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1.  Impact of Margin Assessment Method on Positive Margin Rate and Total Volume Excised 
Annals of surgical oncology  2013;21(1):86-92.
For breast-conserving surgery (BCS), the method of margin assessment that most frequently achieves negative margins without increasing volume of tissue excised is uncertain. We examined our institutional experience with 3 different margin assessment methods used by 6 experienced breast surgeons.
Patients undergoing BCS for invasive carcinoma during July-December of a representative year during which each method was performed (Perpendicular, 2003; Tangential, 2004; Cavity-Shave, 2011) were included. Effect of margin method on positive margin rate at first excision, and total volume excised to achieve negative margins, were evaluated by multivariable analysis, by surgeon, and by tumor size and presence of extensive intraductal component (EIC).
555 patients were identified: Perpendicular, 140; Tangential, 124; Cavity-Shave, 291. Tangential method had a higher rate of positive margins at first excision than Perpendicular and Cavity-Shave methods (49%, 15%, 11%, respectively; p<0.0001). Median volumes to achieve negative margins were similar (55ml, Perpendicular; 64ml Tangential; 62ml Cavity-Shave, p=0.24). Four of 6 surgeons had the lowest rate of positive margins with Cavity-Shave method—significant when compared to Tangential (p<0.0001), but not Perpendicular (p=0.37). Comparison of volume excised using the 3 methods was variable by surgeon (p<0.0001). Perpendicular method was optimal for T1 tumors without EIC; Cavity-Shave tended to be superior for T2/3 tumors and/or EIC.
While the Cavity-Shave method may decrease rates of positive margins, its effect on volume is variable among surgeons and may result in an increase in total volume excised for some surgeons, and for small tumors without EIC.
PMCID: PMC3923624  PMID: 24046114
Margins; breast conservation; lumpectomy; breast cancer
2.  Mesothelin Expression in Triple Negative Breast Carcinomas Correlates Significantly with Basal-Like Phenotype, Distant Metastases and Decreased Survival 
PLoS ONE  2014;9(12):e114900.
Mesothelin is a cell surface associated antigen expressed on mesothelial cells and in some malignant neoplasms. Mesothelin-targeted therapies are in phase I/II clinical trials. The clinicopathologic and prognostic significance of mesothelin expression in triple negative breast carcinomas (TNBC) has not been fully assessed. We evaluated the expression of mesothelin and of basal markers in tissue microarrays of 226 TNBC and 88 non-TNBC and assessed the clinicopathologic features of mesothelin-expressing breast carcinomas. Furthermore, we investigated the impact of mesothelin expression on the disease-free and overall survival of patients with TNBC. We found that mesothelin expression is significantly more frequent in TNBC than in non-TNBC (36% vs 16%, respectively; p = 0.0006), and is significantly correlated with immunoreactivity for basal keratins, but not for EGFR. Mesothelin-positive and mesothelin-negative TNBC were not significantly different by patients’ race, tumor size, histologic grade, tumor subtype, lymphovascular invasion and lymph node metastases. Patients with mesothelin-positive TNBC were older than patients with mesothelin-negative TNBC, developed more distant metastases with a shorter interval, and had significantly lower overall and disease-free survival. Based on our results, patients with mesothelin-positive TNBC could benefit from mesothelin-targeted therapies.
PMCID: PMC4266616  PMID: 25506917
4.  Is there a role for routine screening MRI in women with LCIS? 
Breast cancer research and treatment  2013;142(2):10.1007/s10549-013-2725-5.
Women with lobular carcinoma in situ (LCIS) have an elevated breast cancer risk, yet the benefit of MRI screening is unclear. We examined cancer detection rates with mammography alone versus mammography plus MRI in this high-risk population. From a prospectively maintained, single-institution database, we identified 776 patients diagnosed with LCIS after the adoption of screening MRI in April 1999. In addition to annual mammography and breast exam, MRI was used at the discretion of the physician and patient. Kaplan–Meier methods and landmark analyses at 1, 2, and 3 years following LCIS diagnosis were performed to compare rates of cancer detection with or without MRI. MRI screening was performed in 455 (59 %) patients (median, 3/patient). Median time from LCIS diagnosis to first MRI was 9 months (range 0.3–137 months). Patients undergoing MRI were younger (p < 0.0001), premenopausal (p < 0.0001), and more likely to have ≥1 first-degree relative with breast cancer (p = 0.009). At a median follow-up of 58 months, 98/776 (13 %) patients developed cancer. The crude cancer detection rate in both screening groups was 13 %. MRI was not associated with earlier stage, smaller size, or node negativity. Landmark analyses at 1, 2, and 3 years after LCIS diagnosis failed to demonstrate increased cancer detection rates among women having MRI (p = 0.23, 0.26, and 0.13, respectively). Although a diagnosis of LCIS remains a significant risk factor for breast cancer, the routine use of MRI does not result in increased cancer detection rates (short-term), nor does it result in earlier stage at diagnosis, illustrating the importance of defining optimal screening strategies for high-risk patients based on tumor biology rather than numerical risk.
PMCID: PMC3871867  PMID: 24141896
LCIS; MRI; Screening; High risk; Breast cancer
5.  Long-Term Response to Sunitinib Therapy for Metastatic Renal Cell Carcinoma 
Clinical genitourinary cancer  2013;11(3):297-302.
A subset of patients achieves long-term responses with sunitinib therapy. We present a retrospective study of long-term responders, defined as patients achieving durable complete response (CR) or remaining progression free for > 18 months while receiving sunitinib. Favorable risk factors associated with long-term response include a lack of bone metastases or lung metastases and favorable Memorial Sloan-Kettering Cancer Center (MSKCC) risk status.
Sunitinib achieves objective response and prolongs progression-free survival (PFS) in patients with metastatic renal cell carcinoma (RCC). A subset of patients achieves long-term responses. The characteristics of patients who achieved long-term response (defined as patients achieving ongoing complete response [CR] or remaining progression free for > 18 months while receiving sunitinib) are reported.
Patients and Methods
A database of 186 patients treated with sunitinib alone (n = 89) or in combination (n = 97) in 9 clinical trials was reviewed; all had 1 year or more follow-up from sunitinib start to data cutoff for analysis. Median PFS was 10.8 months (95% CI, 8.3–13.3); median overall survival (OS) was 30.4 months (95% CI, 21.5–36.8 months) for the 186 patients. Thirty-four patients were identified as long-term responders because they either had durable CR or remained progression free while receiving sunitinib for > 18 months.
Best response for 34 long-term responders was CR in 3 patients, partial response (PR) in 24 patients, and stable disease in 7 patients. The median duration of sunitinib therapy was 24.9 months (range, 18.1–73.9 months). The median PFS among the long-term responders was 17.4 months (95% CI, 7–29.9 months) at a landmark PFS analysis performed after 18 months from treatment start. Univariate analysis from the 186 patients identified bone metastasis, lung metastasis, and intermediate/poor risk groups as adverse prognostic factors for long-term response.
Sunitinib achieves long-term response in a subset of patients with metastatic RCC. Lack of bone metastasis or lung metastasis and good MSKCC risk status may predict long-term response.
PMCID: PMC3959735  PMID: 23707221
Metastatic; Renal cell carcinoma; Sunitinib; Systemic therapy; Targeted therapy
6.  The effect of metformin on breast cancer outcomes in patients with type 2 diabetes 
Cancer Medicine  2014;3(4):1025-1034.
Observational data suggest that metformin use decreases breast cancer (BC) incidence in women with diabetes; the impact of metformin on BC outcomes in this population is less clear. The purpose of this analysis was to explore whether metformin use influences BC outcomes in women with type 2 diabetes. Prospective institutional databases were reviewed to identify patients with diabetes who received chemotherapy for stages I–III BC from 2000 to 2005. Patients diagnosed with diabetes before or within 6 months of BC diagnosis were included. Males and those with type I, gestational, or steroid-induced diabetes were excluded. Patients were stratified based on metformin use, at baseline, defined as use at time of BC diagnosis or at diabetes diagnosis if within 6 months of BC diagnosis. Kaplan–Meier methods were used to estimate rates of recurrence-free survival (RFS), overall survival (OS), and contralateral breast cancer (CBC). We identified 313 patients with diabetes who received chemotherapy for BC, 141 (45%) fulfilled inclusion criteria and 76 (54%) used metformin at baseline. There were no differences in clinical presentation or tumor characteristics between metformin users and nonusers. At a median follow-up of 87 months (range, 6.9–140.4 months), there was no difference in RFS (P = 0.61), OS (P = 0.462), or CBC (P = 0.156) based on metformin use. Five-year RFS was 90.4% (95% CI, 84–97) in metformin users and 85.4% (95% CI, 78–94) in nonusers. In this cohort of patients with type 2 diabetes receiving systemic chemotherapy for invasive BC, the use of metformin was not associated with improved outcomes.
PMCID: PMC4303170  PMID: 24944108
Breast neoplasms; diabetes mellitus, type 2; metformin; mortality
7.  Early predictors of not returning to work in low-income breast cancer survivors: a 5-year longitudinal study 
Breast cancer research and treatment  2013;140(2):10.1007/s10549-013-2625-8.
Low-income women may be especially vulnerable to job loss after a breast cancer diagnosis. The identification of early risk factors for not returning to work in the long term could inform interventions to help survivors avoid this outcome. A consecutive sample of low-income, employed, underinsured/uninsured women treated for stage 0–III breast cancer was surveyed 6, 18, 36, and 60 months after diagnosis. Participants were classified according to the survey in which they first reported return to work. If they were not working in every survey they were classified as not returning to work. Correlates of not returning to work were identified. Of 274 participants, 36 % returned to work by 6 months, an additional 21 % by 18, 10 % by 36, and 5 % by 60 months. 27 % never returned to work. Of those not working at 6 months, 43 % never returned. Independent predictors of never returning to work included lowest annual income (<$10,000), Latina ethnicity, high comorbidity burden, and receipt of chemotherapy. Very poor women who stop working during chemotherapy for breast cancer are at risk of not returning to work months and years following treatment. These findings may have clinical and policy implications. Conversely, radiation therapy, axillary node dissection, age, and job type do not appear to be associated with return to work. Clinicians should discuss work-related concerns with patients and facilitate early return to work when desired by the patient. Additional research is needed to develop interventions to optimize return to work.
PMCID: PMC3826956  PMID: 23884596
Breast cancer; Income; Work; Survivorship
8.  Phase II Trial of Bicalutamide in Patients with Androgen Receptor–Positive, Estrogen Receptor–Negative Metastatic Breast Cancer 
Patients with hormone receptor–negative breast cancer generally do not benefit from endocrine-targeted therapies. However, a subset with androgen receptor (AR) expression is predicted to respond to antiandrogen therapies. This phase II study explored bicalutamide in AR-positive, estrogen receptor (ER), and progesterone receptor (PgR)-negative metastatic breast cancer.
Experimental Design
Tumors from patients with ER/PgR-negative advanced breast cancer were tested centrally for AR [immunohistochemistry (IHC) > 10% nuclear staining considered positive]. If either the primary or a metastatic site was positive, patients were eligible to receive the AR antagonist bicalutamide at a dose of 150 mg daily. Clinical benefit rate (CBR), the primary endpoint, was defined as the total number of patients who show a complete response (CR), partial response (PR), or stable disease (SD) > 6 months; secondary endpoints included progression-free survival (PFS) and toxicity. Correlative studies included measurement of circulating endocrine markers and IHC surrogates for basal-like breast cancer.
Of 424 patients with ER/PgR-negative breast cancer, 12% tested AR-positive. The 6-month CBR was19%[95% confidence interval (CI), 7%–39%]for bicalutamide. The median PFS was 12 weeks (95% CI, 11–22 weeks). Bicalutamide was well-tolerated with no grade 4/5 treatment-related adverse events observed.
AR was expressed in 12% of patients with ER/PgR-negative breast cancer screened for this trial. The CBR of 19% observed with bicalutamide shows proof of principle for the efficacy of minimally toxic androgen blockade in a select group of patients with ER/PgR-negative, AR-positive breast cancer.
PMCID: PMC4086643  PMID: 23965901
9.  Blurry Boundaries: Do Epithelial Borderline Lesions of the Breast and Ductal Carcinoma In Situ Have Similar Rates of Subsequent Invasive Cancer? 
Annals of surgical oncology  2012;20(4):10.1245/s10434-012-2719-2.
The histology of epithelial “borderline lesions” of the breast, which have features in between atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS), is well described, but the clinical behavior is not. This study reports subsequent ipsilateral breast events (IBE) in patients with borderline lesions compared with those with DCIS.
Patients undergoing breast-conserving surgery for borderline lesions or DCIS from 1997 to 2010 were identified from a prospective database. IBE was defined as the diagnosis of subsequent ipsilateral DCIS or invasive ductal carcinoma.
A total of 143 borderline-lesion patients and 2,328 DCIS patients were identified. Median follow-up was 2.9 and 4.4 years, respectively. 7 borderline-lesion and 172 DCIS patients experienced an IBE. 5 year IBE rates were 7.7 % for borderline lesions and 7.2 % for DCIS (p = .80). 5 year invasive IBE rates were 6.5 and 2.8 %, respectively (p = .25). Similarly, when analyses were restricted to patients who did not receive radiotherapy, or endocrine therapy, or both, borderline-lesion and DCIS patients did not demonstrate statistically significant differences in rates of IBE or invasive IBE.
When compared with DCIS, borderline lesions do not demonstrate lower rates of IBE or invasive IBE. Despite “borderline” histology, a 5 year IBE rate of 7.7 % and an invasive IBE rate of 6.5 % suggest that the risk of future carcinoma is significant and similar to that of DCIS.
PMCID: PMC3833840  PMID: 23161115
10.  Frequent mutational activation of the PI3K-AKT pathway in trastuzumab-resistant breast cancer 
HER2-amplified breast cancer is sometimes clinically insensitive to HER2 targeted treatment with trastuzumab. Laboratory models of resistance have causally implicated changes in HER2 expression and activation of the PI3K-AKT pathway. We conducted a prospective tissue acquisition study to determine if there is evidence for these lesions in metastatic tumors that have progressed on trastuzumab-containing therapy.
Experimental Design
From 2/2007 to 11/2011, 63 patients with HER2-amplified breast cancer with recurrence of disease after adjuvant trastuzumab therapy or WHO- defined progression of metastatic disease on a trastuzumab-containing regimen were prospectively enrolled and underwent tumor biopsy. Specimens were analyzed for activating mutations in PIK3CA and HER2 by Sequenom® and analyzed for HER2 and PTEN status by immunohistochemistry (IHC).
In 53/60 cases (88%, 3 cases not evaluable for HER2), HER2 overexpression persisted in the metastatic tumor following trastuzumab exposure. Among the 7 cases lacking HER2 overexpression, repeat analysis of the pre-treatment tumor failed to confirm HER2 overexpression in 5 cases. Among cases evaluable for PTEN (56) or PI3K mutation (45), absent or significantly diminished PTEN expression was noted in 33 (59%) and activating mutations in PIK3CA in 13 (29%). The combined rate of PTEN loss and PIK3CA mutation in the trastuzumab-refractory tumors was 71% compared to 44% (p=0.007) in an unexposed cohort of 73 HER2-amplified tumors.
In this series of prospectively collected trastuzumab-refractory human breast cancers, loss of HER2 overexpression was rare while activation of the PI3K-AKT pathway through loss of PTEN or PIK3CA mutation was frequently observed.
PMCID: PMC3525734  PMID: 23092874
11.  Feasibility and toxicity of dose-dense adjuvant chemotherapy in older women with breast cancer 
Breast cancer research and treatment  2008;117(1):10.1007/s10549-008-0116-0.
The objective of this study was to examine the feasibility and toxicity of adjuvant dose-dense chemotherapy in older women with breast cancer.
A search of the Memorial Sloan-Kettering Cancer Center (MSKCC) breast cancer database was performed to identify all patients age 60 and older who underwent an initial consultation with a breast medical oncologist between October 1, 2002 and June 28, 2005. Inclusion criteria were: (1) age ≥ 60, (2) follow-up care obtained at MSKCC, (3) intent to treat with adjuvant dose-dense AC-T (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 2 weeks for 4 cycles followed by paclitaxel 175 mg/m2 every 2 weeks for 4 cycles, with white blood cell growth factor support).
One hundred sixty-two patients (mean age 66, range 60–76) with breast cancer, stages I (n = 5), II (n = 111), and III (n = 46) according to the sixth edition of the AJCC staging system, were included in this analysis. Forty-one percent (n = 67) experienced a grade 3 or 4 toxicity, 9% a grade 3 infection (n = 14), 6% grade 3 fatigue (n = 9), 5% neutropenic fever (n = 8), and 4% thromboembolic events (n = 7). Twenty-two percent (n = 36) did not complete the planned 8 cycles of treatment. There was no statistically significant association between age and either toxicity or treatment discontinuation. In multivariate analysis including age, pretreatment hemoglobin, and comorbidity, the presence of comorbidity (Charlson score ≥ 1) and a lower baseline hemoglobin score were associated with an increased risk of any grade 3 or 4 toxicity.
We found that the risk of toxicity depended more on comorbid medical conditions and baseline hemoglobin value than age in this cohort of older adults receiving dose-dense adjuvant chemotherapy.
PMCID: PMC3811071  PMID: 18622739
Breast Cancer; Dose-Dense Chemotherapy; Older Patient
12.  A 10-Year Trend Analysis of Sentinel Lymph Node Frozen Section and Completion Axillary Dissection for Breast Cancer: Are These Procedures Becoming Obsolete? 
Annals of surgical oncology  2011;19(1):225-232.
Recent results from the ACOSOG Z0011 trial question the use of intraoperative frozen section (FS) during sentinel lymph node (SLN) biopsy and the role of axillary dissection (ALND) for SLN-positive breast cancer patients. Here we present a 10-year trend analysis of SLN-FS and ALND in our practice.
We reviewed our prospective SLN database over 10 years (1997–2006, 7509 SLN procedures) for time trends and variation between surgeons in the use of SLN-FS and ALND in patients with cN0 invasive breast cancer.
Use of SLN-FS decreased from 100% to 62% (P < 0.0001) and varied widely by surgeon (66% to 95%). There were no statistically significant trends in the performance of ALND for patients with SLN metastases detected by FS (n = 1370, 99–99%) or routine hematoxylin and eosin (H&E) (n = 333; 69–77%), but only for those detected by serial section H&E with or without immunohistochemistry (n = 438; 73–48%; P = 0.0054) or immunohistochemistry only (n = 294; 48–28%; P < 0.0001). These trends coincided with an increase in the proportion of completion versus immediate ALND (30–40%; P = 0.0710).
Over 10 years, we have observed a diminishing rate of SLN-FS and, for patients with low-volume SLN metastases, fewer ALND, trends that suggest a more nuanced approach to axillary management. If the Z0011 selection criteria had been applied to our cohort, 66% of SLN-FS (4159 of 6327) and 48% of ALND (939 of 1953) would have been avoided, sparing 13% of all patients the morbidity of ALND.
PMCID: PMC3788632  PMID: 21647763
13.  Prognostic value of quantitative fluorodeoxyglucose measurements in newly diagnosed metastatic breast cancer 
Cancer Medicine  2013;2(5):725-733.
The aim of this study was to determine the prognostic value of quantitative fluorodeoxyglucose (FDG) measurements (maximum standardized uptake value [SUVmax], metabolic tumor volume [MTV], and total lesion glycolysis [TLG]) in patients with newly diagnosed metastatic breast cancer (MBC). An IRB-approved retrospective review was performed of patients who underwent FDG positron emission tomography (PET)/computed tomography (CT) from 1/02 to 12/08 within 60 days of diagnosis MBC. Patients with FDG-avid lesions without receiving chemotherapy in the prior 30 days were included. Target lesions in bone, lymph node (LN), liver, and lung were analyzed for SUVmax, MTV, and TLG. Medical records were reviewed for patient characteristics and overall survival (OS). Cox regression was used to test associations between quantitative FDG measurements and OS. A total of 253 patients were identified with disease in bone (n = 150), LN (n = 162), liver (n = 48), and lung (n = 66) at the time of metastatic diagnosis. Higher SUVmax tertile was associated with worse OS in bone metastases (highest vs. lowest tertile hazard ratio [HR] = 3.1, P < 0.01), but not in LN, liver or lung (all P > 0.1). Higher MTV tertile was associated with worse OS in LN (HR = 2.4, P < 0.01) and liver (HR = 3.0, P = 0.02) metastases, but not in bone (P = 0.22) or lung (P = 0.14). Higher TLG tertile was associated with worse OS in bone (HR = 2.2, P = 0.02), LN (HR = 2.3, P < 0.01), and liver (HR = 4.9, P < 0.01) metastases, but not in lung (P = 0.19). We conclude measures of FDG avidity are prognostic biomarkers in newly diagnosed MBC. SUVmax and TLG were both predictors of survival in breast cancer patients with bone metastases. TLG may be a more informative biomarker of OS than SUVmax for patients with LN and liver metastases.
Measures of fluorodeoxyglucose (FDG) avidity are prognostic biomarkers in newly diagnosed metastatic breast cancer. Volumetric measurements, such as total lesion glycolysis (TLG), may be more informative biomarkers for survival than the more commonly used standardized uptake value (SUV).
PMCID: PMC3892804  PMID: 24403238
Breast cancer; FDG PET/CT; mean tumor volume; SUV max; total lesion glycolysis
14.  Dose Dense Cyclophosphamide, Methotrexate, Fluorouracil is Feasible at 14-Day Intervals: A Pilot Study of Every-14-Day Dosing as Adjuvant Therapy for Breast Cancer 
Clinical breast cancer  2010;10(6):440-444.
Cyclophosphamide/methotrexate/fluorouracil (CMF) is a proven adjuvant option for patients with early-stage breast cancer. Randomized trials with other regimens demonstrate that dose-dense (DD) scheduling can offer greater efficacy. We investigated the feasibility of administering CMF using a DD schedule.
Patients and Methods
Thirty-eight patients with early-stage breast cancer were accrued from March 2008 through June 2008. They were treated every 14 days with C 600, M 40, F 600 (all mg/m2) with PEG-filgrastim (Neulasta®) support on day 2 of each cycle. The primary endpoint was tolerability using a Simon’s 2-stage optimal design. The design would effectively discriminate between true tolerability (as protocol-defined) rates of ≤ 60% and ≥ 80%.
The median age was 52-years-old (range, 38–78 years of age). Twenty-nine of the 38 patients completed 8 cycles of CMF at 14-day intervals.
Dose-dense adjuvant CMF is tolerable and feasible at 14-day intervals with PEG-filgrastim support.
PMCID: PMC3661192  PMID: 21147686
CMF; PEG-filgrastim
15.  Sarcomatoid-variant Renal Cell Carcinoma Treatment Outcome and Survival in Advanced Disease 
Sarcomatoid variant is a spindle cell phenotype of renal cell carcinoma (RCC), which is associated with a poor prognosis. We reviewed outcomes of systemic therapy for metastatic, sarcomatoid-variant RCC.
Clinical features, treatment outcome, and survival were evaluated in 63 patients with sarcomatoid-variant metastatic RCC (47 clear cell, 16 nonclear cell). Initial systemic treatment included antiangiogenesis-targeted therapy (n=34), cytokines (n=20), and chemotherapy (n=9).
Five of 63 patients (8%) achieved an objective response to the first systemic treatment: 1 (5%) to cytokine and 4 (12%) to sunitinib-targeted therapy. Median progression-free survival for 63 patients was 3 months (95% confidence interval), and median overall survival was 10 months (95% confidence interval). The median progression-free survival for patients treated with sunitinib versus all others was 4.4 months versus 2 months (P=0.03), and 3 months for patients with clear-cell histology versus 1.6 months for nonclear-cell histology (P=0.004).
Metastatic sarcomatoid-variant RCC was associated with a poor response to systemic therapy. Sunitinib treatment resulted in a modest response rate, but studies to characterize the underlying tumor biology of sarcomatoid-variant RCC, to assess outcome to targeted agents, and to develop novel treatment strategies are warranted.
PMCID: PMC3661202  PMID: 21127411
metastatic; sarcomatoid; renal cell carcinoma; sunitinib; targeted therapy
16.  Phase I trial of everolimus plus sunitinib in patients with metastatic renal cell carcinoma 
Cancer  2011;118(7):1868-1876.
Simultaneous inhibition of the vascular epithelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR) pathway may improve treatment response in advanced renal cell carcinoma (RCC). Everolimus, an oral mTOR inhibitor, and sunitinib, an oral tyrosine kinase inhibitor (TKI) targeting VEGF are standard agents in the management of metastatic RCC.
Sequential cohorts of 3 to 6 patients with advanced RCC received dose escalated combinations of sunitinib (37.5 or 50 mg daily, 4 weeks on / 2 weeks off) with everolimus (2.5–5 mg daily or 20–30 mg weekly). Dose-limiting toxicities (DLTs) were assessed in the first 6-week cycle to determine MTD. Pharmacokinetic profiles were obtained.
20 patients (13 clear cell and 7 non-clear cell RCC) were enrolled in 5 cohorts. Daily everolimus was not tolerated when combined with sunitinib; the first 2 patients on the 2nd cohort suffered DLTs. With weekly everolimus, the MTD was 30 mg everolimus on days 7, 14, 21, and 28, plus 37.5 mg sunitinib on days 1–28 of a 42-day cycle; however, chronic treatment was associated with grade 3 and 4 toxicities. A schedule of 20 mg everolimus weekly/37.5 mg sunitinib was tolerated as chronic therapy. Five patients (25%) had confirmed partial responses, 3 had non-clear cell RCC. No unexpected accumulation of everolimus, sunitinib, or N-desethyl sunitinib was observed.
The combination everolimus and sunitinib is associated with significant acute and chronic toxicities and is only tolerated at attenuated doses. Responses were observed in non-clear cell and clear cell RCC.
PMCID: PMC3609026  PMID: 21898375
renal cell carcinoma; everolimus; sunitinib; targeted therapy; combination drug therapy
17.  Return to Work in Low-Income Latina and Non-Latina White Breast Cancer Survivors: A Three-Year Longitudinal Study 
Cancer  2011;118(6):1664-1674.
Prior research has found an 80% return-to-work rate in mid-income White breast cancer survivors, but little is known about the employment trajectory of low-income minorities or Whites. We set out to compare the trajectories of low-income Latina and non-Latina White survivors and to identify correlates of employment status.
Participants were low-income women who had localized breast cancer, spoke English or Spanish, and were employed at the time of diagnosis. Interviews were conducted 6, 18, and 36 months after diagnosis. Multivariate logistic regression was used to identify independent correlates of employment status at 18 months.
Of 290 participants, 62% were Latina. Latinas were less likely than non-Latina Whites to be working 6 months (27% vs. 49%, p=0.0002) and 18 months (45% vs. 59%, p=0.02) after diagnosis, but at 36 months there was no significant difference (53% vs. 59%, p=0.29). Latinas were more likely to be manual laborers than were non-Latina Whites (p<0.0001). Baseline job type and receipt of axillary node dissection were associated with employment status among Latinas but not non-Latina Whites.
Neither low-income Latinas nor non-Latina Whites approached the 80% rate of return to work seen in wealthier White populations. Latinas followed a protracted return-to-work trajectory compared to non-Latina Whites, and differences in job type appear to have played an important role. Manual laborers may be disproportionately impacted by surgical procedures that limit physical activity. This can inform the development of rehabilitative interventions and may have important implications for the surgical and postsurgical management of patients.
PMCID: PMC3263326  PMID: 22009703
disparities; employment; breast cancer; survivorship
18.  Phase II trial of sunitinib in patients with metastatic non-clear cell renal cell carcinoma 
Investigational New Drugs  2010;30(1):335-340.
Sunitinib is associated with a robust objective response rate in patients with metastatic clear cell renal cell carcinoma (RCC). The primary objective of this phase II clinical trial was to assess the overall response rate for sunitinib in patients with papillary metastatic RCC as well as other non-clear cell histologies. A Simon 2-stage design was used to determine the number of papillary metastatic RCC patients for enrollment, and allowed for descriptive response data for other non-clear cell histologies. Twenty-three patients were enrolled, including 8 with papillary renal cell carcinoma (RCC) and the remainder with other non-clear cell histologies (unclassified in 5 patients). All patients received 50 mg of oral sunitinib in cycles of 4 weeks followed by 2 weeks of rest (4/2). The trial was stopped early because of slow accrual; no responses were observed in the 8 patients with papillary RCC. In the 22 evaluable patients, best response to sunitinib included a partial response in 1 patient with unclassified RCC, stable disease in 15, and progression in 6. The median progression-free survival was 5.5 months (95% CI, 2.5–7.1) in all 23 patients, and 5.6 months for the 8 papillary patients (95% CI, 1.4–7.1). The robust objective responses sunitinib had produced in clear cell RCC could not be demonstrated in this study comprised of patients with non-clear cell histologies.
PMCID: PMC3257373  PMID: 20711632
Papillary renal cell carcinoma; Non-clear cell renal cell carcinoma; Sunitinib; Phase II trial
19.  Phase II trial of saracatinib (AZD0530), an oral src-inhibitor for the treatment of patients with hormone receptor negative metastatic breast cancer 
Clinical breast cancer  2011;11(5):306-311.
Src activation is associated with cell migration, proliferation and metastasis. Saracatinib is an oral, tyrosine kinase inhibitor (TKI) selective for Src. We performed this trial to evaluate the efficacy and safety of saracatinib monotherapy in patients with estrogen receptor (ER)- and progesterone receptor (PR)-negative, metastatic breast cancer.
Patients and Methods
Patients with ≤1 prior chemotherapy regimen for measurable, ER- and PR-negative metastatic breast cancer received saracatinib 175 mg orally daily. The primary endpoint was disease control defined as complete response (CR) + partial response (PR) + stable disease (SD) >6 months. Secondary endpoints included toxicity and progression-free survival. Levels of circulating tumor cells in response to therapy were measured over time.
Nine patients were treated on study. After a median of 2 cycles (range 1–3), no patients achieved CR, PR, or SD >6 months. The median time to treatment failure was 82 days (12–109).The majority (89%) of patients discontinued saracatinib because of disease progression. One patient developed potentially treatment-related grade 4 hypoxia with interstitial infiltrates and was removed from study. Common adverse events included fatigue, elevated liver chemistries, nausea, hyponatremia, dyspnea, cough, and adrenal insufficiency.
These efficacy results were not sufficiently promising to justify continued accrual to this study. Based on this series, saracatinib does not appear to have significant single-agent activity for the treatment of patients with ER(−)/PR(−) metastatic breast cancer.
PMCID: PMC3222913  PMID: 21729667
20.  Integrated Positron Emission Tomography/Computed Tomography May Render Bone Scintigraphy Unnecessary to Investigate Suspected Metastatic Breast Cancer 
Journal of Clinical Oncology  2010;28(19):3154-3159.
Although the accurate detection of osseous metastases in the evaluation of patients with suspected metastatic breast cancer (MBC) has significant prognostic and therapeutic implications, the ideal diagnostic approach is uncertain. In this retrospective, single-institution study, we compare the diagnostic performance of integrated positron emission tomography/computed tomography (PET/CT) and bone scintigraphy (BSc) in women with suspected MBC.
Patients and Methods
Women with suspected MBC evaluated with PET/CT and BSc (within 30 days) between January 1, 2003 and June 30, 2008, were identified through institutional databases. Electronic medical records were reviewed, and radiology reports were classified as positive/negative/equivocal for osseous metastases. A nuclear medicine radiologist (blinded to correlative and clinical end points) reviewed all equivocal PET/CT and BSc images and reclassified some reports. Final PET/CT and BSc classifications were compared. Baseline patient/tumor characteristics and bone pathology were recorded and compared to the final imaging results.
We identified 163 women who had a median age of 52 years (range, 30 to 90 years); 32% had locally advanced breast cancer, 42% had been diagnosed with breast cancer less than 12 weeks before identification. Twenty studies were originally deemed equivocal (five with PET/CT, and 15 with BSc), and 13 (65%) of these studies were reclassified after radiology review. Overall, PET/CT and BSc were highly concordant for reporting osseous metastases with 132 paired studies (81%); 32 (20%) were positive, and 100 (61%) were negative. Thirty-one occurrences (19%) were discordant. Twelve of these (39%) had pathology confirming osseous metastases: nine (of 18) were PET/CT positive and BSc negative; one (of three) was PET/CT positive and BSc equivocal; and two (of two) were PET/CT equivocal and BSc negative.
This study supports the use of PET/CT in detecting osseous metastases for suspected MBC. Whether PET/CT may supplant BSc in this setting is unknown.
PMCID: PMC3651596  PMID: 20516453
21.  Dose-Dense Doxorubicin and Cyclophosphamide Followed by Weekly Paclitaxel With Trastuzumab and Lapatinib in HER2/neu–Overexpressed/Amplified Breast Cancer Is Not Feasible Because of Excessive Diarrhea 
Journal of Clinical Oncology  2010;28(18):2982-2988.
Dose-dense doxorubicin and cyclophosphamide (AC) followed by paclitaxel and trastuzumab (PT) is feasible. Lapatinib is effective in the treatment of human epidermal growth factor receptor 2 (HER2) –positive metastatic breast cancer. We conducted a pilot study of dose-dense AC followed by PT plus lapatinib (PTL) followed by trastuzumab plus lapatinib (TL).
Patients and Methods
Patients with stages I to III, HER2-positive breast cancer and left ventricular ejection fraction (LVEF) of ≥ 50% were enrolled. Treatment consisted of AC (60 mg/m2 and 600 mg/m2) for 4 cycles every 2 weeks (with pegfilgrastim 6 mg on day 2) followed by paclitaxel (80 mg/m2) for 12 doses weekly plus trastuzumab and lapatinib. Trastuzumab (4 mg/kg loading dose, then 2 mg/kg weekly during paclitaxel then 6 mg/kg every 3 weeks after paclitaxel) and lapatinib (1,000 mg daily) were given for 1 year. The primary end points were feasibility defined as ≥ 80% patients completing the PTL phase without a dose delay/reduction and a cardiac event rate of ≤ 4%.
From March 2007 to April 2008, we enrolled 95 patients. Median age was 46 years (range, 28 to 73 years). At a median follow-up of 22 months, 92 were evaluable. Of the 92 patients, 41 patients (45%) withdrew for PTL-specific toxicities. Overall, 40 (43%) of 92 patients had lapatinib dose reductions, and 27 (29%) of 92 patients had grade 3 diarrhea. Three patients (3%) had congestive heart failure; three patients dropped out because of significant asymptomatic LVEF decline during PTL followed by TL.
Dose-dense AC followed by PTL and then followed by TL was not feasible because of a high rate of lapatinib dose reduction, mostly caused by unacceptable grade 3 diarrhea. Lapatinib (1,000 mg/d) was not feasible combined with weekly PT.
PMCID: PMC3664034  PMID: 20479410
22.  TI-CE High-Dose Chemotherapy for Patients With Previously Treated Germ Cell Tumors: Results and Prognostic Factor Analysis 
Journal of Clinical Oncology  2010;28(10):1706-1713.
We previously reported a dose-finding and phase II trial of the TI-CE regimen (paclitaxel [T] plus ifosfamide [I] followed by high-dose carboplatin [C] plus etoposide [E] with stem-cell support) in germ cell tumor (GCT) patients predicted to have a poor prognosis with conventional-dose salvage therapy. We now report the efficacy of TI-CE with prognostic factors for disease-free survival (DFS) and overall survival (OS) in our full data set of 107 patients.
Patients and Methods
Eligible patients had advanced GCTs with progressive disease following chemotherapy and unfavorable prognostic features (extragonadal primary site, incomplete response [IR] to first-line therapy, or relapse/IR to ifosfamide-cisplatin–based conventional-dose salvage). Univariate and multivariate analyses (MVAs) of prognostic factors were performed. The predictive ability of the Einhorn and Beyer prognostic models was assessed.
Most patients were platinum refractory and had an IR to first-line chemotherapy. There were 54 (5%) complete and eight (8%) partial responses with negative markers; 5-year DFS was 47% and OS was 52% (median follow-up, 61 months). No relapses occurred after 2 years. Five (24%) of 21 primary mediastinal nonseminomatous GCTs are continuously disease free. On MVA, primary mediastinal site (P < .001), two or more lines of prior therapy (P < .001), baseline human chorionic gonadotropin ≥ 1,000 U/L (P = .01), and lung metastases (P = .02) significantly predicted adverse DFS. Poor-risk patients did worse than good- or intermediate-risk patients according to both Beyer (P < .002) and Einhorn (P < .05) models.
TI-CE is effective salvage therapy for GCT patients with poor prognostic features. Mediastinal primary site and two or more lines of prior therapy were most predictive of adverse DFS. Beyer and Einhorn models can assist in predicting outcome.
PMCID: PMC3651604  PMID: 20194867
23.  Feasibility Trial of Letrozole in Combination With Bevacizumab in Patients With Metastatic Breast Cancer 
Journal of Clinical Oncology  2009;28(4):628-633.
Preclinical models suggest that the use of anti–vascular endothelial growth factor (anti-VEGF) therapy with antiestrogens may prevent or delay the development of endocrine therapy resistance. We therefore performed a feasibility study to evaluate the safety of letrozole plus bevacizumab in patients with hormone receptor–positive metastatic breast cancer (MBC).
Patients with locally advanced breast cancer or MBC were treated with the aromatase inhibitor (AI) letrozole (2.5 mg orally daily) and the anti-VEGF antibody bevacizumab (15 mg/kg intravenously every 3 weeks). The primary end point was safety, defined by grade 4 toxicity using the National Cancer Institute Common Toxicity Criteria, version 3.0. Secondary end points included response rate, clinical benefit rate, and progression-free survival (PFS). Prior nonsteroidal AIs (NSAIs) were permitted in the absence of progressive disease.
Forty-three patients were treated. After a median of 13 cycles (range, 1 to 71 cycles), select treatment-related toxicities included hypertension (58%; grades 2 and 3 in 19% and 26%), proteinuria (67%; grades 2 and 3 in 14% and 19%), headache (51%; grades 2 and 3 in 16% and 7%), fatigue (74%; grades 2 and 3 in 19% and 2%), and joint pain (63%; grades 2 and 3 in 19% and 0%). Eighty-four percent of patients had at least stable disease on an NSAI, confounding efficacy results. Partial responses were seen in 9% of patients and stable disease ≥ 24 weeks was noted in 67%. Median PFS was 17.1 months.
Combination letrozole and bevacizumab was feasible with expected bevacizumab-related events of hypertension, headache, and proteinuria. Phase III proof-of-efficacy trials of endocrine therapy plus bevacizumab are in progress (Cancer and Leukemia Group B 40503).
PMCID: PMC3940895  PMID: 19841327
24.  Identification and Validation of a Gene Expression Signature That Predicts Outcome in Adult Men With Germ Cell Tumors 
Journal of Clinical Oncology  2009;27(31):5240-5247.
Germ cell tumor (GCT) is the most common malignancy in young adult men. Currently, patients are risk-stratified on the basis of clinical presentation and serum tumor markers. The introduction of molecular markers could improve outcome prediction.
Patients and Methods
Expression profiling was performed on 74 nonseminomatous GCTs (NSGCTs) from cisplatin-treated patients (ie, training set) and on 34 similarly treated patients with NSGCTs (ie, validation set). A gene classifier was developed by using prediction analysis for microarrays (PAM) for the binary end point of 5-year overall survival (OS). A predictive score was developed for OS by using the univariate Cox model.
In the training set, PAM identified 140 genes that predicted 5-year OS (cross-validated classification rate, 60%). The PAM model correctly classified 90% of patients in the validation set. Patients predicted to have good outcome had significantly longer survival than those with poor predicted outcome (P < .001). For the OS end point, a 10-gene model had a predictive accuracy (ie, concordance index) of 0.66 in the training set and a concordance index of 0.83 in the validation set. Dichotomization of the samples on the basis of the median score resulted in significant differences in survival (P = .002). For both end points, the gene-based predictor was an independent prognostic factor in a multivariate model that included clinical risk stratification (P < .01 for both).
We have identified gene expression signatures that accurately predict outcome in patients with GCTs. These predictive genes should be useful for the prediction of patient outcome and could provide novel targets for therapeutic intervention.
PMCID: PMC3651602  PMID: 19770384
25.  Distress in Older Patients With Cancer 
Journal of Clinical Oncology  2009;27(26):4346-4351.
To determine the predictors of distress in older patients with cancer.
Patients and Methods
Patients age ≥ 65 years with a solid tumor or lymphoma completed a questionnaire that addressed these geriatric assessment domains: functional status, comorbidity, psychological state, nutritional status, and social support. Patients self-rated their level of distress on a scale of zero to 10 using a validated screening tool called the Distress Thermometer. The relationship between distress and geriatric assessment scores was examined.
The geriatric assessment questionnaire was completed by 245 patients (mean age, 76 years; standard deviation [SD], 7 years; range, 65 to 95 years) with cancer (36% stage IV; 71% female). Of these, 87% also completed the Distress Thermometer, with 41% (n = 87) reporting a distress score of ≥ 4 on a scale of zero to 10 (mean score, 3; SD, 3; range, zero to 10). Bivariate analyses demonstrated an association between higher distress (≥ 4) and poorer physical function, increased comorbid medical conditions, poor eyesight, inability to complete the questionnaire alone, and requiring more time to complete the questionnaire. In a multivariate regression model based on the significant bivariate findings, poorer physical function (increased need for assistance with instrumental activities of daily living [P = .015] and lower physical function score on the Medical Outcomes Survey [P = .018]) correlated significantly with a higher distress score.
Significant distress was identified in 41% of older patients with cancer. Poorer physical function was the best predictor of distress. Further studies are needed to determine whether interventions that improve or assist with physical functioning can help to decrease distress in older adults with cancer.
PMCID: PMC2799049  PMID: 19652074

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