epidermal growth factor receptor-negative (HR+/HER2-) metastatic breast cancer (mBC).
Authors: Princic Nicole , Brouillette Matthew , Tang Derek , Lin Chinjune , Lanoue Brad , Barghout Victoria E.
Published: September 2018

e12528

Background: This study sought to describe dosing patterns of post-menopausal women with HR+/HER2- mBC treated with everolimus during a second or later lines of therapy in the US. Methods: MarketScan Commercial and Medicare Supplemental administrative claims databases were used to select post-menopausal HR+/HER2- mBC females who initiated an everolimus-based line of therapy during 1/1/2013- 7/31/2016. The first secondary malignancy diagnosis was the index date. Patients had 6 months of continuous enrollment in their health plans pre- and post- index, and were followed until the earliest date of disenrollment, inpatient death, or end of study. A line of therapy ended at discontinuation (gap >60 days in all treatment) or switch to a new treatment. Dose modification during 2L, 3L, or 4L was defined by a change in daily dose of >2.5 mg compared to the prior prescription and treatment interruption was defined as a gap >60 days of everolimus followed by a restart of therapy during follow-up. Results: There were 645 mBC patients with everolimus-based line(s) of therapy eligible for analysis (mean age = 61.1 [SD 11.7], mean days to treatment initiation = 33.4 [SD 65.1]). Across all lines, the majority (72.5%-80.8%) of patients were on a combination regimen with endocrine therapy and <10% were on a combination regimen with chemotherapy. Among patients with valid dose data (96.2%), mean initial dose in mg was 8.6 (SD 2.6) in 2L, 8.3 (SD 2.8) in 3L and 9.1 (SD 5.9) in 4L, the majority (71.4%-79%) did not have a dose modification, and <5% had a treatment interruption (Table). Conclusions: Results from this analysis of real-world data suggest that 71%-79% of patients did not experience any modification to the initial dose during an everolimus-based 2L, 3L, or 4L of therapy and less than 4% experienced a treatment interruption. [Table: see text]