Alvaro Moreno Aspitia

IgM multiple myeloma: disease definition, prognosis, and differentiation from Waldenstrom's macroglobulinemia.

IgM multiple myeloma (MM) and Waldenstroms macroglobulinemia (WM) are two distinct hematologic entities with the common finding of an IgM monoclonal gammopathy. Distinguishing these two diagnoses is critical as the approach to therapy is different. A priori, we defined IgM MM as a symptomatic clonal plasma cell proliferative disorder characterized by an IgM monoclonal protein (regardless of size), 10% or more plasma cells on bone marrow biopsy, plus the presence of lytic bone lesions and/or translocation t(11;14). Twenty‐one patients met this definition of IgM MM. All 21 patients had lytic bone lesions. Of the 16 evaluated with FISH, 6 (38%) demonstrated t(11;14). Median overall survival was 30 months, which is similar to non‐IgM myeloma patients treated during this period and shorter than what would be expected for WM. In this, the largest series of patients with IgM MM, we describe the clinical features and prognosis of patient with IgM MM using a strict definition for the disease. The subset of patients without lytic lesions or t(11;14) but with immunophenotypic features suggestive of MM need further study. Am. J. Hematol., 2010.

A Pilot Program in Collaboration with African American Churches Successfully Increases Awareness of the Importance of Cancer Research and Participation in Cancer Translational Research Studies among African Americans

African Americans are underrepresented in cancer research. We evaluate whether collaboration with African American churches can improve cancer awareness and increase participation in translational research protocols among African Americans. From February to April 2010, the Mayo Clinic partnered with African American Jacksonville churches to provide educational programs focused on cancer research and healthy behaviors. Education on multiple myeloma and on-site access to a translational cancer research pilot project evaluating the prevalence of monoclonal gammopathies and t(14,18) in African Americans was offered. Seventy-four percent, 236 out of 318 participants, returned the questionnaires. The majority of participants had never received information on multiple myeloma (67%), had never received clinical research study information (57%), and were enrolled in the translational research studies (55%). Partnerships with African American churches in community education projects that bring research to church venues are effective in improving cancer awareness and in increasing research participation among African Americans.

The definition of IgM multiple myeloma

We read with interest the recent report of Schuster et al. [1], who described the clinical presentation and outcome of 21 patients diagnosed with immunoglobulin M (IgM) multiple myeloma (MM). In this report, the authors defined IgM MM according to the following criteria—IgM monoclonal gammopathy, equal or greater than 10% bone marrow plasma cells and the presence of lytic bone disease and/or translocation t(11;14). We believe that this definition is restrictive and will fail to capture a proportion of patients particularly those with asymptomatic disease and other cytogenetic abnormalities. Ideally IgM MM should be defined according to principles identical to those used in standard MM. We have previously reported the clinicopathological features of 10 patients with IgM MM [2] and in this current report detail the features of two additional patients (Table I) to further clarify the immunophenotypic and genotypic characteristics of IgM MM. The cytogenetic characteristics of IgM MM were first evaluated by AvetLoiseau et al. [3], who demonstrated the t(11;14) by fluorescence in situ hybridization in seven of eight cases (88%). Similarly, in our initial study, we demonstrated the translocation in 5/8 evaluable cases and have also demonstrated it in a further patient included in this current report (overall incidence 6/10, 60%). Schuster and coworkers demonstrated the translocation in a lower proportion of patients (38%), although a further report has failed to demonstrate it in two further cases [1,4]. It is clear, therefore, that although the t(11;14) appears to occur at a higher frequency in IgM MM, it cannot be regarded as a defining abnormality. Similarly, we reported a patient with the t(4;14) in our original cohort and also include a patient with a t(14;16) in this current report (overall incidence 10% in each instance). Both patients have been reported in detail elsewhere [5,6]. Myeloma plasma cells are characterized by distinct phenotypic differences, when compared to normal plasma cells, and these typically include loss of CD19, CD27, CD45 along with aberrant expression of CD56, CD20, CD117, and cyclin D1 [7]. In our original analysis, an aberrant plasma cell phenotype was demonstrable in 7/10 cases [2] and is also demonstrable in each of the additional cases included in this report confirming the applicability of extended plasma cell phenotyping by either flow cytometry or immunohistochemistry in the diagnosis of IgM MM. This is particularly useful in distinguishing IgM MM from Waldenstrom macroglobulinemia (WM). Our data would also suggest that the immunophenotypic profile of IgM MM differs from that of classswitched myeloma in that there appears to be a lower incidence of CD56 expression [2]. The presence of lytic bone disease was also included in the selection criteria used by Schuster et al. [1]. In our cohort of patients, bone disease was demonstrable in 5/8 (63%), whereas 2/10 (20%) showed neither the t(11;14) nor bone disease. It is interesting to note that the two patients, who lacked both bone disease and the t(11;14), were the patients with the t(4;14) and t(14;16). The inclusion of lytic bone disease and/or the t(11;14) as defining criteria will systematically exclude patients with asymptomatic disease as well as those with other distinct cytogenetic abnormalities. We would conclude that the immunophenotypic and genotypic characteristics of IgM MM are now better characterized and allow for more definitive diagnostic criteria. IgM MM should be defined by IgM monoclonal gammopathy and 10% bone marrow plasma cells. The plasma cells should express monotypic IgM and will frequently demonstrate aberrant expression of a range of antigens including CD19 and cyclin D1, although the incidence of CD56 expression appears lower than in standard MM. Similarly, IgM MM is characterized, in contrast to WM, by immunoglobulin heavy chain (IGH) translocations, and these include not only the t(11;14) but also the t(4;14) and t(14;16).

High p95HER2/HER2 Ratio Associated With Poor Outcome in Trastuzumab-Treated HER2-Positive Metastatic Breast Cancer NCCTG N0337 and NCCTG 98-32-52 (Alliance)

Purpose: p95HER2 is a truncated form of HER2 that confers resistance to trastuzumab in vitro, but clinical results have been conflicting to date. Given that p95HER2 levels correlate with total HER2 expression levels, which confer better outcomes, we sought to evaluate the p95HER2/HER2 ratio in the North Central Cancer Treatment Group N0337 and N98-32-52 trials. Experimental Design: The HERmark assay and VeraTag technology (Monogram Biosciences) were used to measure total HER2 and p95HER2 expression levels in 91 patient samples. Results: In the multivariate model, increasing total HER2 level was significantly associated with longer (OS; HR, 0.33; P = 0.002) and decreasing p95HER2 level was significantly associated with longer OS (HR, 4.2; P = 0.01). Total HER2 expression level was significantly associated with longer progression-free survival (PFS) (HR, 0.57; P = 0.04), whereas p95HER2 level was not (HR, 1.7; P = 0.25). However, there was a positive association between p95HER2 and total HER2 expression levels (R2 = 0.48; P < 0.001). Consistent with our hypothesis, the ratio of p95HER2/HER2 was significantly associated with worsening PFS (HR, 1.7; P = 0.04) and OS (HR, 2.8; P = 0.002). Patients with the highest tertile of p95HER2/HER2 values had significantly less favorable PFS (HR, 1.8; P = 0.06) and OS (HR, 2.3; P = 0.02). Conclusions: A high p95HER2/HER2 ratio identified patients with metastatic breast cancer with poor outcomes on trastuzumab-based therapies. Further investigation of the p95HER2/HER2 ratio as a potential prognostic or predictive biomarker for HER2-targeted therapy is warranted. Clin Cancer Res; 24(13); 3053–8. ©2018 AACR.

Abstract 4761: Characterization of individual foci of multifocal invasive lobular breast cancer using gene expression profiling

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Introduction: Invasive lobular carcinoma (ILC) comprises approximately ∼10-20% of breast cancers (BC) and appears to have a distinct biology from invasive ductal carcinoma (IDC). ILC is known to have a higher incidence of multifocal (MF) disease when compared to IDC (Biglia N, EJSO, 2013) and in general, MF BC has been associated with an increased rate of regional lymph node metastases (Cabioglu N, JACS, 2009). Treatment decisions are most often defined by the largest of the MF tumors without targeting potentially relevant biologic heterogeneity of the disease. We conducted a genomic analysis of MF ILC to help address this knowledge void. Methods: We characterized gene expression in multiple foci from 11 patients (pts) with MF ILC (all ER+ and HER2-, mean number of foci = 2.62) and 13 benign breast tissues. RNA was extracted from 3×1.5mm cores from each foci and gene expression was measured in 730 known cancer genes using the NanoString PanCancer pathways panel. Differential gene expression analyses were performed between 1) MF tumors and benign tissue (BT) accounting for pairing of pts and 2) different foci of MF tumors from the same ILC pt by ANOVA. The association of clinical covariates (age, number of tumors, grade and stage) in the top genes that were differentially expressed between multiple foci was assessed by linear mixed models accounting for pt and tumor. Results: A total of 20 genes (including MET and EGFR, top 5 genes: SPRY2, SOX17, FIGF, PDGFA, IL6) were differentially expressed (p<0.05) between malignant foci from the same pt, after correction by false discovery rate (FDR). EGFR expression was also negatively associated with the number of positive lymph nodes (N1a vs N0 absolute fold change = 0.51, p = 0.043). We observed an excess of genes that were down-regulated in MF ILC compared to BT. 277 genes were differentially expressed at p<0.05 after correction by FDR. The top 5 differentially expressed genes (by fold change) between ILC and BT were COL11A1, COL1A1, WIF1, FIGF and PROM1. CDH1, a known marker of ILC, was down-regulated in ILC compared to benign (absolute fold change = 2.54, p = 6.02×10−6), ranked only 39/277 genes by fold change. MET and EGFR ranked 29 and 42/277 genes (p = 5.99×10−9 and 3.32×10−8 respectively). Conclusion: We observed significant heterogeneity for 20/730 genes between individual foci of MF ILC within the same pt suggesting that MF synchronous ILC lesions may have different biologic behavior. This in turn may have important prognostic implications with potential therapeutic utility. Our analyses also shows significant down-regulation of gene expression between ILC tumors and BT for many genes other than CDH1 suggesting that additional biomarkers can be used to further characterize ILC Study funded in part by Mayo Clinic Cancer Focus Research Team, the 26.2 with Donna Foundation and the Serene M. and Frances C. Durling endowment. Citation Format: Pooja Advani, Nadine Norton, Daniel J. Serie, Xochiquetzal Geiger, Julia E. Crook, Aubrey E. Thompson, Edith A. Perez, Alvaro Moreno Aspitia. Characterization of individual foci of multifocal invasive lobular breast cancer using gene expression profiling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4761. doi:10.1158/1538-7445.AM2015-4761

Abstract 1195: Feasibility of using percutaneous tumor biopsies from a prospective neoadjuvant breast cancer study to develop patient derived xenografts and assess in vivo chemotherapy sensitivity

INTRODUCTION Patient derived xenografts (PDX) may better reflect individual patient (pt) tumor biology; however, the feasibility of collecting PDX from percutaneous tumor biopsies (PTB) in the neoadjuvant setting is unknown. Furthermore, drug response phenotypes observed in PDX have not been prospectively compared to the corresponding pt clinical outcomes. METHODS The Breast Cancer Genome Guided Therapy Study (BEAUTY) is a prospective Mayo study of pts with high-risk breast cancer treated with neoadjuvant weekly paclitaxel (T) +/- trastuzumab followed by anthracycline based chemotherapy. PTB (at baseline) and residual surgical tissue (after all chemotherapy) are obtained for next generation sequencing (NGS) and PDX. Tumor biopsies (1-2 cores from 14 gauge needle) were implanted with Matrigel 50 mm3. Take rate was defined as development of at least 1 stably transplantable xenograft line/pt. To determine whether clinical T response assessed by MRI corresponded with in vivo T response, pretreatment PDX from 5 pts were injected into NOD-SCID mice (20 mice per pt PDX) and when tumors reached 100-200mm3, mice were randomized to no treatment vs T (20 mg/kg, ip. every 3-4 days). Two of these 5 patients had a MRI response defined as >30% decrease in longest lesion. RESULTS Pretreatment PTB from 81 unique pts were implanted in 251 mice (2-4 mice/pt). PDX outgrowth rates were 33.3% (27/81 pts) and 22 stable PDX were established (overall take rate 27.2%). Take rates were as follows: triple negative breast cancer (46%; 13/28); HER2 (27%; 6/22), Luminal B (13%; 3/22), and luminal A (0%; 0/9). Residual surgical tumor (after all treatment) from 17 pts was injected into 85 mice (average 5 mice/pt) and the initial outgrowth rate was 23% (4/17) with 3 stably transplantable lines established. PDX, derived from pretreatment PTB of 5 pts (2 responders and 3 non-responders), were assessed for in vivo T response. The size of the T treated group was significantly smaller than the no treatment group for the PDX derived from the 2 clinical responders, with complete disappearance of tumor by 18 days. In contrast, the PDX derived from the 3 clinical non-responders had no evidence for T response. CONCLUSIONS We have demonstrated the feasibility of using PTB to establish PDX in a prospective neoadjuvant clinical study and have demonstrated similar T drug response phenotypes in in the PDX as seen in the corresponding pt. These data suggest that PDX generated prospectively may be useful for biomarker validation and the development and individualization of new drug therapy. Funded by the Mayo Clinic Center for Individualized Medicine and the Mayo Clinic Cancer Center Citation Format: Jia Yu, Ping Yin, Bowen Gao, Jason P. Sinnwell, Ann M. Moyer, Daniel W. Visscher, Amy L. Conners, Travis J. Dockter, Krishna R. Kalari, Xiaojia Tang, Kevin J. Thompson, Hugues Sicotte, Douglas W. Mahoney, Steven N. Hart, Peter T. Vedell, Poulami Barman, Katie N. Jones, Sarah A. McLaughlin, John A. Copland, Alvaro Moreno Aspitia, Donald W. Northfelt, Richard J. Gray, Vera J. Suman, Jeanette E. Eckel Passow, Eric D. Wieben, James N. Ingle, Zhenkun Lou, Gianrico Farrugia, Richard Weinshilboum, Matthew P. Goetz, Judy C. Boughey, Liewei Wang. Feasibility of using percutaneous tumor biopsies from a prospective neoadjuvant breast cancer study to develop patient derived xenografts and assess in vivo chemotherapy sensitivity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1195. doi:10.1158/1538-7445.AM2014-1195

Abstract A38: A pilot program in collaboration with African American churches successfully increases the African American population awareness of the importance of cancer research and their participation in cancer translational research studies

Background: African Americans are underrepresented in cancer research trials. We propose that a collaborative effort with African American churches that brings cancer education events and a translational research project to the community with a mobile research unit will facilitate cancer awareness education and increase participation in translational research protocols among African Americans. Methods: From February 2010 through April 2010, Mayo Clinic partnered with predominantly African American Jacksonville churches, with the Volunteers in Medicine Clinic for the working uninsured, and with the local chapter of the Leukemia and Lymphoma Society, to provide 12 education programs focused on five behaviors that reduce cancer risk: proper nutrition, adequate fitness, tobacco cessation, breastfeeding, and limited alcohol consumption. Also offered during these programs was on site access to a translational cancer research pilot project evaluating the prevalence of t(14,18) and monoclonal proteins in African Americans and other racial/ethnic minorities. Translational research participation was facilitated by a mobile research unit (MRU), a converted RV that has sample collection, processing, and storage capabilities. Participants were surveyed on health knowledge and their willingness to participate in research. Results: A total of 236 of 318 participants (74%) returned written questionnaires provided during the education events. Forty-three percent resided in a health zone of Jacksonville that has worse health outcomes compared with any other sections of the city. Eighty-three percent responded that they had some type of health insurance and 88% had a primary care provider. Sixty-seven percent had never received any information on multiple myeloma, and 57% had never received information about clinical research studies. Sixty percent responded that they would participate in research studies and 61 % indicated that they would participate if the research focused on health issues that impacted African Americans. A total of 175 of 318 participants (55%) were enrolled in the translational research feasibility study. Seventy-two percent of the research study participants were female and 77% were African American, 19% Caucasians, and 4% Hispanic or of other racial/ethnic group. Ninety-three percent agreed to have their samples used for research of other health conditions and 85% agreed to have their samples shared with other research institutions. Conclusions: A high rate of participation in a blood collection translational research project was observed among this predominantly African American population. Most participants expressed a positive attitude towards research participation. Partnerships with African American churches in projects that provide community education and bring research to church venues with a mobile research unit are effective in improving health literacy related to a targeted topic, and in increasing translational research participation among African Americans. Funded by Mayo Clinic Comprehensive Cancer Center (NCI grant number P50-CA01508), Mayo Clinic CTSA (NCRR/NIH Grant Number 1 UL1 RR024150) and Active SPORE CA 90297052. Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):A38.