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ABSTRACT: BACKGROUND: Germ cell tumors (GCTs) primarily affect adolescent and young adult men. Detailed clinical and treatment characteristics in older men are lacking. METHODS: Patients with GCT seen over a 20-year period at Memorial Sloan-Kettering Cancer Center were identified. Primary tumor site and histology were compared for patients aged ≥ 50 years at diagnosis versus younger men. For patients aged ≥ 50, individual chart review was performed and treatment delays, changes, and toxicities were recorded for those treated with first-line chemotherapy. RESULTS: Of 4235 diagnoses of GCT, 3999 (94.4%) were made at age < 50 versus 236 (5.6%) at age ≥ 50. Compared with patients diagnosed before age 50, older men more frequently had seminoma (62.7% versus 36.7%) and less frequently, nonseminoma (34.7% versus 63.2%) (P < .0001). Predominant histology switched from nonseminoma to seminoma around age 35. Distribution of primary sites also differed for older versus younger men (testis: 89.4% versus 92.9%; retroperitoneal: 3.8% versus 0.7%; CNS 0% versus 1.7%) except for mediastinal primary tumors, which remained constant across age groups. Fifty patients age ≥ 50 received first-line platinum-based chemotherapy; 30 experienced complications leading to treatment discontinuation, delay ≥ 7 days, or regimen change. Twenty-two (44%) patients experienced neutropenic fever, 6 despite prophylactic growth factor support. Estimated 5-year survival for chemotherapy-treated patients was 84.9%. CONCLUSIONS: Men aged ≥ 50 years comprise less than 10% of GCT diagnoses and have distinct clinical and histological characteristics as compared with younger patients. Although complications from chemotherapy occur frequently in older men, prognosis remains excellent when risk-directed treatment is administered with curative intent. Cancer 2013. © 2013 American Cancer Society.
Cancer 04/2013; · 4.77 Impact Factor
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ABSTRACT: 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.
Annals of Surgical Oncology 11/2012; · 4.17 Impact Factor
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Susan M Domchek,
Komal Jhaveri, Sujata Patil,
Jill E Stopfer,
Clifford Hudis,
Jacquelyn Powers,
Zsofia Stadler,
Laura Goldstein,
Noah Kauff,
Mustafa Khasraw,
Kenneth Offit,
Katherine L Nathanson,
Mark Robson
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ABSTRACT: BACKGROUND: This study sought to estimate the risk of breast cancer (BC) after a diagnosis of ovarian cancer (OC) associated with mutation of the BRCA1/2 (breast cancer, early onset) genes (BRCA-OC). METHODS: The Memorial Sloan-Kettering Cancer Center and the University of Pennsylvania, clinical genetics databases were searched to identify women with BRCA-OC who participated in genetic testing and follow-up studies from 1995 to 2009. The primary objective was to determine the risk of developing BC after BRCA-OC. Overall survival (OS) and BC-free survival (BCFS) were determined by the Kaplan-Meier method; patients were censored at the time of last follow-up. RESULTS: A total of 164 patients had BRCA-OC (115 with BRCA1; 49 with BRCA2). Of these 164 patients, 152 developed OC prior to BRCA testing (median time to testing, 2.4 years [0.01-55 years]). Median follow-up from OC for those not developing BC was 5.8 years (0.25-55.6 years). There were 46 deaths, but none were due to BC. The 5- and 10-year OS were 85% (95% confidence interval [CI] = 0.78, 0.90) and 68% (95% CI = 0.59, 0.76), respectively. There were 18 metachronous BC diagnoses. The 5- and 10-year BCFS were 97% (95% CI = 0.92, 0.99) and 91% (95% CI = 0.82, 0.95), respectively. A subset of 64 women were tested either before or within 12 months of BRCA-OC. In this pseudo-incident subset, 5- and 10- year OS was 71% (95% CI = 0.53, 0.83) and 62% (95% CI = 0.44, 0.75), respectively, and 5- and 10-year BCFS were 100% and 87% (95% CI = 0.56, 0.96), respectively. CONCLUSIONS: OS was dominated by OC deaths. Metachronous BC risk was lower than reported for unaffected BRCA mutation carriers. These results support nonsurgical management of BC risk in women with BRCA-OC. Cancer 2012. © 2012 American Cancer Society.
Cancer 11/2012; · 4.77 Impact Factor
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Sarat Chandarlapaty,
Rita A Sakr,
Dilip Giri, Sujata Patil,
Adriana Heguy,
Monica Morrow,
Shanu Modi,
Larry Norton,
Neal Rosen,
Clifford A Hudis,
Tari A King
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ABSTRACT: 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.
Clinical Cancer Research 10/2012; · 7.74 Impact Factor
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ABSTRACT: BACKGROUND: In a previous study of the relationship between breast density and primary tumor features, we observed a higher mastectomy rate in patients with extremely dense breasts. Here we examine possible reasons for this finding. METHODS: Data were obtained from a prospectively maintained database of 1,056 invasive breast cancer patients from January 2005 to June 2007. Mammographic density was assigned by Breast Imaging-Reporting and Data System (BI-RADS) classification. Initial and final surgical procedures, and patient and tumor variables were recorded. RESULTS: Breast-conserving surgery (BCS) was attempted in 758 patients (72 %), 385 (51 %) of whom had preoperative magnetic resonance imaging (MRI). Initial BCS was less common among patients with the highest (BI-RADS 4) breast density compared to patients with less-dense breasts (52 vs. 74 %; p < 0.0001), but MRI use was more common (65 vs. 33 %; p < 0.0001). Adjusting for clinical and pathologic variables, patients with the highest breast density had 1.94-times (95 % confidence interval 1.44-2.62; p < 0.0001) the odds of initial mastectomy compared to patients with less-dense breasts. After initial BCS, 387 patients (51 %) had positive shaved margins, 96 (25 %) of whom converted to mastectomy. MRI did not correlate with the rate of positive margins overall or among those with dense breasts. Adjusting for clinical and pathologic variables, density did not predict margin status or conversion to mastectomy. In a multivariate model, age, histologic grade, extensive intraductal component, and multicentricity/multifocality were independently associated with conversion to mastectomy. CONCLUSIONS: Density alone seems to influence the decision to proceed with initial mastectomy. When BCS was attempted, breast density was not associated with positive margins or conversion to mastectomy. A benefit of MRI in decreasing positive margins was not observed. These data do not support the use of breast density as a selection criterion for BCS.
Annals of Surgical Oncology 09/2012; · 4.17 Impact Factor
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Journal of Clinical Oncology 07/2012; 30(25):3143-4; author reply 3144-5. · 18.37 Impact Factor
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Patrick G Morris,
Conleth G Murphy,
Divya Mallam,
Melissa Accordino, Sujata Patil,
Jane Howard,
Antonio Omuro,
Kathryn Beal,
Andrew D Seidman,
Clifford A Hudis,
Monica N Fornier
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ABSTRACT: Patients with breast cancer, which lacks ER, PR, and HER2; "triple negative" (TNBC), are at increased risk of brain metastases (BMs). However, the impact of modern therapy on the risk of BMs and outcomes remains largely unknown. In this retrospective, single-institution study we assessed the incidence of BMs, the therapeutic options, and overall survival, in a recent cohort of patients with TNBC. Women diagnosed with early stage TNBC from January 1, 1998 to December 31, 2007 were identified through institutional databases. Electronic medical records were reviewed to assess patterns of recurrence, treatment, and survival. In total, 1,323 patients, median age 53 years (range 20-91), were identified. There were 298 patients (23%) who developed metastatic disease, of whom, 99 (33%) developed BMs, representing 7.5% of the entire cohort. Following BM diagnosis, treatment consisted of: radiotherapy 87 (88%) patients, resection 26 (26%) patients, and systemic chemotherapy 70 (71%) patients, with a median of 1.0 (range 0-8) chemotherapy regimens. The actuarial median survival from diagnosis of BMs is 5 months (95% CI 4-7 months). This single-institution, retrospective study confirms that the prognosis for patients with BMs from TNBC remains poor. This group of patients urgently needs improved therapies.
The Breast Journal 05/2012; 18(4):345-50. · 1.64 Impact Factor
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ABSTRACT: BRCA1 germline mutation carriers usually develop ER, PR and HER2 negative breast carcinoma. Somatic BRCA1 mutations are rare in sporadic breast cancers, but other mechanisms could impair BRCA1 functions in these tumors, particularly in triple-negative breast carcinomas (TNBCs). Id4, a helix-loop-helix DNA binding factor, blocks BRCA1 gene transcription in vitro and could downregulate BRCA1 in vivo. We compared Id4 immunoreactivity in 101 TNBCs versus 113 non-TNBCs, and correlated the results with tumor morphology and immunoreactivity for CK5/6, CK14, EGFR, and androgen receptor (AR). Id4 was present in 76 out of 101 (75 %) TNBCs: 40 (40 %) TNBCs displayed Id4 positivity in >50 % of neoplastic cells, 23 (23 %) in 5-50 %, and 13 (13 %) in <5 %. In contrast, only 6 (5 %) of 113 non-TNBCs showed focal Id4 positivity, limited to fewer than 5 % of the tumor (p < 0.0001). Id4 expression significantly associated with high histologic grade (p = 0.0002) and mitotic rate (p = 0.006). Id4 decorated all 12 TNBCs with large central acellular zone of necrosis in our series, with positive staining in 10-90 % of the cells. Id4 signal strongly correlated with cytokeratin CK14 reactivity (p < 0.0001), but not with CK5/6 and EGFR. All apocrine carcinomas in our series were positive for AR and most for EGFR, but they were negative for CK5/6, CK14, and Id4, with only two exceptions. Our results document substantial expression of Id4 in most TNBCs, which could result in functional downregulation of BRCA1 pathways in these tumors.
Breast Cancer Research and Treatment 04/2012; 135(1):93-102. · 4.43 Impact Factor
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Patrick G Morris,
Gary A Ulaner,
Anne Eaton,
Maurizio Fazio,
Komal Jhaveri, Sujata Patil,
Laura Evangelista,
Joseph Y Park,
Cristian Serna-Tamayo,
Jane Howard,
Steven Larson,
Clifford A Hudis,
Heather L McArthur,
Maxine S Jochelson
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ABSTRACT: BACKGROUND: In this retrospective, single-institution study, the authors examine the maximum standardized uptake value (SUVmax) on positron emission tomography/computed tomography (PET/CT) images as a prognostic variable in patients with newly diagnosed metastatic breast cancer (MBC). METHODS: Patients with ≥1 metastatic lesion on PET/CT images that were obtained within 60 days of their MBC diagnosis between January 1, 2001 and December 31, 2008 were included. Patients were excluded if they had received chemotherapy ≤30 days before the PET/CT images were obtained. Electronic medical reports were reviewed to determine the SUVmax and overall survival. Because of intraindividual variation in the SUV by body site, separate analyses were conducted by metastatic site. Relationships between site-specific PET/CT variable tertiles and overall survival were assessed using Cox regression; hazard ratios for the highest tertile versus the lowest tertile were reported. RESULTS: In total, 253 patients were identified, and their median age was 57 years (range, 27-90 years). Of these, 152 patients (60%) died, and the median follow-up was 40 months. On univariate analysis, SUVmax tertile was strongly associated with overall survival in patients who had bone metastases (N = 141; hazard ratio, 3.13; 95% confidence interval, 1.79-5.48; P < .001). This effect was maintained on multivariate analysis (HR = 3.19; 95% confidence interval, 1.64-6.20, P = .002) after correcting for known prognostic variables. A greater risk of death was associated with SUVmax tertile in patients who had metastases to the liver (N = 46; hazard ratio, 2.07; 95% confidence interval, 0.90-4.76), lymph nodes (N = 149; hazard ratio, 1.1; 95% confidence interval, 0.69-1.88), and lung (N = 62; hazard ratio, 2.2; 95% confidence interval, 0.97-4.95), although these results were not significant (P = .18, P = .31, and P = .095, respectively). CONCLUSIONS: The current results indicate that PET/CT has value as a prognostic tool in patients with newly diagnosed MBC to bone. Cancer 2012. © 2012 American Cancer Society.
Cancer 04/2012; · 4.77 Impact Factor
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ABSTRACT: Previous 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 = .0002) and 18 months (45% vs 59%; P = .02) after diagnosis, but at 36 months there was no significant difference (53% vs 59%; P = .29). Latinas were more likely to be manual laborers than were non-Latina whites (P < .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.
Cancer 03/2012; 118(6):1664-74. · 4.77 Impact Factor
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Patrick G Morris,
Maurizio Fazio,
Azeez Farooki,
Cherry Estilo,
Divya Mallam,
Alison Conlin, Sujata Patil,
Martin Fleisher,
Serge Cremers,
Joseph Huryn,
Clifford A Hudis,
Monica N Fornier
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ABSTRACT: PURPOSE: Oversuppression of bone turnover can be a critical factor in the pathogenesis of osteonecrosis of the jaw (ONJ). We investigated N-telopeptide of type I collagen (NTX) and bone-specific alkaline phosphatase (BAP) as potential predictors of ONJ onset. PATIENTS AND METHODS: Patients with ONJ and available stored serum were identified retrospectively from the institutional databases. Four approximate points were examined: point of ONJ diagnosis and 12, 6, and 1 month before the diagnosis. NTX and BAP were measured using enzyme-linked immunosorbent assays and examined as possible predictors of ONJ. RESULTS: From March 1998 to September 2009, we identified 122 patients with ONJ. Of these, 56 (46%) had one or more serum samples available. Overall, 55 patients (98%) received bisphosphonates. Using the exact dates, no obvious patterns in either NTX or BAP were noted. Similarly, using the ordinal points, no evidence of suppression of NTX or BAP over time was seen. The consecutive median values were as follows: The median NTX values were 8.0 nmol/L (range 3.8 to 32.9) at 12 months before ONJ; 9.5 nmol/L (range 4.7 to 42.7) at 6 months; 9.5 nmol/L (range 4.5 to 24.6) at 1 month, and 10.4 nmol/L (range 4.4 to 32.5) at the ONJ diagnosis. The median BAP values were BAP 18.0 U/L (range 7.0 to 74) at 12 months before ONJ; 18.0 U/L (range 4.0 to 134) at 6 months; 14.0 U/L (range 4.0 to 132) at 1 month, and 18.0 U/L (range 0.7 to 375) at the ONJ diagnosis. Only 2 patients (4%) had NTX and 17 (30%) had BAP below the normal range at the ONJ diagnosis. CONCLUSIONS: In the present large retrospective study, no trends were seen in the NTX and BAP levels before the ONJ diagnosis.
Journal of oral and maxillofacial surgery: official journal of the American Association of Oral and Maxillofacial Surgeons 02/2012; · 1.58 Impact Factor
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Ana M Molina,
Darren R Feldman,
Michelle S Ginsberg,
Glenn Kroog,
Satish K Tickoo,
Xiaoyu Jia,
Murielle Georges, Sujata Patil,
Michael S Baum,
Victor E Reuter,
Robert J Motzer
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ABSTRACT: 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.
Investigational New Drugs 02/2012; 30(1):335-40. · 3.36 Impact Factor
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ABSTRACT: Pregnancy-associated breast cancer (PABC) may be defined as breast cancer diagnosed during pregnancy or within 1 year of giving birth. Conflicting data exist regarding the impact of pregnancy on clinical features and prognosis of breast cancer.
A single-institution retrospective chart review was performed of 99 patients identified with PABC between 1992 and 2007. Non-PABC controls were matched 2:1 to PABC cases by year of diagnosis and age. The differences in clinical features were compared between cases and controls using chi-square tests. Univariate and multivariate analyses were performed to assess the effect of PABC on survival.
Of the 99 PABC cases, breast cancer was diagnosed during pregnancy in 36 patients, and after delivery in 63. PABC cases were more likely than controls to be negative for estrogen receptor (59% vs 31%, P < .0001) and negative for progesterone receptor (72% vs 40%, P < .0001). Cases were also more likely to have advanced T class (P = .0271) and N class (P = .0104) and higher grade tumors (P = .0115). With a median follow-up of 6.3 years for cases and 4.7 years for controls, overall survival did not differ between cases and controls (P = .0787). On multivariate analysis, the independent prognostic factors for overall survival were estrogen receptor status (P = .0031) and N class (P = .0003). The diagnosis of PABC was not an independent prognostic factor (P = .1317).
PABC is associated with more adverse tumor features than non-PABC matched for age and year of diagnosis. After correcting for pathologic features, the diagnosis of PABC is not in itself an adverse prognostic factor for survival.
Cancer 11/2011; 118(13):3254-9. · 4.77 Impact Factor
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ABSTRACT: 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 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 maximum tolerated dose (MTD). Pharmacokinetic profiles were obtained.
Twenty patients (13 clear cell and 7 nonclear cell RCC) were enrolled in 5 cohorts. Daily everolimus was not tolerated when combined with sunitinib; the first 2 patients on the second 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 to 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, and 3 had nonclear cell RCC. No unexpected accumulation of everolimus, sunitinib, or N-desethyl sunitinib was observed.
The combination of everolimus and sunitinib is associated with significant acute and chronic toxicities and is only tolerated at attenuated doses. Responses were observed in nonclear cell and clear cell RCC.
Cancer 09/2011; 118(7):1868-76. · 4.77 Impact Factor
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Devika Gajria,
Joseph Gonzalez,
Kimberly Feigin, Sujata Patil,
Carol Chen,
Maria Theodoulou,
Pamela Drullinsky,
Gabriella D'Andrea,
Diana Lake,
Larry Norton,
Clifford A Hudis,
Tiffany A Traina
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ABSTRACT: Our group applied mathematical modeling to capecitabine dosing and predicted 7 days of treatment followed by 7 days of rest (7-7) would improve efficacy and minimize toxicity. The conventional schedule of capecitabine limits full dosing in combination with other agents due to toxicity. Lapatinib inhibits the tyrosine kinase of HER2 and has activity when added to conventionally scheduled capecitabine for the treatment of patients with trastuzumab-refractory, HER2-positive, metastatic breast cancer (MBC). We performed this study to evaluate the activity and tolerability of capecitabine 7-7 with lapatinib in patients with trastuzumab-refractory MBC. Eligible patients had measurable, HER2-positive, MBC that progressed following exposure to trastuzumab. Treatment consisted of capecitabine 2,000 mg orally twice daily, 7-7 and lapatinib 1,250 mg orally daily. The primary endpoint was response rate. Secondary endpoints included toxicity, progression-free survival, and stable disease ≥ 6 months. Twenty-three patients were treated on study. More than 60% had prior chemotherapy for MBC and all had prior trastuzumab. After a median of 23 weeks (range 2-96+), five patients had partial responses (23; 95 CI, 7-44%) and six (27; 95 CI, 10-48%) had stable disease ≥ 6 months. Median progression-free survival was 9.4 months. The most common treatment-related toxicities ≥ grade (gr) 2 were hand-foot syndrome (gr 2 43%; gr 3 4% gr 4 0%), diarrhea (gr 2 26%; gr 3/4 0%), elevated liver chemistries (gr 2 17%; gr 3/4 0%), and anemia (gr 2 13%; gr 3 4%; gr 4 4%). No grade ≥ 3 nausea, vomiting, or diarrhea events occurred. This study demonstrated feasibility and after meeting biostatistical requirements for continued accrual was terminated in anticipation of slow enrollment. Capecitabine 7-7 with lapatinib was well tolerated with minimal gastrointestinal toxicity. Antitumor activity was observed in patients with trastuzumab-refractory MBC.
Breast Cancer Research and Treatment 09/2011; 131(1):111-6. · 4.43 Impact Factor
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ABSTRACT: Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer have a higher risk of locoregional recurrence (LRR), even in the setting of early stage, lymph node-negative disease. In this sequential, retrospective study, the authors evaluated whether adjuvant trastuzumab was associated with reduced LRR in women with lymph node-negative, HER2-positive disease who received breast-conservation therapy (BCT).
By using an institutional database, 197 women were identified who had lymph node-negative, HER2-positive breast cancer measuring ≤5 cm diagnosed between 2002 and 2008 and who received BCT, including whole-breast irradiation. Two cohorts were compared: 70 women who did not receive trastuzumab (the no-trastuzumab cohort) and 102 women who did receive trastuzumab (the trastuzumab cohort). Kaplan-Meier methods were used to estimate LRR-free survival.
The 2 cohorts were similar in age, tumor size, histology, and hormone receptor status. Chemotherapy was received by 73% of the no-trastuzumab cohort and by 100% of the trastuzumab cohort. In both groups, 99% of patients completed radiotherapy with a median dose of 60 Gray. The median recurrence-free follow-up was 86 months for the no-trastuzumab cohort and 47 months for the trastuzumab cohort. The 3-year LRR-free survival rate was 90% (95% confidence interval, 83%-97%) for the no-trastuzumab cohort and 99% (95% confidence interval, 97%-100%) for the trastuzumab cohort. In the no-trastuzumab cohort, LRR occurred in 7 patients (median time to LRR, 14 months). In the trastuzumab cohort, there was 1 LRR at 14 months.
Even among women with lower risk breast cancer, the relatively high locoregional failure rates associated with positive HER2 status could be reduced markedly with adjuvant trastuzumab chemotherapy. Within 3 years, a 10% LRR rate without trastuzumab and a 1% LRR rate with trastuzumab were observed in women with lymph node-negative disease who received BCT.
Cancer 09/2011; 118(8):1982-8. · 4.77 Impact Factor
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ABSTRACT: Refractory germ cell tumor (GCT) patients have a poor prognosis and limited treatment options. The identification of novel active agents may be impaired by use of response as the primary endpoint in phase 2 trials. Improved endpoints could enhance the development of new effective agents.
The characteristics and outcome of refractory GCT patients enrolled in 7 single-agent phase 2 trials conducted at Memorial Sloan-Kettering Cancer Center from 1990 to 2008 were reviewed. The study agents were suramin, all-transretinoic acid, topotecan, pyrazoloacridine, temozolomide, ixabepilone, and sunitinib. The major endpoints evaluated were response, progression-free survival (PFS), and overall survival (OS).
Ninety patients (87 male, 3 female) were treated. The primary tumor site was testis in 65 patients, mediastinum in 17 patients, retroperitoneum in 4 patients, and other in 4 patients. Eighty-six patients had nonseminoma, and 4 patients had pure seminoma. Best responses were 1 (1%) partial response (ixabepilone), 15 (17%) stable disease, and 74 (82%) progressive disease. Median PFS and OS were 1.0 month (95% confidence interval [CI], 0.8-1.3) and 4.7 months (95% CI, 3.5-6.4), respectively. Eighty-six of the 90 patients have died. The 12- and 16-week PFS rates were 9% (95% CI, 3-15%) and 6% (95% CI, 1%-11%), respectively.
Patients with refractory GCT progressed rapidly to these single agents. PFS and OS may be useful endpoints for designing phase 2 trials testing novel agents in this population. Twelve-week PFS (with comparison to the 9% benchmark rate reported herein) is the recommended endpoint for phase 2 trial design and median OS (using 4.7 months as the predicted median for the control arm) is suggested for phase 3 trials.
Cancer 07/2011; 118(4):981-6. · 4.77 Impact Factor
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ABSTRACT: Several large, randomized trials established the benefits of adjuvant trastuzumab with chemotherapy. However, the benefit for women with small, node-negative HER2-positive (HER2+) disease is unknown, as these patients were largely excluded from these trials. Therefore, a retrospective, single-institution, sequential cohort study of women with small, node-negative, HER2+ breast cancer who did or did not receive adjuvant trastuzumab was conducted.
Women with ≤ 2 cm, node-negative, HER2+ (immunohistochemistry 3+ or fluorescence in situ hybridization ≥ 2) breast cancer were identified through an institutional database. A "no-trastuzumab" cohort of 106 trastuzumab-untreated women diagnosed between January 1, 2002 and May 14, 2004 and a "trastuzumab" cohort of 155 trastuzumab-treated women diagnosed between May 16, 2005 and December 31, 2008 were described. Survival and recurrence outcomes were estimated by Kaplan-Meier methods.
The cohorts were similar in age, median tumor size, histology, hormone receptor status, hormone therapy, and locoregional therapy. Chemotherapy was administered in 66% and 100% of the "no trastuzumab" and "trastuzumab" cohorts, respectively. The median recurrence-free and survival follow-up was: 6.5 years (0.7-8.5) and 6.8 years (0.7-8.5), respectively, for the "no trastuzumab" cohort and 3.0 years (0.5-5.2) and 3.0 years (0.6-5.2), respectively, for the "trastuzumab" cohort. The 3-year locoregional invasive recurrence-free, distant recurrence-free, invasive disease-free, and overall survival were 92% versus 98% (P = .0137), 95% versus 100% (P = .0072), 82% versus 97% (P < .0001), and 97% versus 99% (P = .18) for the "no trastuzumab" and "trastuzumab" cohorts, respectively.
Women with small, node-negative, HER2+ primary breast cancers likely derive significant benefit from adjuvant trastuzumab with chemotherapy.
Cancer 06/2011; 117(24):5461-8. · 4.77 Impact Factor
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ABSTRACT: Older women are less likely to receive standard of care treatment for breast cancer.
We examined variables that affected the outcome of elderly patients ≥70 years old among 1,470 patients with invasive cancer with positive sentinel lymph nodes (SLNs).
Elderly patients were less likely to undergo mastectomy, completion axillary node dissection (ALND), adjuvant chemotherapy, and radiotherapy (RT) following breast-conserving therapy (BCT) compared with patients <70 years old. The 5-year risk of disease progression and cumulative incidence of breast cancer-specific deaths were not significantly different for both groups. On multivariate analysis, hormone receptor-negative status, number of metastatic lymph nodes, high nuclear grade, and tumor size were the factors independently associated with increased risk of disease progression.
Tumor factors were the primary determinants of breast cancer outcomes in our cohort. Elderly patients are less likely to receive aggressive surgical interventions and adjuvant therapy because of perceived life expectancy.
American journal of surgery 06/2011; 201(6):734-40. · 2.36 Impact Factor
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ABSTRACT: PIK3CA gene mutations are the most common activating mutations in human breast cancer. Its association with hormone receptor-positive breast cancer makes it a prime target for clinical therapeutic advances to maintain anti-estrogen responsiveness. In anticipation of this therapeutic approach, we have evaluated intratumoral heterogeneity in primary breast cancers with regard to PIK3CA mutation status. In addition, we have assessed for the presence of the mutation in paired pre-invasive breast cancer and metastases. To assess for intratumoral heterogeneity, separate tumor blocks from primary breast cancers (n = 63) were genotyped for PIK3CA mutations. Available paired tissue samples from breast tumors known to harbor mutations underwent massARRAY genotyping (n = 70) to identify PIK3CA and AKT1(E17K) mutations. Cores were macro-dissected from matched tissue, including normal breast, benign lymph nodes (LN), ductal carcinoma in situ, regional LN metastases, and distant metastases. Matched samples underwent genetic fingerprinting by multiple SNP genotyping to confirm genetic identity. Intratumoral heterogeneity is minimal with a concordance rate of 95.2% between two different blocks from primary breast cancers. Complete concordance of PIK3CA mutations is noted between primary breast cancer and DCIS. PIK3CA mutations in primary breast cancer are detected in matched regional LNs (91.7%) and distant metastases (100%). Mutation detection by massARRAY genotyping is sensitive but may be affected by sample quality. Intratumoral heterogeneity as measured by PIK3CA genotype is rare; PIK3CA mutations occur early and are selected for in breast cancer progression. HapMap analysis is an essential control for paired sample analysis. This data is clinically important, particularly, for the design of therapies targeting the PI3K/AKT pathway, as it offers confidence that the detection of PIK3CA mutations in the invasive primary tumor will accurately reflect breast cancer biology.
Breast Cancer Research and Treatment 05/2011; 129(2):635-43. · 4.43 Impact Factor
