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1.  Causes of Death in Long-term Survivors of Head and Neck Cancer 
Cancer  2014;120(10):1507-1513.
Background
Survivors of head and neck squamous cell carcinoma (HNSCC) face excess mortality from multiple causes.
Methods
We used population-based Surveillance, Epidemiology, and End Results (SEER) cancer registry data to evaluate the causes of death in patients with non-metastatic HNSCC diagnosed between 1992 and 2005 who survived at least three years from diagnosis (long-term survivors). We used competing-risks proportional hazards regression to estimate probabilities of death from causes: HNSCC, second primary malignancy (SPM) excluding HNSCC, cardiovascular disease (CVD), and other causes.
Results
We identified 35,958 3-year survivors of HNSCC with a median age at diagnosis of 60 years (range 18 to 100 years) and a median follow-up of 7.7 years (range 3 to 18 years). There were 13,120 deaths during the study period. Death from any cause at 5 and 10 years was 15.4% (95% confidence interval [CI], 15.0% to 15.8%) and 41.0% (95% CI, 40.4% to 41.6%), respectively. There were 3,852 HNSCC deaths including both primary and subsequent head and neck tumors. The risk of death from HNSCC was greater in patients with nasopharynx or hypopharynx cancer and in patients with locally advanced disease. SPM was the leading cause of non-HNSCC death, and the most common sites of SPM death were lung (53%), esophagus (10%), and colorectal (5%) cancer.
Conclusion
Many long-term HNSCC survivors die from cancers other than HNSCC and from non-cancer causes. Routine follow-up care for HNSCC survivors should expand beyond surveillance for recurrence and new head and neck cancers.
doi:10.1002/cncr.28588
PMCID: PMC4101810  PMID: 24863390
competing mortality; head and neck cancer; survivorship; second primary malignancy; competing risk
2.  Impact of Molecular Subtype on Locoregional Recurrence in Mastectomy Patients with T1-2 Breast Cancer and 1-3 Positive Lymph Nodes 
Annals of surgical oncology  2014;21(5):1569-1574.
Introduction
Postmastectomy radiation (PMRT) in T1-T2 tumors with 1-3 positive axillary lymph nodes (ALNs) is controversial. Impact of molecular subtype (MST) on locoregional recurrence (LRR) and PMRT benefit is uncertain. We examined the association between MST and LRR, recurrence-free survival (RFS), and overall survival (OS), in T1-T2 tumors with 1-3 positive ALNs.
Methods
From an institutional database, we identified mastectomy patients with 1-3 positive ALNs between 1995-2006. Patients who received neoadjuvant chemotherapy, had T3-4 tumors, or ≥4 positive ALNs were excluded. MST was defined as: hormone receptor (HR)+/HER2-(Luminal A/B), HR+/HER2+(Luminal HER2), HR-/HER2+(HER2), and HR-/HER2-(basal). Kaplan-Meier method and Cox regression analysis were used to examine association between MST and LRR, RFS, and OS.
Results
884 patients (700 no PMRT,141 PMRT) were included: 72.8% luminal A/B,7.8% luminal HER2,6.8% HER2, and 12.6% basal. Median follow-up was 6.3 years; 39 LRRs occurred. Luminal A/B subtype had the smallest tumors (p=0.03), lowest intraductal component (p=0.01), histologic grade (p<0.0001), lymphovascular invasion (LVI)(p=0.008) and multifocality/multicentricity (p=0.02). On univariate analyses, there was no association between MST and LRR. MST was associated with RFS and OS; the basal and HER2 subtype had the lowest RFS (p=0.0002) and OS (p<0.0001). On multivariate analysis, only age ≤50 years (p=0.002) and presence of LVI (p=0.0003) were predictive of LRR; MST was not (p=0.38).
Conclusion
In patients with T1-2 breast cancer and 1-3 positive lymph nodes who did not receive PMRT, MST was not a independent predictor of LRR and may not be useful in selecting PMRT candidates in that group.
doi:10.1245/s10434-014-3488-x
PMCID: PMC4366059  PMID: 24488216
molecular subtype; locoregional recurrence; mastectomy; axillary lymph nodes
3.  Feasibility and Predictability of Perioperative PET and Estrogen Receptor Ligand in Patients with Invasive Breast Cancer 
The presence of estrogen receptor (ER) in breast cancer is a prognostic indicator for both disease-free and overall survival. 16α-18F-fluoro-17β-estradiol (18F-FES) with PET is a noninvasive test for evaluation of ER expression and has been used for predicting response to endocrine therapy in patients with ER-positive metastatic breast cancer. The purpose of this study was to correlate 18F-FES PET and ER expression in patients with primary, operable breast cancer.
Methods
Forty-eight patients were prospectively enrolled in an institutional review board–approved protocol and signed an informed consent form. All patients had undergone 18F-FES PET preoperatively. Clinical characteristics, tumor characteristics, and treatment outcomes were recorded. Immunohistochemical analysis for ER and progesterone receptor (PgR) percentage expression (46 surgical, 2 core biopsy specimens) was performed. 18F-FES PET standardized uptake value (SUV) of the breast lesion was correlated with percentage immunohistochemistry ER and PgR expression. 18F-FES PET SUV was quantified, with a value of 1.5 or more considered positive, and ER and PgR was quantified, with 1% or more considered positive. Formalin-fixed paraffin-embedded tissue was available for 44 patients (42 surgical, 2 core biopsy specimens). We used a microarray platform, and estrogen-related gene expression data (ESR1, ESR2, and PGR) were compared with 18F-FES PET SUV (Spearman rank correlation). Tumor size, ductal histology, grade, HER2-neu overexpression, PgR expression, estradiol level, body mass index (BMI), and lean BMI were compared with 18F-FES PET uptake using univariate and multivariate analysis.
Results
Forty-eight patients completed our protocol, and 2 patients did not undergo surgery because bone metastases were identified preoperatively on 18F-FES PET. Eighty-three percent of our patients were stage I or II, with a median tumor size of 1.9 cm. Forty-one patients underwent a sentinel node biopsy. Twenty-one patients had nodal involvement. 18F-FES PET identified 5 patients with axillary nodal uptake (median SUV, 3.0; range, 1.7–6.9). These 5 patients had ER-positive breast cancer, and all had more than 4 positive nodes at the time of axillary node dissection. 18F-FES PET SUV was associated with immunohistochemistry ER expression. The sensitivity and specificity of the 18F-FES PET for the breast lesion were 0.85 and 0.75, respectively. Estrogen and progesterone gene expression (ESR1, ESR2, and PGR) was not associated with 18F-FES PET SUV (Spearman rank correlation). We found a significant correlation between 18F-FES PET SUV and tumor size (P = 0.0015) but not with ductal histology, grade, HER2-neu overexpression, PgR, estradiol, BMI, or lean BMI (logistic regression). ER expression (P < 0.001) and tumor size (P < 0.0001) were significant on multivariate regression analysis.
Conclusion
18F-FES PET SUV correlated with ER immunohistochemistry expression but not gene expression in our patients with early breast cancer. We found that size of primary tumor was significantly associated with 18F-FES PET SUV. 18F-FES PET is highly predictive for metastatic disease and helped in the identification of patients with metastatic disease in a preoperative setting.
doi:10.2967/jnumed.112.113373
PMCID: PMC4404505  PMID: 23970364
PET imaging; breast cancer; estrogen receptor; ligand
4.  Effect of Margin Width on Local Recurrence in Triple Negative Breast Cancer Patients Treated with Breast-Conserving Therapy 
Annals of surgical oncology  2013;21(4):1209-1214.
Background
The effect of increasing negative margin width following breast conserving therapy (BCT) on local recurrence (LR) is controversial. LR rates vary by subtype, with the highest rates seen in triple negative breast cancer (TNBC). This study examined LR rates in relationship to margin width in TNBC treated with BCT.
Methods
Women with TNBC who underwent BCT between 1999-2009 were identified. Margins were defined as positive (ink on tumor), 0.1-2.0, and 2 mm. Patients with positive margins were excluded. Statistical comparisons were by t tests, Fishers exact test and Wilcoxon rank sum test. Cumulative incidence of LR was compared using competing-risks methodology.
Results
Of 535 cancers, 71 had margins ≤2mm and 464 had margins >2mm. At median follow-up of 84 months (range 8-165 months) there were 37 local, 18 regional, and 77 distant recurrences or deaths as first events. 10 patients had a locoregional recurrence prior to planned radiation therapy and were excluded from cumulative incidence analyses. The cumulative incidence of LR at 60 months for margins ≤2mm was 4.7% (95% CI 0, 10.0), and for >2mm 3.7% (1.8, 5.5), p=0.11. After controlling for chemotherapy and tumor size, there was no difference in LR between the two margin groups (p=.06). A difference in the risk of distant recurrence or death was not observed (p=.53).
Conclusions
Margin width greater than 2mm was not associated with reduced LR rates. This data supports a negative margin definition of no ink on tumor, even in this high risk TNBC cohort.
doi:10.1245/s10434-013-3416-5
PMCID: PMC4349354  PMID: 24327132
triple negative breast cancer; local recurrence; margin; breast conserving therapy
5.  Axillary Dissection Can Be Avoided in the Majority of Clinically Node-Negative Patients Undergoing Breast-Conserving Therapy 
Annals of surgical oncology  2013;21(1):22-27.
Background or Purpose
The extent to which ACOSOG Z0011 findings are applicable to patients undergoing breast-conserving therapy (BCT) is uncertain. We prospectively assessed how often axillary dissection (ALND) was avoided in an unselected, consecutive patient cohort meeting Z0011 eligibility criteria and whether subgroups requiring ALND could be identified preoperatively.
Methods
Patients with cT1,2cN0 breast cancer undergoing BCT were managed without ALND for metastases in <3 sentinel nodes (SNs) and no gross extracapsular extension (ECE). Patients with and without indications for ALND were compared using Fisher's exact and Wilcoxon rank sum tests.
Results
From 8/2010-11/2012, 2157 invasive cancer patients had BCT. 380 had histologic nodal metastasis; 93 did not meet Z0011 criteria. Of 287 with ≥1 H&E-positive SN (209 macrometastases), 242(84%) had indications for SN only. ALND was indicated in 45 for ≥3 positive SNs (n=29) or ECE (n=16). The median number of SNs removed in the SN group was 3 versus 5 in the ALND group (p<.0001). Age, hormone receptor and HER2 status, and grade did not differ between groups; tumors were larger in the ALND group (p<0.0001). 72% of ALND patients had additional positive nodes (median=1;1-19). No axillary recurrences have occurred (median follow-up, 13 months).
Conclusions
ALND was avoided in 84% of a consecutive series of patients having BCT, suggesting that most patients meeting ACOSOG Z0011 eligibility have a low axillary tumor burden. Age, ER, and HER2 status were not predictive of ALND, and the criteria used for ALND (≥3SNs, ECE) reliably identified patients at high risk for residual axillary disease.
doi:10.1245/s10434-013-3200-6
PMCID: PMC4349525  PMID: 23975314
axillary dissection; positive sentinel node; ACOSOG Z0011; breast-conserving therapy; ALND
6.  Impact of Margin Assessment Method on Positive Margin Rate and Total Volume Excised 
Annals of surgical oncology  2013;21(1):86-92.
Background
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.
Methods
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).
Results
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.
Conclusions
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.
doi:10.1245/s10434-013-3257-2
PMCID: PMC3923624  PMID: 24046114
Margins; breast conservation; lumpectomy; breast cancer
7.  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.
doi:10.1371/journal.pone.0114900
PMCID: PMC4266616  PMID: 25506917
9.  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.
doi:10.1007/s10549-013-2725-5
PMCID: PMC3871867  PMID: 24141896
LCIS; MRI; Screening; High risk; Breast cancer
10.  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.
Background
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.
Results
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.
Conclusion
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.
doi:10.1016/j.clgc.2013.04.001
PMCID: PMC3959735  PMID: 23707221
Metastatic; Renal cell carcinoma; Sunitinib; Systemic therapy; Targeted therapy
11.  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.
doi:10.1002/cam4.259
PMCID: PMC4303170  PMID: 24944108
Breast neoplasms; diabetes mellitus, type 2; metformin; mortality
12.  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.
doi:10.1007/s10549-013-2625-8
PMCID: PMC3826956  PMID: 23884596
Breast cancer; Income; Work; Survivorship
13.  Phase II Trial of Bicalutamide in Patients with Androgen Receptor–Positive, Estrogen Receptor–Negative Metastatic Breast Cancer 
Purpose
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.
Results
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.
Conclusion
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.
doi:10.1158/1078-0432.CCR-12-3327
PMCID: PMC4086643  PMID: 23965901
14.  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.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1245/s10434-012-2719-2
PMCID: PMC3833840  PMID: 23161115
15.  Frequent mutational activation of the PI3K-AKT pathway in trastuzumab-resistant breast cancer 
Purpose
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).
Results
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.
Conclusions
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.
doi:10.1158/1078-0432.CCR-12-1785
PMCID: PMC3525734  PMID: 23092874
16.  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.
Introduction
The objective of this study was to examine the feasibility and toxicity of adjuvant dose-dense chemotherapy in older women with breast cancer.
Methods
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).
Results
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.
Conclusions
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.
doi:10.1007/s10549-008-0116-0
PMCID: PMC3811071  PMID: 18622739
Breast Cancer; Dose-Dense Chemotherapy; Older Patient
17.  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.
Background
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1245/s10434-011-1823-z
PMCID: PMC3788632  PMID: 21647763
18.  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).
doi:10.1002/cam4.119
PMCID: PMC3892804  PMID: 24403238
Breast cancer; FDG PET/CT; mean tumor volume; SUV max; total lesion glycolysis
19.  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.
Purpose
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%.
Results
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.
Conclusion
Dose-dense adjuvant CMF is tolerable and feasible at 14-day intervals with PEG-filgrastim support.
doi:10.3816/CBC.2010.n.057
PMCID: PMC3661192  PMID: 21147686
CMF; PEG-filgrastim
20.  Sarcomatoid-variant Renal Cell Carcinoma Treatment Outcome and Survival in Advanced Disease 
Objectives
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.
Methods
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).
Results
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).
Conclusions
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.
doi:10.1097/COC.0b013e3181f47aa4
PMCID: PMC3661202  PMID: 21127411
metastatic; sarcomatoid; renal cell carcinoma; sunitinib; targeted therapy
21.  Phase I trial of everolimus plus sunitinib in patients with metastatic renal cell carcinoma 
Cancer  2011;118(7):1868-1876.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1002/cncr.26429
PMCID: PMC3609026  PMID: 21898375
renal cell carcinoma; everolimus; sunitinib; targeted therapy; combination drug therapy
22.  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.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1002/cncr.26478
PMCID: PMC3263326  PMID: 22009703
disparities; employment; breast cancer; survivorship
23.  Phase II trial of sunitinib in patients with metastatic non-clear cell renal cell carcinoma 
Investigational New Drugs  2010;30(1):335-340.
Summary
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.
doi:10.1007/s10637-010-9491-6
PMCID: PMC3257373  PMID: 20711632
Papillary renal cell carcinoma; Non-clear cell renal cell carcinoma; Sunitinib; Phase II trial
24.  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.
Background
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.
Results
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.
Conclusions
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.
doi:10.1016/j.clbc.2011.03.021
PMCID: PMC3222913  PMID: 21729667
25.  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.
Purpose
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.
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.
Conclusion
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.
doi:10.1200/JCO.2009.27.5743
PMCID: PMC3651596  PMID: 20516453

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