Abstract
Background: Little is known regarding central nervous system (CNS) miliary metastasis (MiM), which was first described as “carcinomatous encephalitis” by Madow and Alpers in 1951. The ...majority of reported cases arise from primary lung and gastrointestinal adenocarcinomas, with occasional melanoma primaries and one reported case in breast cancer. Moreover, clinicopathologic correlates, disease outcomes and prognostic factors in these patients are poorly understood. Although identified most frequently on neuroimaging, radiographic criteria to objectively diagnose MiM do not exist. In this analysis of patients with brain metastasis from primary breast cancer, we propose objective, stringent radiographic criteria for CNS MiM diagnosis and identify clinicopathologic factors contributing to disease outcomes.
Methods: Using a prospectively maintained electronic database, 1,002 female patients diagnosed with brain metastasis from primary breast cancer between 2000 and 2015 were identified. Only patients with neuroimaging available for direct review (CT or MRI) were included. Our radiographic criteria for MiM diagnosis were: 1) ≥20 metastatic lesions per image slice on ≥2 noncontiguous image slices by MRI, or 2) ≥10 lesions per image slice on ≥2 noncontiguous image slices by CT, and 3) MiM lesions were required to be present bilaterally and in both the supra- and infratentorial compartments. These criteria were established upon direct review of all neuroimaging by a neuroradiologist. Number and anatomic distribution of metastatic lesions were the patterns best observed to identify cases of CNS MiM on case review; lesion size was not a reliable pattern for MiM identification. Log rank tests were used for statistical analyses.
Results: Using stringent criteria, 486 patients were included in this analysis. Twenty patients with MiM were identified (4.1%). Ten patients were diagnosed with MiM at initial brain metastasis presentation; 10 developed MiM after known brain metastasis. Biomarker based subtype distribution was as follows: HR-/HER2- (TNBC) (n=8), HR+/HER2+ (n=3), HR+/HER2- (n=4), HR-/HER2+ (n=4), unknown (n=1).
Table 1: Disease Outcomes Based on Biomarker SubtypeBiomarker SubtypeMedian Time to MiM (months) (p=0.104)Median Survival after MiM (months) (p=0.008)TNBC (n=8)32.3 (12.1-132.5)1.8 (0.5-4.0)HR+/HER2+ (n=3)44.2 (33.2-71.5)10.8 (10.2-13.3)HR+/HER2- (n=4)110.2 (23.0-156.0)4.8 (0.8-9.8)HR-/HER2+ (n=4)27.1 (3.7-39.4)4.0 (1.8-5.0)All* (n=20)37.4 (3.7-156.0)3.7 (0.4-12.3)Key: BM: Brain metastasis; * Includes 1 patient with unknown subtype.
Conclusions: Reports of MiM consist overwhelmingly of lung and gastrointestinal adenocarcinoma primaries. This retrospective, observational study is the first to establish that CNS MiM occurs in breast cancer with an incidence of roughly 4%. Review of an additional 1,600 patient charts is underway, but this preliminary study is the first to identify clinicopathologic correlates and determine disease outcomes in patients with MiM; it is also the first to propose stringent radiographic criteria for the diagnosis of CNS MiM, and further updated data will be presented at the meeting.
Citation Format: Bashour SI, Ibrahim NK, Schomer DF, Colen RR, Sawaya R, Suki D, Rao G, Murthy RK, Moulder SL, Abugabal Y, Hess KR, Fuller GN. Central nervous system miliary metastasis in breast cancer patients abstract. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-03-04.
The goals were to critically review all complications resulting within 30 days after craniotomies performed for excision of intra-axial brain tumors relative to factors likely to affect complication ...rates and to assess the value of these data in predicting the risk of surgical morbidity, particularly for surgery in eloquent brain regions.
Neurosurgical outcomes were studied for 327 patients who underwent 400 craniotomies for removal of intra-axial parenchymal brain neoplasms in a 21-month period. Tumors removed included gliomas (206 tumors) and metastases (194 tumors) located both supratentorially (358 tumors) and infratentorially (42 tumors).
The major complication incidence was 13%, and the operative mortality rate was 1.7%. The overall morbidity rate was 32%, but more types of complications were considered than in previous studies. The major neurological morbidity rate was 8.5%. Based on pre- versus postoperative (at 4 wk) Karnofsky Performance Scale scores, 9% of patients deteriorated neurologically, 32% improved, and 58% showed no change. The median postoperative hospital stay was 5 days. Tumors were defined as Grade I, II, or III based on their location relative to brain function, and this tumor functional grade was the most important variable affecting the incidence of any neurological deficit. Patients with tumors in eloquent (Grade III) or near-eloquent (Grade II) brain areas incurred more neurological deficits than did patients with tumors in noneloquent areas (Grade I). Neither repeat surgery for recurrent disease nor extent of surgical resection affected outcome significantly. Although most tumors in this study, including those in eloquent regions, were removed by gross total resection, this did not lead to more major neurological deficits. Regional complications (at the surgical sites) and systemic complications (medical) were more prevalent among older patients (age >60 yr) with lower preoperative Karnofsky Performance Scale scores (< or = 50) and posterior fossa masses. We showed how our data can be used to predict the total risk of surgical morbidity for a given patient, to facilitate patient counseling and surgical decision-making.
The finding that gross total resections could be performed in eloquent brain regions with an acceptable level of neurological impairment suggested that the mere presence of a tumor in eloquent brain does not automatically contraindicate surgery. Our results have practical risk-predictive value, and they should aid in the construction of subsequent outcome studies, because we have identified the key areas to monitor.
Results of reoperation in 48 patients who developed recurrent brain metastases between January 1984 and April 1993 are presented. Median time from first craniotomy to diagnosis of recurrence (time to ...recurrence) was 6.7 months. Median Karnofsky performance scale (KPS) score prior to reoperation was 80. Recurrence was local in 30 patients, distant in 16 patients, and both local and distant in two patients. Median survival time after reoperation was 11.5 months. There were no operative mortalities. Multivariate analysis revealed that presence of systemic disease (p = 0.008), KPS scores less than or equal to 70 (p = 0.008), time to recurrence of less than 4 months (p = 0.008), age greater than or equal to 40 years (p = 0.51), and primary tumor type of breast or melanoma (p = 0.028) negatively affected patient survival time. These five factors were used to develop a grading system (Grades I-IV). Patients categorized in Grade I had a 5-year survival rate of 57%, whereas the median survival time of patients in Grades II, III, and IV was 13.4, 6.8, and 3.4 months, respectively (p < 0.0001). Overall, 26 patients developed a second recurrence after reoperation. Seventeen patients underwent a second reoperation, whereas nine did not. Patients undergoing a second reoperation survived a median of 8.6 additional months versus 2.8 months for those who did not (p < 0.0001). This study concludes that reoperation for recurrent brain metastasis can prolong survival and improve quality of life. A second reoperation can also increase survival. Five factors influence survival: status of systemic disease, KPS score, time to recurrence, age, and type of primary tumor. The grading system using these five factors correlates with survival time. Reoperation should be approached with caution in Grade IV patients because of their poor prognosis.
Purpose: Molecular classification of breast cancer has been proposed based on gene expression profiles of human tumors. Luminal, basal-like,
normal-like, and erbB2+ subgroups were identified and were ...shown to have different prognoses. The goal of this research was
to determine if these different molecular subtypes of breast cancer also respond differently to preoperative chemotherapy.
Experimental Design: Fine needle aspirations of 82 breast cancers were obtained before starting preoperative paclitaxel followed by 5-fluorouracil,
doxorubicin, and cyclophosphamide chemotherapy. Gene expression profiling was done with Affymetrix U133A microarrays and the
previously reported “breast intrinsic” gene set was used for hierarchical clustering and multidimensional scaling to assign
molecular class.
Results: The basal-like and erbB2+ subgroups were associated with the highest rates of pathologic complete response (CR), 45% 95%
confidence interval (95% CI), 24-68 and 45% (95% CI, 23-68), respectively, whereas the luminal tumors had a pathologic CR
rate of 6% (95% CI, 1-21). No pathologic CR was observed among the normal-like cancers (95% CI, 0-31). Molecular class was
not independent of conventional cliniocopathologic predictors of response such as estrogen receptor status and nuclear grade.
None of the 61 genes associated with pathologic CR in the basal-like group were associated with pathologic CR in the erbB2+
group, suggesting that the molecular mechanisms of chemotherapy sensitivity may vary between these two estrogen receptor–negative
subtypes.
Conclusions: The basal-like and erbB2+ subtypes of breast cancer are more sensitive to paclitaxel- and doxorubicin-containing preoperative
chemotherapy than the luminal and normal-like cancers.
Mixed lineage leukemia (MLL) fusion proteins are derived from translocations at 11q23 that occur in aggressive subtypes of leukemia. As a consequence, MLL is joined to different unrelated proteins to ...form oncogenic transcription factors. Here we demonstrate a direct interaction between several nuclear MLL fusion partners and present evidence for a role of these proteins in histone binding. In two-hybrid studies, ENL interacted with AF4 and AF5q31 as well as with a fragment of AF10. A structure-function analysis revealed that the AF4/AF5q31/AF10 binding domain in ENL coincided with the C-terminus that is essential for transformation by MLL-ENL. The ENL/AF4 association was corroborated by GST-pulldown experiments and by mutual coprecipitation. Both proteins colocalized in vivo in a nuclear speckled pattern. Moreover, AF4 and ENL coeluted on sizing columns together with the known ENL binding partner Polycomb3, suggesting the presence of a multiprotein complex. The overexpression of ENL alone activated a reporter construct and a mutational screen indicated the conserved YEATS domain as essential for this function. Overlay and pulldown-assays finally showed a specific and YEATS domain-dependent association of ENL with histones H3 and H1. In summary, our studies support a common role for nuclear MLL fusion partners in chromatin biology.
To examine recurrence and survival rates for patients treated with hepatic resection only, radiofrequency ablation (RFA) plus resection or RFA only for colorectal liver metastases.
Thermal ...destruction techniques, particularly RFA, have been rapidly accepted into surgical practice in the last 5 years. Long-term survival data following treatment of colorectal liver metastasis using RFA with or without hepatic resection are lacking.
Data from 358 consecutive patients with colorectal liver metastases treated for cure with hepatic resection +/- RFA and 70 patients found at laparotomy to have liver-only disease but not to be candidates for potentially curative treatment were compared (1992-2002).
Of 418 patients treated, 190 (45%) underwent resection only, 101 RFA + resection (24%), 57 RFA only (14%), and 70 laparotomy with biopsy only or arterial infusion pump placement ("chemotherapy only," 17%). RFA was used in operative candidates who could not undergo complete resection of disease. Overall recurrence was most common after RFA (84% vs. 64% RFA + resection vs. 52% resection only, P < 0.001). Liver-only recurrence after RFA was fourfold the rate after resection (44% vs. 11% of patients, P < 0.001), and true local recurrence was most common after RFA (9% of patients vs. 5% RFA + resection vs. 2% resection only, P = 0.02). Overall survival rate was highest after resection (58% at 5 years); 4-year survival after resection, RFA + resection and RFA only were 65%, 36%, and 22%, respectively (P < 0.0001). Survival for "unresectable" patients treated with RFA + resection or RFA only was greater than chemotherapy only (P = 0.0017).
Hepatic resection is the treatment of choice for colorectal liver metastases. RFA alone or in combination with resection for unresectable patients does not provide survival comparable to resection, and provides survival only slightly superior to nonsurgical treatment.
Marbling, or intramuscular fat, is an important factor in meat quality. As a key regulator of lipid metabolism, AMP activated protein kinase (AMPK) may be associated with intramuscular fat ...accumulation. Our objective was to evaluate the relationship among AMPK and its associated signaling mediators, with marbling and lean growth in beef cattle. Steers with high intramuscular fat content (High IMF, 5.71
±
0.36%,
n
=
5) and low intramuscular fat content (Low IMF, 2.09
±
0.19%,
n
=
5) were selected. High IMF was associated with increased tenderness (
P
<
0.05) and backfat thickness (
P
<
0.01). Muscle weights were higher in Low compared to High IMF (
P
<
0.05). High IMF steers had a reduced AMPK activity (
P
<
0.01), reduced acetyl-CoA carboxylase phosphorylation (
P
<
0.05), and reduced total mTOR (
P
=
0.02) content. Data provide evidence that AMPK is involved in IMF deposition in beef cattle.
Abstract
Background: Serial biopsies (bx) of triple-negative breast cancer (TNBC) in the curative neoadjuvant setting provides critical information on dynamic changes in the tumor in response to ...neoadjuvant systemic therapy (NAST) and can help inform the development of novel therapeutic strategies. However, neoplastic seeding following image guided breast bx has previously been reported in TNBC, raising concerns that serial bx may worsen clinical outcomes. Thus, we sought to determine if serial bx were associated with poorer clinical outcomes (using rates of pathologic complete response pCR) in TNBC pts receiving NAST.
Methods: We identified 370 TNBC pts who received NAST at MD Anderson Cancer Center from 2011-2017. 200 pts did not have any research bx done (controls) on the index breast carcinoma and 170 pts had at least one research bx done (cases) on the index breast carcinoma as part of the prospective molecular triaging ARTEMIS trial. Baseline characteristics were compared between cases and controls using the Student t-test, Wilcoxon Rank Sum test or Fisher's exact test as appropriate. Univariable and multivariable logistic regression was used to determine if rates of pCR following NAST were significantly different between cases and controls.
Results: Demographic characteristics demonstrate no significant differences (Table). However, cases were more likely to have received an anthracycline (99% vs 96%, p=0.02) and a targeted agent (22% vs 0%, p<0.01) in the neoadjuvant setting as part of the ARTEMIS trial. A total of 211 bx of the index carcinoma were performed in the 200 controls, of whom, 6% (11/200) had a second bx of the index carcinoma done solely for diagnostic purposes. In contrast, a total of 407 bx of the index carcinoma were performed in the 170 cases (mean: 2.4 biopsies). Of the 407 bx done in the 170 cases, 58% (237/407) were done for research purposes. The pCR rate in controls and cases was 48% (96/200, 95% confidence interval CI: 41-55%) and 42% (72/170, 95% CI: 35-50%), respectively. The odds of pCR following NAST were not significantly different between controls and cases on both univariable (odds ratio OR: 0.80; 95% CI: 0.53-1.20, p=0.28) and multivariable logistic regression (adjusted OR: 0.94; 95% CI: 0.58-1.51; p=0.79).
Conclusion: This is the first study examining the impact of serial bx on clinical outcomes in TNBC pts in the curative neoadjuvant setting. Our data suggest that research bx in this setting do not compromise rates of pCR.
Baseline and Treatment CharacteristicsCharacteristicControls (n=200)Cases (n=170)p valueMean age - years (standard deviation SD)52 (12)53 (12)0.54Ethnicity White – n (%)113 (57)115 (68)0.09Black – n (%)48 (24)29 (17) Other – n (%)39 (20)26 (15) Mean tumor size – cm (SD)3.2 (1.4)3.3 (1.7)0.62T stage – n (%) T134 (17)35 (21)0.96T2145 (73)111 (65) T314 (7)17 (10) T47 (4)7 (4) N stage – n (%) N0101 (51)89 (52)0.83N170 (35)55 (32) N27 (4)6 (4) N322 (11)20 (12) Stage – n (%) I19 (10)21 (12)0.74II140 (70)113 (66) III41 (21)36 (21) Grade – n (%) 19 (5)00.14227 (14)22 (13) 3164 (82)148 (87) Neoadjuvant therapy – n (%) Anthracycline191 (96)169 (99)0.02Taxane199 (100)166 (98)0.18Platinum23 (12)23 (14)0.63Targeted agent037 (22)<0.01
Citation Format: Yam C, Raghavendra A, Hess KR, Adrada BE, Candelaria RP, Damodaran S, Gilcrease MZ, Helgason T, Hortobagyi GN, Huo L, Layman RM, Lim B, Litton JK, Mittendorf EA, Murthy RK, Piwnica-Worms H, Rauch GM, Santiago L, Symmans F, Thompson AM, Tripathy D, Ueno NT, Valero V, Barcenas CH, Moulder SL, Yang W. Impact of serial biopsies in triple-negative breast cancer patients receiving neoadjuvant systemic therapy abstract. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-15-06.
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