Alexandra Thomas

The response to neoadjuvant chemotherapy predicts clinical outcome and increases breast conservation in advanced breast cancer

BACKGROUND The aim of this study was to determine outcomes in patients with breast cancer treated with neoadjuvant chemotherapy. METHODS Seventy-two consecutive patients receiving neoadjuvant chemotherapy for breast cancer were enrolled. RESULTS Mastectomy was avoided in 46% of patients, and 42% converted to negative nodes after neoadjuvant chemotherapy. Thirteen patients (18%) achieved a pathologic complete response, which was associated with the estrogen receptor (ER)-negative/human epidermal growth factor receptor 2 (Her2)-negative subtype (58%) and was significantly less likely to occur in the ER+/Her2- subtype (2%) (P < .01). Patients with the ER+/Her2+ subtype were most likely to have no response or progression during chemotherapy, compared with those with the ER-/Her2- subtype (50% vs 0%, P = .01). Five-year survival for patients achieving a pathologic complete response was 100%, compared with 74% in the group with partial response and 48% in the group with no response or progression (P = .01). CONCLUSIONS Neoadjuvant chemotherapy for patients with advanced breast cancer provided prognostic information, allowed evaluation of response to chemotherapy, decreased the mastectomy rate, and potentially reduced the need for axillary lymph node dissection.

Initial Surgery and Survival in Stage IV Breast Cancer in the United States, 1988-2011.

IMPORTANCE Management of the primary tumor site in patients with metastatic breast cancer remains controversial. OBJECTIVE To evaluate the patterns of receipt of initial breast surgery for female patients with stage IV breast cancer in the United States, with particular attention to women who survived at least 10 years. DESIGN, SETTING, AND PARTICIPANTS A retrospective cohort study using data from the Surveillance, Epidemiology, and End Results (SEER) program. Female patients diagnosed as having stage IV breast cancer between 1988 and 2011 and who did not receive radiation therapy as part of the first course of treatment were included (N = 21 372). Kaplan-Meier estimates of median survival and descriptive statistics were used to compare patient and tumor characteristics by receipt of breast surgery at diagnosis. A Royston-Parmar survival model and logistic regression analysis assessed demographic and clinical factors associated with survival and prolonged survival (of at least 10 years). MAIN OUTCOMES AND MEASURES Differences in survival, particularly survival of at least 10 years, by receipt of initial surgery to the primary tumor. RESULTS Among the 21 372 patients, the median survival increased from 20 months (1988-1991) to 26 months (2007-2011). During this time, the rate of surgery declined (odds ratio [OR], 0.16; 95% CI, 0.12-0.21). Even so, receipt of surgery was associated with improved survival in multivariate analysis, which controlled for patient and clinical characteristics, along with time period (hazard ratio, 0.60; 95% CI, 0.57-0.63). For women diagnosed as having cancer before 2002 (n = 7504), survival of at least 10 years was seen in 9.6% (n = 353) and 2.9% (n = 107) of those who did and did not receive surgery, respectively (OR, 3.61; 95% CI, 2.89-4.50). In multivariate analysis, survival of at least 10 years was associated with receipt of surgery (odds ratio, 2.80; 95% CI, 2.08-3.77), hormone receptor-positive disease (OR, 1.76; 95% CI, 1.25-2.48), older age (OR, 0.41; 95% CI, 0.32-0.54), larger tumor size (OR, 0.37; 95% CI, 0.27-0.51), marital status of being separated at the time of diagnosis (OR, 0.67; 95% CI, 0.51-0.88), and more recent year of diagnosis (OR, 1.43; 95% CI, 1.02-1.99). CONCLUSIONS AND RELEVANCE Survival in stage IV breast cancer has improved and is increasingly of prolonged duration, particularly for some women undergoing initial breast surgery. As systemic therapy advances provide better control of distant disease in stage IV breast cancer, and as women present with lower distant disease burdens, these findings on initial surgery to the primary tumor may be of importance.

18-Fluoro-deoxyglucose positron emission tomography report interpretation as predictor of outcome in diffuse large B-cell lymphoma including analysis of ‘indeterminate’ reports

This study evaluates the predictive value of post-therapy 18-fluoro-deoxyglucose positron emission tomography (FDG-PET), including indeterminate studies, following curative-intent therapy in diffuse large B-cell lymphoma (DLBCL). Consecutive patients from September 2002 to December 2005 were prospectively offered enrollment in an observational registry. Available FDG-PET reports after primary therapy were interpreted by hematologist–oncologists as positive, negative, or indeterminate. One hundred twenty-five patients with DLBCL had a median follow-up of 35.2 months. Ninety-three percent were treated with R-CHOP-like therapy. Twenty percent of PET reports were judged indeterminate. Event-free survival (EFS) at 3 years for the negative and indeterminate groups was 85% and 71%, respectively (p = 0.28 by log-rank). Overall survival (OS) at 3 years for negative, indeterminate, and positive groups was 89%, 88%, and 48%. Combining the pre-therapy International Prognostic Index (IPI) with the post-therapy FDG-PET result added to the predictive value of the study for patients. Three-year EFS for patients with low or low-intermediate IPI risk and an indeterminate FDG-PET report was 93%, while for those with high or high-intermediate pre-therapy IPI the 3-year EFS was 45% (p < 0.02). Interpreting FDG-PET reports following curative-intent chemotherapy in patients is informative but imprecise, and incorporation of pre-therapy prognosis can improve predictive utility.

Inhibition of RET increases the efficacy of antiestrogen and is a novel treatment strategy for luminal breast cancer.

Purpose: Recent findings suggest that combination treatment with antiestrogen and anti-RET may offer a novel treatment strategy in a subset of patients with breast cancer. We investigated the role of RET in potentiating the effects of antiestrogen response and examined whether RET expression predicted the ability for tyrosine kinase inhibitor (TKI) to affect extracellular signal–regulated kinase 1/2 (ERK1/2) activation in primary breast cancer. Experimental Design: Growth response, ERK1/2 activation, Ki-67, and terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling were assessed in breast cancer cell lines in vitro and in xenografts with vandetanib and/or tamoxifen. Thirty tumors with matched normal breast tissue were evaluated for RET expression and response to TKI treatment. Results: Vandetanib potentiated the inhibitory effect of tamoxifen in hormone responsive (P = 0.01) and hormone insensitive (P < 0.001) estrogen receptor α (ERα)-positive breast cancer cells. Vandetanib significantly repressed tumorigenesis of MCF-7 xenografts (P < 0.001), which displayed decreased activation of ERK1/2 and AKT. Vandetanib and tamoxifen reduced the growth of established tumors with a greater effect of dual therapy compared with single agent (P = 0.003), with tamoxifen-reducing proliferative index and vandetanib-inducing apoptosis. In primary breast cancers, RET expression correlated with the ERα-positive subtype. Relative decrease in ERK1/2 phosphorylation with TKI treatment was 42% (P < 0.001) in RET-positive tumors versus 14% (P = ns) in RET-negative tumors. Conclusions: Vandetanib potentiated the antigrowth effects of tamoxifen in breast cancer, which was mediated through RET activation. RET predicted response to TKI therapy with minimal effects on ERK1/2 activation in RET-negative tumors. The preclinical data support evaluation of antiestrogen in combination with TKI as a potential treatment strategy for RET-positive luminal breast cancer. Clin Cancer Res; 20(8); 2115–25. ©2014 AACR.

Primary Breast Lymphoma in the United States: 1975–2013

Background Primary breast lymphoma (PBL) has gained attention with the description of breast implant-associated anaplastic large cell lymphoma (ALCL). Less is known about PBL incidence, treatment, and survival by lymphoma subtype. Methods The Surveillance, Epidemiology, and End Results (SEER) registry database was queried for patients with PBL as first malignancy, with attention to non-Hodgkin Lymphoma PBL subtypes: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, marginal zone lymphoma (MZL), and ALCL. Incidence was estimated by age and subtype with joinpoint analyses, along with initial local therapy. Five-year relative and overall survival estimates were compared using z and two-sided log-rank tests. Results PBL incidence (per 1 000 000 women) increased from 0.66 (1975-1977) to 2.96 (2011-2013) with an annual percentage change (APC) of 5.3% (95% confidence interval [CI] = 3.8% to 6.9%, P <  .001) from 1975 to 1999 and no statistically significant change thereafter. Incidence continues to increase for women younger than age 50 years (APC = 2.8%, 95% CI = 1.0% to 4.6%, P = .003) and for ALCL-PBL (APC = 11.8%, 95% CI = 0.2% to 24.9%, P =  .047) and MZL-PBL (APC = 2.3%, 95% CI = -0.2% to 4.9%, P =  .07), with the latter increasing significantly from 1995 to 2013 (APC = 7.5%, 95% CI = 3.4% to 11.8%, P =  .001). Surgery and surgery with radiation declined from 2000 to 2013 as initial local therapy for PBL. Five-year relative survival for PBL improved markedly over four decades and was superior for stage I DLBCL-PBL and stage I follicular PBL than for corresponding systemic presentations. Conclusions PBL has increased in incidence over the last four decades and continues to increase for younger women and for some subtypes. The rise in imaging and procedures to the breast might enhance diagnostic sensitivity for PBL. Further study of the etiologies of PBL is needed.

Circulating mutational portrait of cancer : manifestation of aggressive clonal events in both early and late stages

BackgroundSolid tumors residing in tissues and organs leave footprints in circulation through circulating tumor cells (CTCs) and circulating tumor DNAs (ctDNA). Characterization of the ctDNA portraits and comparison with tumor DNA mutational portraits may reveal clinically actionable information on solid tumors that is traditionally achieved through more invasive approaches.MethodsWe isolated ctDNAs from plasma of patients of 103 lung cancer and 74 other solid tumors of different tissue origins. Deep sequencing using the Guardant360 test was performed to identify mutations in 73 clinically actionable genes, and the results were associated with clinical characteristics of the patient. The mutation profiles of 37 lung cancer cases with paired ctDNA and tumor genomic DNA sequencing were used to evaluate clonal representation of tumor in circulation. Five lung cancer cases with longitudinal ctDNA sampling were monitored for cancer progression or response to treatments.ResultsMutations in TP53, EGFR, and KRAS genes are most prevalent in our cohort. Mutation rates of ctDNA are similar in early (I and II) and late stage (III and IV) cancers. Mutation in DNA repair genes BRCA1, BRCA2, and ATM are found in 18.1% (32/177) of cases. Patients with higher mutation rates had significantly higher mortality rates. Lung cancer of never smokers exhibited significantly higher ctDNA mutation rates as well as higher EGFR and ERBB2 mutations than ever smokers. Comparative analysis of ctDNA and tumor DNA mutation data from the same patients showed that key driver mutations could be detected in plasma even when they were present at a minor clonal population in the tumor. Mutations of key genes found in the tumor tissue could remain in circulation even after frontline radiotherapy and chemotherapy suggesting these mutations represented resistance mechanisms. Longitudinal sampling of five lung cancer cases showed distinct changes in ctDNA mutation portraits that are consistent with cancer progression or response to EGFR drug treatment.ConclusionsThis study demonstrates that ctDNA mutation rates in the key tumor-associated genes are clinical parameters relevant to smoking status and mortality. Mutations in ctDNA may serve as an early detection tool for cancer. This study quantitatively confirms the hypothesis that ctDNAs in circulation is the result of dissemination of aggressive tumor clones and survival of resistant clones. This study supports the use of ctDNA profiling as a less-invasive approach to monitor cancer progression and selection of appropriate drugs during cancer evolution.

A Randomized Controlled Study Comparing Educational Outcomes of Examination Room Versus Conference Room Staffing

Background: This prospective randomized controlled study examined outpatient clinical teaching in the presence of the patient. Methods: In 2006, patients in ambulatory internal medicine clinics at the University of Iowa were randomized to have faculty-learner presentations either in their presence or in the conference room. Staffing encounters were timed and faculty, learners and patients completed postencounter surveys. Results: Participation included 254 patients and 12 faculty. Comparison of patient encounters randomized to exam room ( n = 120) or conference room ( n = 134) staffing demonstrated increased time spent with the patient in exam room staffing (91% vs. 54% of total staffing time; p < .0001) but no significant differences in mean total staffing time. Patients, learners, and faculty preferred exam room staffing. Conclusions: Concerns about time efficiency and patient and learner satisfaction during exam room staffing were not supported. This approach may allow attending physicians to maximize billing levels while increasing learner/patient involvement.

Serum Vitamin D Levels Affect Pathologic Complete Response in Patients Undergoing Neoadjuvant Systemic Therapy for Operable Breast Cancer

Introduction: There has been increasing interest in the potential benefit of vitamin D in improving breast cancer outcome. Preclinical studies suggest that vitamin D enhances chemotherapy‐induced cell death. We investigated the impact of serum vitamin D levels during neoadjuvant chemotherapy (NAC) on the rates of achieving pathologic complete response (pCR) after breast cancer NAC. Patients and Methods: Patients from 1 of 2 Iowa registries who had serum vitamin D level measured before or during NAC were included. French patients enrolled onto a previous study of the impact of NAC on vitamin D and bone metabolism were also eligible for this study. Vitamin D deficiency was defined as < 20 ng/mL. pCR was defined as no residual invasive disease in breast and lymph nodes. A Firth penalized logistic regression multivariable model was used. Results: The study included 144 women. There was no difference between the French and Iowan cohorts with regard to age at diagnosis (P = .20), clinical stage (P = .22), receptor status (P = .32), and pCR rate (P = .34). French women had lower body mass index (mean 24.8 vs. 28.8, P < .01) and lower vitamin D levels (mean 21.5 vs. 27.5, P < .01) compared to Iowan patients. In multivariable analysis, after adjusting for the effects of cohort, clinical stage, and receptor status, vitamin D deficiency increased the odds of not attaining pCR by 2.68 times (95% confidence interval, 1.12‐6.41, P = .03). Conclusion: Low serum vitamin D levels were associated with not attaining a pCR. Prospective trials could elucidate if maintaining vitamin D levels during NAC, a highly modifiable variable, may be utilized to improve cancer outcomes.

Optoacoustic imaging identifies ovarian cancer using a microenvironment targeted theranostic wormhole mesoporous silica nanoparticle

At the intersection of the newly emerging fields of optoacoustic imaging and theranostic nanomedicine, promising clinical progress can be made in dismal prognosis of ovarian cancer. An acidic pH targeted wormhole mesoporous silica nanoparticle (V7-RUBY) was developed to serve as a novel tumor specific theranostic nanoparticle detectable using multispectral optoacoustic tomographic (MSOT) imaging. We report the synthesis of a small, < 40 nm, biocompatible asymmetric wormhole pore mesoporous silica core particle that has both large loading capacity and favorable release kinetics combined with tumor-specific targeting and gatekeeping. V7-RUBY exploits the acidic tumor microenvironment for tumor-specific targeting and tumor-specific release. In vitro, treatment with V7-RUBY containing either paclitaxel or carboplatin resulted in increased cell death at pH 6.6 in comparison to drug alone (p < 0.0001). In orthotopic ovarian xenograft mouse models, V7-RUBY containing IR780 was specifically detected within the tumor 7X and 4X higher than the liver and >10X higher than in the kidney using both multispectral optoacoustic tomography (MSOT) imaging with secondary confirmation using near infrared fluorescence imaging (p < 0.0004). The V7-RUBY system carrying a cargo of either contrast agent or an anti-neoplastic drug has the potential to become a theranostic nanoparticle which can improve both diagnosis and treatment of ovarian cancer.

Rapid and Sensitive Detection of Breast Cancer Cells in Patient Blood with Nuclease-Activated Probe Technology

A challenge for circulating tumor cell (CTC)-based diagnostics is the development of simple and inexpensive methods that reliably detect the diverse cells that make up CTCs. CTC-derived nucleases are one category of proteins that could be exploited to meet this challenge. Advantages of nucleases as CTC biomarkers include: (1) their elevated expression in many cancer cells, including cells implicated in metastasis that have undergone epithelial-to-mesenchymal transition; and (2) their enzymatic activity, which can be exploited for signal amplification in detection methods. Here, we describe a diagnostic assay based on quenched fluorescent nucleic acid probes that detect breast cancer CTCs via their nuclease activity. This assay exhibited robust performance in distinguishing breast cancer patients from healthy controls, and it is rapid, inexpensive, and easy to implement in most clinical labs. Given its broad applicability, this technology has the potential to have a substantive impact on the diagnosis and treatment of many cancers.