Citations

SummaryMantle cell lymphoma (MCL) is still considered incurable and the course of the disease is highly variable. Established risk factors include the Mantle Cell Lymphoma International Prognostic Index (MIPI) and the quantification of the proliferation rate of the tumour cells, e.g. by Ki‐67 immunohistochemistry. In this study, we aimed to validate the prognostic value of the gene expression‐based MCL35 proliferation assay in patient cohorts from randomized trials of the European Mantle Cell Lymphoma Network. Using this assay, we analysed the gene expression proliferation signature in routine diagnostic lymph node specimens from MCL Younger and MCL Elderly trial patients, and the calculated MCL35 score was used to assign MCL patients to low (61%), standard (27%) or high (12%) risk groups with significantly different outcomes. We confirm here in our prospective clinical trial cohort of MCL patients, that the MCL35 assay is strongly prognostic, providing additional information to the Ki‐67 index and the MIPI. Thus, this robust assay may assist in making treatment decisions or in devising risk‐adapted prospective clinical trials in the future.

Background More than 1.5 million women per year have a benign breast biopsy resulting in concern about their future breast cancer (BC) risk. This study examined the performance of 2 BC risk models that integrate clinical and histologic findings in this population. Methods The BC risk at 5 and 10 years was estimated with the Breast Cancer Surveillance Consortium (BCSC) and Benign Breast Disease to Breast Cancer (BBD‐BC) models for women diagnosed with benign breast disease (BBD) at the Mayo Clinic from 1997 to 2001. Women with BBD were eligible for the BBD‐BC model, but the BCSC model also required a screening mammogram. Calibration and discrimination were assessed. Results Fifty‐six cases of BC were diagnosed among the 2142 women with BBD (median age, 50 years) within 5 years (118 were diagnosed within 10 years). The BBD‐BC model had slightly better calibration at 5 years (0.89; 95% confidence interval [CI], 0.71‐1.21) versus 10 years (0.81; 95% CI, 0.70‐1.00) but similar discrimination in the 2 time periods: 0.68 (95% CI, 0.60‐0.75) and 0.66 (95% CI, 0.60‐0.71), respectively. In contrast, among the 1089 women with screening mammograms (98 cases of BC within 10 years), the BCSC model had better calibration (0.94; 95% CI, 0.85‐1.43) and discrimination (0.63; 95% CI, 0.56‐0.71) at 10 years versus 5 years (calibration, 1.31; 95% CI, 0.94‐2.25; discrimination, 0.59; 95% CI, 0.46‐0.71) where discrimination was not different from chance. Conclusions The BCSC and BBD‐BC models were validated in the Mayo BBD cohort, although their performance differed by 5‐year risk versus 10‐year risk. Further enhancement of these models is needed to provide accurate BC risk estimates for women with BBD.

Purpose Women with atypical hyperplasia (AH) on breast biopsy have an aggregate increased risk of breast cancer (BC), but existing risk prediction models do not provide accurate individualized estimates of risk in this subset of high-risk women. Here, we used the Mayo benign breast disease cohort to develop and validate a model of BC risk prediction that is specifically for women with AH, which we have designated as AH-BC. Patients and Methods Retrospective cohorts of women age 18 to 85 years with pathologically confirmed benign AH from Rochester, MN, and Nashville, TN, were used for model development and external validation, respectively. Clinical risk factors and histologic features of the tissue biopsy were selected using L1-penalized Cox proportional hazards regression. Identified features were included in a Fine and Gray regression model to estimate BC risk, with death as a competing risk. Model discrimination and calibration were assessed in the model-building set and an external validation set. Results The model-building set consisted of 699 women with AH, 142 of whom developed BC (median follow-up, 8.1 years), and the external validation set consisted of 461 women with 114 later BC events (median follow-up, 11.4 years). The final AH-BC model included three covariates: age at biopsy, age at biopsy squared, and number of foci of AH. At 10 years, the AH-BC model demonstrated good discrimination (0.63 [95% CI, 0.57 to 0.70]) and calibration (0.87 [95% CI, 0.66 to 1.24]). In the external validation set, the model showed acceptable discrimination (0.59 [95% CI, 0.51 to 0.67]) and calibration (0.91 [95% CI, 0.65 to 1.42]). Conclusion We have created a new model with which to refine BC risk prediction for women with AH. The AH-BC model demonstrates good discrimination and calibration, and it validates in an external data set.

The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, which antagonizes B cell receptor (BCR) signals, demonstrates remarkable clinical activity in chronic lymphocytic leukemia (CLL). The lymphocytosis experienced by most patients under ibrutinib has previously been attributed to inhibition of BTK-dependent integrin and chemokine cues operating to retain the tumor cells in nodal compartments. Here, we show that the VLA-4 integrin, as expressed by CD49d-positive CLL, can be inside-out activated upon BCR triggering, thus reinforcing the adhesive capacities of CLL cells. In vitro and in vivo ibrutinib treatment, although reducing the constitutive VLA-4 activation and cell adhesion, can be overcome by exogenous BCR triggering in a BTK-independent manner involving PI3K. Clinically, in three independent ibrutinib-treated CLL cohorts, CD49d expression identifies cases with reduced lymphocytosis and inferior nodal response and behaves as independent predictor of shorter progression-free survival, suggesting the retention of CD49d-expressing CLL cells in tissue sites via activated VLA-4. Evaluation of CD49d expression should be incorporated in the characterization of CLL undergoing therapy with BCR inhibitors.

Abstract Purpose: To determine the dose limiting toxicities (DLT), maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of veliparib in combination with weekly topotecan in patients with solid tumors. Correlative studies were included to assess the impact of topotecan and veliparib on poly(ADP-ribose) levels in peripheral blood mononuclear cells, serum pharmacokinetics of both agents, and potential association of germline repair gene mutations with outcome. Experimental Design: Eligible patients had metastatic nonhematologic malignancies with measurable disease. Using a 3 + 3 design, patients were treated with veliparib orally twice daily on days 1–3, 8–10, and 15–17 and topotecan intravenously on days 2, 9, and 16 every 28 days. Tumor responses were assessed by RECIST. Results: Of 58 patients enrolled, 51 were evaluable for the primary endpoint. The MTD and RP2D was veliparib 300 mg twice daily on days 1–3, 8–10, and 15–17 along with topotecan 3 mg/m2 on days 2, 9, and 16 of a 28-day cycle. DLTs were grade 4 neutropenia lasting >5 days. The median number of cycles was 2 (1–26). The objective response rate was 10%, with 1 complete and 4 partial responses. Twenty-two patients (42%) had stable disease ranging from 4 to 26 cycles. Patients with germline BRCA1, BRCA2, or RAD51D mutations remained on study longer than those without homologous recombination repair (HRR) gene mutations (median 4 vs. 2 cycles). Conclusions: Weekly topotecan in combination with veliparib has a manageable safety profile and appears to warrant further investigation.

2 Background: Women with atypical hyperplasia (AH) on breast biopsy have an aggregate increased risk of breast cancer (BC), but accurate personalized risk prediction is desirable to facilitate individual clinical management decisions. Currently used models provide poor BC risk prediction for women with AH. Our goal was to develop and validate an improved risk prediction model for women with AH. Methods: From a cohort of 13,538 women with benign breast disease from 1967-2001, pathology review confirmed 699 with AH. Clinical risk factors and histologic features of the tissue biopsy were recorded, and BC events were ascertained from study questionnaires, tumor registry, and review of medical records. Using a lasso approach, 23 variables were assessed for model inclusion. Lasso-identified features were then fit in a Cox regression model to estimate BC risk. Model discrimination was assessed with C-statistics in the model-building set and in a separate external validation set. Calibration was assessed by comparing observed to predicted breast cancer counts. Results: The model-building set comprised 699 women with 142 BC events (median follow-up 8.1 years), and the external validation set comprised 461 women with 114 BC events (median follow-up 11.4 years). The final model included three covariates: age at biopsy, age squared, and number of foci of AH. Model performance was good, with a C-statistic of 0.622 (SE = 0.027) in the model-building set and 0.594 (SE = 0.029) in the external validation set. The model is well-calibrated, with observed to expected numbers of BCs nearly equal across all post-biopsy follow-up years. Conclusions: We propose a new model for predicting BC risk in women with AH based on age at biopsy and number of foci of atypia. This model provides absolute risk estimates for women with AH, has good discriminatory ability, is well-calibrated, and validates in an external cohort.

PURPOSE: To estimate the efficacy of contralateral prophylactic mastectomy in women with a personal and family history of breast cancer. PATIENTS AND METHODS: We followed the course of 745 women with a first breast cancer and a family history of breast and/or ovarian cancer who underwent contralateral prophylactic mastectomy at the Mayo Clinic between 1960 and 1993. Family history information and cancer follow-up information were obtained from the medical record, a study-specific questionnaire, and telephone follow-up. Life-tables for contralateral breast cancers, which consider age at first breast cancer, current age, and type of family history, were used to calculate the number of breast cancers expected in our cohort had they not had a prophylactic mastectomy. RESULTS: Of the 745 women in our cohort, 388 were premenopausal (age < 50 years) and 357 were post- menopausal. Eight women developed a contralateral breast cancer. Six events were observed among the premenopausal women, compared with 106.2 predicted, resulting in a risk reduction of 94.4% (95% confidence interval [CI], 87.7% to 97.9%). For the 357 postmenopausal women, 50.3 contralateral breast cancers were predicted, whereas only two were observed, representing a 96.0% risk reduction (95% CI, 85.6% to 99.5%). CONCLUSION: The incidence of contralateral breast cancer seems to be reduced significantly after contralateral prophylactic mastectomy in women with a personal and family history of breast cancer.