Publications by authors named "Maysa M Abu-Khalaf"

23 Publications

  • Page 1 of 1

Prognostic value of HER2 status on circulating tumor cells in advanced-stage breast cancer patients with HER2-negative tumors.

Breast Cancer Res Treat 2020 Jun 4;181(3):679-689. Epub 2020 May 4.

Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, 19107, USA.

Purpose: Discordance between HER2 expression in tumor tissue (tHER2) and HER2 status on circulating tumor cells (cHER2) has been reported. It remains largely underexplored whether patients with tHER2/cHER2 can benefit from anti-HER2 targeted therapies.

Methods: cHER2 status was determined in 105 advanced-stage patients with tHER2 breast tumors. Association between cHER2 status and progression-free survival (PFS) was analyzed by univariate and multivariate Cox models and survival differences were compared by Kaplan-Meier method.

Results: Compared to the patients with low-risk cHER2 (cHER2  < 2), those with high-risk cHER2 (cHER2  ≥ 2) had shorter survival time and an increased risk for disease progression (hazard ratio [HR] 2.16, 95% confidence interval [CI] 1.20-3.88, P = 0.010). Among the patients with high-risk cHER2, those who received anti-HER2 targeted therapies had improved PFS compared with those who did not (HR 0.30, 95% CI 0.10-0.92, P = 0.035). In comparison, anti-HER2 targeted therapy did not affect PFS among those with low-risk cHER2 (HR 0.70, 95% CI 0.36-1.38, P = 0.306). Similar results were obtained after adjusting covariates. A longitudinal analysis of 67 patients with cHER2 detected during follow-ups found that those whose cHER2 status changed from high-risk at baseline to low-risk at first follow-up exhibited a significantly improved survival compared to those whose cHER2 remained high-risk (median PFS: 11.7 weeks vs. 2.0 weeks, log-rank P = 0.001).

Conclusion: In advanced-stage breast cancer patients with tHER2 tumors, cHER2 status has the potential to guide the use of anti-HER2 targeted therapy in patients with high-risk cHER2.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10549-020-05662-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299127PMC
June 2020

Examining the cost-effectiveness of baseline left ventricular function assessment among breast cancer patients undergoing anthracycline-based therapy.

Breast Cancer Res Treat 2019 Jul 24;176(2):261-270. Epub 2019 Apr 24.

Cardiovascular Institute of Rhode Island, Warren Alpert Medical School of Brown University, Providence, RI, USA.

Background: There is a lack of consensus to guide which breast cancer patients require left ventricular function assessment (LVEF) prior to anthracycline therapy; the cost-effectiveness of screening this patient population has not been previously evaluated.

Methods: We performed a retrospective analysis of the Yale Nuclear Cardiology Database, including 702 patients with baseline equilibrium radionuclide angiography (ERNA) scan prior to anthracycline and/or trastuzumab therapy. We sought to examine associations between abnormal baseline LVEF and potential cardiac risk factors. Additionally, we designed a Markov model to determine the incremental cost-effectiveness ratio (ICER) of ERNA screening for women aged 55 with stage I-III breast cancer from a payer perspective over a lifetime horizon.

Results: An abnormal LVEF was observed in 2% (n = 14) of patients. There were no significant associations on multivariate analysis performed on self-reported risk factors. Our analysis showed LVEF screening is cost-effective with ICER of $45,473 per QALY gained. For a willingness-to-pay threshold of $100,000/ QALY, LVEF screening had an 81.9% probability of being cost-effective. Under the same threshold, screening was cost-effective for non-anthracycline cardiotoxicity risk of RR ≤ 0.58, as compared to anthracycline regimens.

Conclusions: Age, preexisting cardiac risk factors and coronary artery disease did not predict a baseline abnormal LVEF. While the prevalence of an abnormal baseline LVEF is low in patients with breast cancer, our results suggest that cardiac screening prior to anthracycline is cost-effective.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10549-019-05178-zDOI Listing
July 2019

Association of clinical outcomes in metastatic breast cancer patients with circulating tumour cell and circulating cell-free DNA.

Eur J Cancer 2019 01 4;106:133-143. Epub 2018 Dec 4.

Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA. Electronic address:

Background: Both circulating tumour cell (CTC) and total circulating cell-free DNA (ccfDNA) predict cancer patient prognosis. However, no study has explored the prognostic value of the combined use of CTC and ccfDNA. We aimed to investigate individual and joint effects of CTC and ccfDNA on clinical outcomes of metastatic breast cancer (MBC) patients.

Methods: We collected 227 blood samples from 117 MBC patients. CTCs were enumerated using the CellSearch System. ccfDNAs were quantified by quantitative real-time polymerase chain reaction and Qubit fluorometer. The individual and joint effects of CTC and ccfDNA levels on patient progression-free survival (PFS) and overall survival (OS) were analysed using Cox proportional hazards models.

Results: Compared to patients with <5 CTCs, patients with ≥5 CTCs had a 2.58-fold increased risk of progression and 3.63-fold increased risk of death. High level of ccfDNA was associated with a 2.05-fold increased risk of progression and 3.56-fold increased risk of death. These associations remained significant after adjusting for other important clinical covariates and CTC/ccfDNA levels. CTC and ccfDNA levels had a joint effect on patient outcomes. Compared to patients with low levels of both CTC and ccfDNA, those with high levels of both markers exhibited a >17-fold increased death risk (P < 0.001). Moreover, longitudinal analysis of 132 samples from 22 patients suggested that the inconsistency between CTC level and outcome in some patients could possibly be explained by ccfDNA level.

Conclusions: CTC and total ccfDNA levels were individually and jointly associated with PFS and OS in MBC patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2018.10.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347110PMC
January 2019

Racial and Ethnic Disparities in Oncotype DX Test Receipt in a Statewide Population-Based Study.

J Natl Compr Canc Netw 2017 03;15(3):346-354

Cancer Outcomes Public Policy Effectiveness Research (COPPER) Center, Yale University, New Haven, Connecticut

Racial disparities have been reported in breast cancer care, yet little is known about disparities in access to gene expression profiling (GEP) tests. Given the impact of GEP test results, such as those of Oncotype DX (ODx), on treatment decision-making for hormone receptor-positive (HR+) breast cancer, it is particularly important to assess disparities in its use. We conducted a retrospective population-based study of 8,784 patients diagnosed with breast cancer in Connecticut during 2011 through 2013. We assessed the association between race, ethnicity, and ODx receipt among women with HR+ breast cancer for whom NCCN does and does not recommend ODx testing, using bivariate and multivariate logistic analyses. We identified 5,294 women who met study inclusion criteria: 83.8% were white, 6.3% black, and 7.4% Hispanic. Overall, 50.9% (n=4,131) of women in the guideline-recommended group received ODx testing compared with 18.5% (n=1,163) in the nonrecommended group. More white women received the ODx test compared with black and Hispanic women in the recommended and nonrecommended groups (51.4% vs 44.6% and 47.7%; and 21.2% vs 9.0% and 9.7%, respectively). After adjusting for tumor and clinical characteristics, we observed significantly lower ODx use among black (odds ratio [OR], 0.64; 95% CI, 0.47-0.88) and Hispanic women (OR, 0.59; 95% CI, 0.45-0.77) compared with white women in the recommended group and in the guideline-discordant group (blacks: OR, 0.39; 95% CI, 0.20-0.78, and Hispanics: OR, 0.44; 95% CI, 0.23-0.85). In this population-based study, we identified racial disparities in ODx testing. Disparities in access to innovative cancer care technologies may further exacerbate existing disparities in breast cancer outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.6004/jnccn.2017.0034DOI Listing
March 2017

Chemotherapy for Elderly Ovarian Cancer Patients.

Gynecol Obstet (Sunnyvale) 2016 Aug 31;6(8). Epub 2016 Aug 31.

Section of Medical Oncology, Yale University School of Medicine, Yale Cancer Center, New Haven CT, USA.

Objective: Ovarian cancer is the most lethal cancer involving the female pelvic reproductive system. Its incidence increases with age and with an aging population, its prevalence should also increase. The goal of our retrospective study is to report our experience in treating women over 65 years of age, with a diagnosis of primary ovarian cancer, using standard intravenous chemotherapy.

Methods: The medical records of 78 patients>65 years of age diagnosed with primary ovarian cancer at the Yale Cancer Center between 1996-2006 were retrospectively reviewed and included in our analysis. Patients had stage I-IV disease (stage I n=5, stage II n=8, stage III n=36, stage IV n=25, unknown n=4).

Results: Sixty-three of 78 women (80.8%) completed the prescribed regimen; and 62 women did not require a dose reduction or chemotherapy discontinuation. The most common reason for a dose reduction or treatment discontinuation was fatigue (6.4%), neutropenia (2.6%), patient preference (2.6%), and multiple co-morbidities (2.6%). The most commonly used regimen was paclitaxel 175mg/m and carboplatin AUC 5. The hazard ratio for PFS and OS for patients who had dose reduction/discontinuation versus those who completed the prescribed dose was 1.3 (95% CI 0.51-3.26) and 0.63 (95% CI 0.17-2.33), respectively.

Conclusions: Our findings illustrate that elderly women are able to tolerate standard chemotherapy with relatively few significant adverse effects. While different treatment modalities in ovarian cancer are continually being evaluated, additional prospective studies are required to better understand the tolerability and efficacy of such treatment in the elderly population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5042145PMC
http://dx.doi.org/10.4172/2161-0932.1000397DOI Listing
August 2016

Patient preferences regarding incidental genomic findings discovered during tumor profiling.

Cancer 2016 May 11;122(10):1588-97. Epub 2016 Mar 11.

Section of Medical Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut.

Background: During the process of tumor profiling, there is the potential to detect germline variants. To the authors' knowledge, there currently is no accepted standard of care for how to deal with these incidental findings. The goal of the current study was to assess disclosure preferences among patients with cancer regarding incidental genomic variants that may be discovered during tumor profiling.

Methods: A 45-item questionnaire was administered to 413 patients in ambulatory oncology clinics. The survey captured demographic and disease variables and personal and family history, and presented case scenarios for different types of incidental germline variants that could theoretically be detected during genomic analysis of a patient's tumor.

Results: The possibility of discovering non-cancer-related, germline variants did not deter patients from tumor profiling: 77% wanted to be informed concerning variants that could increase their risk of a serious but preventable illness, 56% wanted to know about variants that cause a serious but unpreventable illness, and 49% wanted to know about variants of uncertain significance. The majority of patients (75%) indicated they would share hereditary information regarding predisposition to preventable diseases with family and 62% would share information concerning unpreventable diseases. The most frequent concerns about incidental findings were ability to obtain health (48%) or life (41%) insurance. Only 21% of patients were concerned about privacy of information.

Conclusions: Patients with cancer appear to prefer to receive information regarding incidental germline variants, but there is substantial variability with regard to what information patients wish to learn. The authors recommend that personal preferences for the disclosure of different types of incidental findings be clarified before a tumor profiling test is ordered. Cancer 2016;122:1588-97. © 2016 American Cancer Society.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.29951DOI Listing
May 2016

New Strategies in Breast Cancer: Immunotherapy.

Clin Cancer Res 2016 05 11;22(9):2105-10. Epub 2016 Feb 11.

Department of Medical Oncology, IRCCS Ospedale San Raffaele, Milan, Italy.

More than 70% of breast cancers contain lymphocytic infiltration in the stroma, and preclinical studies suggest that immunoediting and partial control of cancer progression by the local immune microenvironment operate in most breast cancers. Consistent with this hypothesis, a large number of studies demonstrated a favorable prognostic and chemotherapy response predictive role for immune infiltration in breast cancer. The evidence is particularly strong for triple-negative and HER2-positive cancers. The development of clinically effective immune checkpoint inhibitors now provides an opportunity to test the therapeutic potential of augmenting the local antitumor immune response. Several phase I clinical trials using single-agent anti-PD-1 and anti-PD-L1 antibodies demonstrated objective tumor response rates, with remarkably durable responses, in heavily pretreated, metastatic, triple-negative cancers and somewhat lower responses in estrogen receptor-positive cancers. Currently, close to 50 ongoing, or soon to open, clinical trials evaluate the role of this new treatment modality in breast cancer. Clin Cancer Res; 22(9); 2105-10. ©2016 AACR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-15-1315DOI Listing
May 2016

Immune Signatures Following Single Dose Trastuzumab Predict Pathologic Response to PreoperativeTrastuzumab and Chemotherapy in HER2-Positive Early Breast Cancer.

Clin Cancer Res 2016 07 3;22(13):3249-59. Epub 2016 Feb 3.

Case Western Reserve University School of Medicine, Cleveland, Ohio.

Purpose: Recent data suggest that intrinsic subtype and immune cell infiltration may predict response to trastuzumab-based therapy. We studied the interaction between these factors, changes in immune signatures following brief exposure to trastuzumab, and achievement of pathologic complete response (pCR) to subsequent preoperative trastuzumab and chemotherapy in HER2-positive breast cancer.

Experimental Design: In patients enrolled on two multicenter trials (03-311 and 211B), tumor core biopsies were obtained at baseline and after brief exposure to single-agent trastuzumab or nab-paclitaxel. Gene expression profiles were assessed to assign PAM50 subtypes, measure immune cell activation, and were correlated with response.

Results: The pCR rate was significantly higher in HER2-enriched tumors in the Discovery, 03-311 (36%, P = 0.043) dataset, as compared with other subtypes, which validated in 211B (50%, P = 0.048). Significant increases in a signature of immune cell admixture (Immune Index) were observed only following brief exposure to trastuzumab in HER2-enriched tumors (Discovery/03-311, P = 0.05; Validation/211B, P = 0.02). Increased Immune Index was predictive of response after brief exposure (03-311, P = 0.03; 211B, P = 0.04), but not at baseline, in addition to increased expression of a CD4(+) follicular helper T-cell signature (03-311, P = 0.05; 211B, P = 0.04). Brief exposure to trastuzumab significantly increased gene expression of the T-cell marker PD-1 in HER2-enriched tumors (Discovery/03-311, P = 0.045) and PD-1 positivity by IHC (Validation/211B, P = 0.035).

Conclusions: Correlations between pCR rates, increases in Immune Index and markers of T-cell activity following brief exposure to trastuzumab in HER2-enriched tumors provide novel insights into the interaction between tumor biology, antitumor immunity, and response to treatment, and suggest potential clinically useful biomarkers in HER2(+) breast cancers. Clin Cancer Res; 22(13); 3249-59. ©2016 AACR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-15-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5439498PMC
July 2016

Association of 21-gene recurrence score assay and adjuvant chemotherapy use in the medicare population, 2008-2011.

J Geriatr Oncol 2016 Jan 17;7(1):15-23. Epub 2015 Dec 17.

Cancer Outcomes, Public Policy, and Effectiveness Research (COPPER) Center, Yale Comprehensive Cancer Center and Yale University School of Medicine, Harkness Office Building, 367 Cedar Street, New Haven CT, 06510, United States; Section of General Internal Medicine, Yale University School of Medicine, PO Box 208025, New Haven, CT 06520-8025, United States; Yale Cancer Center, Yale University School of Medicine, PO Box 208028, New Haven, CT 06520-8028, United States. Electronic address:

Objectives: The 21-gene recurrence score (RS) assay helps guide adjuvant chemotherapy use for patients with breast cancer, and is predicted to reduce overall chemotherapy use. Little is known about recent patterns of testing in the Medicare program and the impact of testing on chemotherapy use as a function of patient age.

Materials And Methods: We conducted a national claims-based study of Medicare beneficiaries age ≥ 66 years. We assessed trends in assay use (using multivariable regression), adjuvant chemotherapy use, and associated expenditures, for all patients and for two age strata: age 66-74 years and 75-94 years. Geographic variations in assay adoption and regional-level correlation between assay and chemotherapy use were measured.

Results: We identified 132,222 women who underwent breast surgery from 2008-2011. Assay use increased from 9.0% to 17.2% from 2008-2011 (p<.001), but chemotherapy use remained stable at 12.5% (p=.49). In younger patients, assay use increased from 14.3% to 23.7% (p<.001), while chemotherapy use decreased from 18.2% to 16.2% (p<.001). In older patients, assay use increased from 4.1% to 9.9% (p<.001), while chemotherapy use remained stable at 6.8% (p=.67). Mean per-beneficiary expenditures for testing and chemotherapy increased from $2030 to $2430 (p<.001). Regions with increased assay adoption were not more likely to reduce chemotherapy.

Conclusion: Despite increased RS testing for both younger and older Medicare patients, there has only been a modest decrease in chemotherapy use for younger patients and no change for older patients, resulting in an overall increase in costs associated with gene expression profiling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jgo.2015.11.002DOI Listing
January 2016

Use of neoadjuvant chemotherapy for patients with stage I to III breast cancer in the United States.

Cancer 2015 Aug 22;121(15):2544-52. Epub 2015 Apr 22.

Cancer Outcomes, Public Policy, and Effectiveness Research Center, Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Connecticut.

Background: Neoadjuvant chemotherapy (NAC) is the standard of care for patients with locally advanced breast cancer and can yield clinical advantages in individuals with lower stage cancers as well. To the authors' knowledge, the extent and patterns of use of NAC remain unknown. The objective of the current study was to assess temporal trends in NAC use and to examine what clinical, demographic, and treatment site characteristics influence its use.

Methods: Data from the National Cancer Data Base regarding 395,486 patients with stage I to stage III breast cancer who received adjuvant or neoadjuvant chemotherapy in the United States from 2003 through 2011 were analyzed. Chi-square tests and logistic regression analyses were used to assess the association between NAC use and patient, tumor, and facility characteristics.

Results: Overall, 17.4% of patients received NAC, including 4% of patients with stage I disease, 17.8% of patients with stage II disease, and 41.6% of patients with stage III disease. NAC use increased over time from 12.2% to 24.0%, particularly among patients with more advanced cancers. Rates increased from 12.9% to 39.3% in patients with stage IIIA, from 72.3% to 86.4% in patients with stage IIIB, and from 30.1% to 59.3% in patients with stage IIIC cancers. On multivariate analysis, patients aged <60 years, African American individuals, and those treated in academic centers were more likely to receive NAC. NAC use also varied by geographic region and was the highest in the West South Central region (21%) and lowest in the Midwest (15.2%).

Conclusions: Although NAC use increased between 2003 and 2011, <50% of all patients with stage III breast cancer were treated with NAC. Substantial regional and practice-related variations exist.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.29348DOI Listing
August 2015

Systematic approach to providing breast cancer survivors with survivorship care plans: a feasibility study.

J Oncol Pract 2015 Mar;11(2):e170-6

Yale University School of Public Health; and Yale University School of Medicine, New Haven, CT

Purpose: This was a feasibility study with the primary purpose to identify women with a diagnosis of breast cancer for survivorship care plan (SCP) delivery at the postoperative visit and deliver an SCP after treatment. The secondary purpose was to determine if patients' knowledge about their diagnosis, treatment, and risk for future adverse events improved with the SCP.

Methods: Sixty-seven English-speaking women older than age 18 years with stage I-III breast cancer were enrolled at their postoperative appointment. The participants' treatment was tracked through the electronic medical record; SCPs were generated based on information abstracted from the records. After treatment completion, participants received an SCP during a routine follow-up appointment. Knowledge of tumor, treatments, adverse events, and screening recommendations were assessed before receiving the SCP and 2 months later. Accuracy at baseline and follow-up were compared using the McNemar test.

Results: One hundred twenty-nine visits were screened to identify 75 eligible participants. Seventy-five eligible participants (100%) agreed to enroll, and 71 (95%) were given an SCP. Participants were more accurate in reporting details about their history, screening recommendations, and potential adverse events at follow-up than they were at baseline for most measures, but the only statistically significant changes were found with stage (P = .0016) and increased risk of leukemia (P = .0348).

Conclusion: It is feasible to identify and deliver SCPs to women with breast cancer who are approached during the postoperative visit in a surgical clinic. Additionally, SCPs seem to improve patient knowledge in several areas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JOP.2015.005173DOI Listing
March 2015

Sirolimus and trastuzumab combination therapy for HER2-positive metastatic breast cancer after progression on prior trastuzumab therapy.

Breast Cancer Res Treat 2015 Feb 17;150(1):157-67. Epub 2015 Feb 17.

Section of Medical Oncology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT, 06520, USA,

Constitutive activation of the PI3K/Akt/mTOR pathway has been suggested as a mechanism of resistance to trastuzumab therapy. This phase II trial was designed to evaluate the safety and clinical activity of daily oral sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, in combination with trastuzumab in HER2-positive metastatic breast cancer following disease progression on prior trastuzumab therapy. Sirolimus 6 mg oral daily dose was administered with a standard dose and schedule of trastuzumab weekly or every 3 weeks. Pharmacodynamic studies included Western blot analysis of S6K1, phosphoS6K1, and mTOR in peripheral mononuclear cells, circulating tumor cells (CTC), and endothelial cells (CEC). Eleven patients were evaluable for safety; and nine were evaluable for response assessment. Subsequent enrollment was stopped due to slow accrual. Study treatment-related grade 3 toxicity included pneumonitis, myelosuppression (leukopenia/anemia), and dermatologic reactions (mucositis, nail changes and rash), with no grade 4 events. One patient received eight cycles (58 weeks) and achieved a partial response. Five patients treated for a total of 101 weeks (median 12 weeks, range 8-47 weeks) achieved stable disease as best response. Overall response rate was 1/9 (11 %) and clinical benefit rate was 4/9 (44 %). There was no statistically significant correlation between response and post-treatment change in levels of the mTOR pathway biomarkers, CTCs, HER2 CTCs, or CECs. Sirolimus 6 mg administered daily with trastuzumab appears to be well tolerated in patients with metastatic HER2-positive breast cancer following disease progression on prior trastuzumab therapy, with evidence of disease activity. mTOR inhibition may overcome resistance to trastuzumab in some HER2-positive tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10549-015-3292-8DOI Listing
February 2015

Phase 1b study of the mammalian target of rapamycin inhibitor sirolimus in combination with nanoparticle albumin-bound paclitaxel in patients with advanced solid tumors.

Cancer 2015 Jun 3;121(11):1817-26. Epub 2015 Feb 3.

Department of Medical Oncology, Case Western University, Cleveland, Ohio.

Background: The optimal weekly oral dose of sirolimus and intravenous nanoparticle albumin-bound paclitaxel (nab-paclitaxel) were evaluated.

Methods: A phase 1b study was performed to evaluate escalating doses of oral sirolimus (5-60 mg) on days 2, 9, and 16 with intravenous nab-paclitaxel (100 mg/m(2) ) on days 1, 8, and 15 in a 28-day cycle. A run-in treatment of nab-paclitaxel (day -14) and sirolimus (day -7) was administered for pharmacokinetic and pharmacodynamic assessments. Clinical trial endpoints included dose-limiting toxicities (DLTs), maximum tolerated doses, and response rates. Pharmacodynamics included immunohistochemistry for phosphatase and tensin homolog, mammalian target of rapamycin (mTOR), AKT, phosphorylated AKT, S6K1, and phosphorylated S6K1; exploratory gene expression analysis; and [(18) F]fludeoxyglucose (FDG) positron emission tomography.

Results: Twenty-three patients with advanced solid tumors were treated. Fifteen patients had prior taxane therapy. Twenty-two patients were evaluable for responses. One patient had a complete response, and 5 patients had a partial response (3 confirmed). DLTs were seen in 1 patient each at 10 (grade 3 dyspnea/hypoxia) and 40 mg (grade 4 leukopenia/neutropenia) and in 2 patients at 60 mg (grade 3 fatigue and grade 4 pericardial effusion). Patients with higher expression of posttreatment AKT and a greater decline in FDG activity were more likely to have a treatment response or stable disease.

Conclusions: Sirolimus showed an acceptable safety profile at a weekly dose of 40 mg with weekly intravenous nab-paclitaxel at 100 mg/m(2) on days 1, 8, and 15 every 28 days. The posttreatment AKT score and changes in FDG activity may have roles as early predictors of responses to mTOR inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.29254DOI Listing
June 2015

Quantitative measurements of HER2 and phospho-HER2 expression: correlation with pathologic response to neoadjuvant chemotherapy and trastuzumab.

BMC Cancer 2014 May 8;14:326. Epub 2014 May 8.

Department of Pathology, Yale University School of Medicine, 310 Cedar Street, PO Box 208023, New Haven, CT 06520-8023, USA.

Background: Preoperative therapy with chemotherapy and the HER2-targeted monoclonal antibody trastuzumab is valuable for patients with large or locally advanced HER2-positive (HER2+) breast cancers but traditional methods of measuring HER2 expression do not accurately stratify patients for likelihood of response. Quantitative immunofluorescent approaches have the potential to provide a mathematically continuous measure of HER2. Here we seek to determine whether quantitative measurement of HER2 or phospho-HER2 correlates with likelihood of response to trastuzumab- containing neoadjuvant therapy.

Methods: We evaluated core biopsy samples from 27 HER2+ breast cancer patients enrolled in a preoperative clinical trial using trastuzumab, nab-paclitaxel and carboplatin combination therapy (BrUOG BR-211B (NCT00617942)). Tumor core biopsies were taken before initiation of treatment and 9-13 days after patients received "run-in" doses of either single agent trastuzumab or nab-paclitaxel. The AQUA method of quantitative immunofluorescence was used for analysis of in situ protein expression. Patients then received 18 weeks of treatment, followed by surgery to assess pathologic response to the neoadjuvant regimen.

Results: A HER2 score of 2111 by AQUA analysis has been shown to be equivalent to HER2 3+ by immunohistochemical staining in previous studies. Of 20 evaluable patients, 10 cases who achieved a pathologic complete response (pathCR) with neoadjuvant treatment had a mean HER2 level of 10251 compared with 4766 in the patients without pathCR (p = 0.0021). Measurement of phospho-HER2 showed no difference in pathCR vs non-pathCR groups. In 9 patients who had HER2 levels repeated after a single treatment with trastuzumab there was no evidence of a reduction in the HER2 or phospho-HER2 levels following that exposure.

Conclusions: High levels of HER2 are associated with achievement of a pathCR in the preoperative setting, while levels of Phospho-HER2 were not predictive of response. This data suggests that accurate measurement of HER2 may help determine the likelihood of response in the pre-surgical setting. Further validation in larger cohorts is required, but this pilot data shows the feasibility of this approach.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1471-2407-14-326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4037428PMC
May 2014

Phase I clinical trial of the mammalian target of rapamycin inhibitor everolimus in combination with oral topotecan for recurrent and advanced endometrial cancer.

Int J Gynecol Cancer 2014 Mar;24(3):528-33

Sections of *Medical Oncology, and †Gynecologic Oncology, and ‡Department of Therapeutic Radiology, School of Medicine, Yale University, Yale Comprehensive Cancer Center, New Haven, CT; and §Novartis Pharmaceuticals Corp, East Hanover, NJ.

Objectives: Preclinical data suggest that mammalian target of rapamycin inhibitors may potentiate the efficacy of topotecan. We evaluated the optimal schedule of oral topotecan in combination with everolimus in patients with endometrial cancer.

Methods: Women with a history of advanced or recurrent endometrial cancer were enrolled. Escalating dose of oral topotecan (1.5 mg/m, 1.9 mg/m, and 2.3 mg/m) daily on days 1 to 5 and everolimus (5 mg every other day, 5 mg daily, and 10 mg daily) were administered in a 21-day cycle. A "run-in" treatment of topotecan daily for 5 days followed by everolimus for 7 days (4-7 doses depending on dose level) was administered for the purpose of pharmacokinetic assessments.

Results: Ten patients were enrolled on the study, and 9 were evaluable for safety analysis. A total of 28 cycles were administered (range, 1-10 cycles per patient). The patients had a median age of 73 years (range, 42-79 years). Previous lines of chemotherapy were 1 (n = 2), 2 (n = 5), 3 (n = 2), and 4 (n = 1). Seven patients had previous vaginal brachytherapy, and 2 had pelvic external beam radiation therapy. The median number of cycles (including cycle 1) is 2 (range, 1-10). Dose-limiting toxicity occurred in 3 patients (1 patient treated with 1.9-mg/m topotecan and 5-mg everolimus given every other day as well as 2 patients treated with 1.9-mg/m topotecan and 5-mg of everolimus daily) and included neutropenia and thrombocytopenia. Seven patients were evaluable for response. Stable disease was the best response in 3 patients who completed the 3, 4, and 10 cycles each.

Conclusions: The dose-limiting toxicity for the combination of oral topotecan and everolimus was myelosuppression. The maximum tolerated dose was topotecan 1.9 mg/m on days 1 to 5 in combination with oral everolimus 5 mg every other day. Administration of higher dose of each agent in combination was limited because of overlapping myelosuppression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/IGC.0000000000000085DOI Listing
March 2014

The cost of breast cancer screening in the Medicare population.

JAMA Intern Med 2013 Feb;173(3):220-6

Cancer Outcomes, Public Policy, and Effectiveness Research (COPPER) Center, Yale Comprehensive Cancer Center and Yale University School of Medicine, New Haven, CT 06520, USA.

Background: Little is known about the cost to Medicare of breast cancer screening or whether regional-level screening expenditures are associated with cancer stage at diagnosis or treatment costs, particularly because newer breast cancer screening technologies, like digital mammography and computer-aided detection (CAD), have diffused into the care of older women.

Methods: Using the linked Surveillance, Epidemiology, and End Results-Medicare database, we identified 137 274 women ages 66 to 100 years who had not had breast cancer and assessed the cost to fee-for-service Medicare of breast cancer screening and workup during 2006 to 2007. For women who developed cancer, we calculated initial treatment cost. We then assessed screening-related cost at the Hospital Referral Region (HRR) level and evaluated the association between regional expenditures and workup test utilization, cancer incidence, and treatment costs.

Results: In the United States, the annual costs to fee-for-service Medicare for breast cancer screening-related procedures (comprising screening plus workup) and treatment expenditures were $1.08 billion and $1.36 billion, respectively. For women 75 years or older, annual screening-related expenditures exceeded $410 million. Age-standardized screening-related cost per beneficiary varied more than 2-fold across regions (from $42 to $107 per beneficiary); digital screening mammography and CAD accounted for 65% of the difference in screening-related cost between HRRs in the highest and lowest quartiles of cost. Women residing in HRRs with high screening costs were more likely to be diagnosed as having early-stage cancer (incidence rate ratio, 1.78 [95% CI, 1.40-2.26]). There was no significant difference in the cost of initial cancer treatment per beneficiary between the highest and lowest screening cost HRRs ($151 vs $115; P = .20).

Conclusions: The cost to Medicare of breast cancer screening exceeds $1 billion annually in the fee-for-service program. Regional variation is substantial and driven by the use of newer and more expensive technologies; it is unclear whether higher screening expenditures are achieving better breast cancer outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamainternmed.2013.1397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3638736PMC
February 2013

DTCs/CTCs in breast cancer: five decades later.

Recent Results Cancer Res 2012 ;195:217-25

Yale University, New Haven, CT, USA.

Since circulating tumor cells were first reported in 1955, the field has seen major advances in their detection and has established their prognostic impact. Here we review the current evidence for the prognostic and predictive value of circulating tumor cells in metastatic breast cancer. We then evaluate the role of CTCs and DTCs in early stage breast cancer. The weight of the evidence supports the role of CTCs and DTCs as prognostic indicators, however their role in therapy prediction remains unclear. Ongoing trials may provide answers and newer detection methods which improve sensitivity and specificity may have greater impact. At this point, the data does not support incorporation into clinical practice for early breast cancer patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-3-642-28160-0_20DOI Listing
July 2012

Ocular complications of cancer therapy: a primer for the ophthalmologist treating cancer patients.

Curr Opin Ophthalmol 2009 Jul;20(4):308-17

Faculty of Arts and Sciences, Harvard University, Cambridge, Massachusetts, USA.

Purpose Of Review: Cancer patients may develop ocular complications secondary to direct or metastatic involvement with cancer, radiation exposure, or chemotherapy. As many as 1.4 million new cancer cases arise in the United States annually.

Recent Findings: Chemotherapy administration remains a critical aspect of treating many cancers and offers improved prognosis and prolonged survival in many cases; however, these therapies are known to cause a wide range of toxicities.

Summary: Ocular side effects such as photophobia, cataracts, glaucoma, retinopathy, and other ocular toxicities have been reported following chemotherapy administration. To effectively treat cancer patients, oncologists, primary care clinicians, and ophthalmologists should be aware of the potential ophthalmic toxicities certain widely used chemotherapeutic agents and radiation therapy may pose to their patients, particularly in the setting of preexisting ocular conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/ICU.0b013e32832c9007DOI Listing
July 2009

Anthracycline-induced cardiotoxicity: risk assessment and management.

Oncology (Williston Park) 2009 Mar;23(3):239, 244, 252

Breast Cancer Program, Section of Medical Oncology, Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
March 2009

The prognostic and predictive values of circulating HER-2/neu extracellular domain in patients with metastatic breast cancer.

Breast Cancer Res Treat 2009 Apr 2;114(3):513-5. Epub 2008 Aug 2.

Medical and Gynecologic Oncology, Yale Comprehensive Cancer Center, New Haven, CT, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10549-008-0145-8DOI Listing
April 2009

Long-term assessment of cardiac function after dose-dense and -intense sequential doxorubicin (A), paclitaxel (T), and cyclophosphamide (C) as adjuvant therapy for high risk breast cancer.

Breast Cancer Res Treat 2007 Sep 19;104(3):341-9. Epub 2006 Oct 19.

Department of Internal Medicine, Section of Medical Oncology, Yale University School of Medicine, Yale Cancer Center, New Haven, CT 06520-8032, USA.

Objectives: This study evaluated the incidence of late cardiotoxicity after dose-dense and -intense adjuvant sequential doxorubicin (A), paclitaxel (T), and cyclophosphamide (C) for breast cancer (BC) with > or = 4 involved ipsilateral axillary lymph nodes.

Methods: Patients were enrolled from 1994 to 2001 after definitive BC surgery if > or =4 axillary nodes were involved. Planned treatment was A 90 mg/m(2) q 14 days x 3, T 250 mg/m(2) q 14 days x 3, C 3 g/m(2 )q 14 days x 3 with filgrastim (G) support. Left ventricular ejection fraction (LVEF) was monitored using equilibrium radionuclide angiography (ERNA) before the initiation of chemotherapy, and after three cycles of each chemotherapeutic agent. At a median follow-up of 7 years, we obtained ERNA scans on 32 patients to evaluate the long-term cardiotoxicity of this regimen.

Results: Eighty-five eligible patients enrolled on the treatment protocol. Clinical heart failure developed in one patient. Seven (8%) patients had LVEF < 50% at the end of therapy. No cardiac-related deaths occurred. Thirty-two (46%) of 69 surviving patients have consented to late cardiac imaging. At a median follow-up of 7 years, the median absolute change in LVEF from baseline was -5.5%; [range (-8%) to (+36%)], and from the end of chemotherapy was -2.0%; [range (-25%) to (+16%)]. Four patients (12%) had a LVEF < 50%; two of these four patients had an LVEF of < 50% at the end of chemotherapy.

Conclusions: Late development of asymptomatic decline in cardiac function may occur after dose-dense and -intense adjuvant therapy, but is uncommon.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10549-006-9413-7DOI Listing
September 2007

Five-year update of an expanded phase II study of dose-dense and -intense doxorubicin, paclitaxel and cyclophosphamide (ATC) in high-risk breast cancer.

Oncology 2005 24;69(5):372-83. Epub 2005 Nov 24.

Jersey Shore University Medical Center, Neptune, N.J., USA.

Objectives: This study evaluated the safety and efficacy of dose-dense and -intense sequential doxorubicin (A), paclitaxel (T) and cyclophosphamide (C) as adjuvant therapy for breast cancer (BC) with >or=4 ipsilateral axillary lymph nodes.

Methods: Patients were recruited after BC surgery if >or=4 axillary nodes were involved by metastatic cancer. Planned treatment was A 90 mg/m(2) three times every 14 days (q14d x 3), T 250 mg/m(2) q14d x 3 and C 3 g/m(2) q14d x 3 combined with filgrastim support.

Results: The study enrolled 85 eligible patients. The median number of lymph nodes involved was 9. Mean dose intensity was >94% of planned for each drug. Common grade 3 toxicities included nausea and/or vomiting (24%), mucositis (18%), neuropathy (16%), palmar-plantar erythrodysesthesia (12%), myalgia (6%) and arthralgia (6%). Grade 3/4 neutropenia occurred in 77 (91%) patients, and 32 (38%) patients had neutropenic fever. One patient developed acute leukemia. Sixty-nine (81%) patients are alive, and 59 (69%) patients are alive and free of distant disease at a median follow-up of 5 years.

Conclusions: ATC is a feasible regimen for adjuvant therapy of high-risk BC, with a relatively low rate of relapse at the 5-year follow up.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000089991DOI Listing
January 2006