Tumor genomics and response to CDK 4/6 inhibitors for patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1046-1046 ◽  
Author(s):  
Laura Spring ◽  
Andrzej Niemierko ◽  
Dejan Juric ◽  
Mark Zangardi ◽  
Elizabeth Abraham ◽  
...  

1046 Background: The combination of endocrine therapy with a cyclin-dependent kinase (CDK) 4/6 inhibitor, such as palbociclib, has changed the treatment paradigm of HR+ MBC, particularly as 1stline therapy. However, there are no predictive biomarkers at present, and little is known about the impact of tumor genomics on outcomes. For example, mutations in TP53 could impact the ability of p53 to negatively regulate p21, thereby promoting cell cycle progression despite CDK 4/6 inhibition. The aim of this study was to evaluate the association between tumor genomics, particularly PIK3CA and TP53 mutations, and response to CDK 4/6 inhibitors in HR+ MBC. Methods: All HR+/HER2- MBC patients at our institution receiving a CDK 4/6 inhibitor in the second line or beyond were identified. Tumor genomics were analyzed utilizing the institutional tumor genotyping next generation sequencing (NGS) assay known as “Snapshot-NGS assay” on DNA isolated from the tumor, covering key oncogenic driver mutations and tumor suppressor genes. The log-rank test was used for statistical analysis. Results: A total of 83 patients with HR+/HER2- MBC were identified, of which 61 had available tumor genotyping results available (52 metastatic specimens). The median line of therapy was three. Median progression-free survival (PFS) on CDK 4/6 inhibitor-based therapy, as second line or beyond, was 9.2 months (mo) overall. No significant difference in PFS was seen among patients with PIK3CA (n = 31) mutations (7.1 vs. 9.7 mo; p = 0.28) or with any alteration in the PI3K/Akt/mTOR (n = 36) pathway (8.2 vs. 9.3 mo; p = 0.40). The presence of a p53 mutation (n = 9) or complex tumor genomics (n = 14) demonstrated a trend towards shorter PFS (5.5 vs. 9.2 mo; 5.5 vs. 9.5 mo, respectively), although statistical significance was not reached due to small numbers (p = 0.76; p = 0.31). In a multivariable analysis adjusting for age and prior lines of therapy, similar results were observed. Conclusions: This study suggests patients with HR+ MBC harboring p53 mutations or complex tumor genomics may experience shorter PFS on CDK 4/6 inhibitor-based therapy in the second line and beyond, and these novel findings require validation in additional studies.

2021 ◽  
pp. 1-9
Author(s):  
Leonard Naymagon ◽  
Douglas Tremblay ◽  
John Mascarenhas

Data supporting the use of etoposide-based therapy in hemophagocytic lymphohistiocytosis (HLH) arise largely from pediatric studies. There is a lack of comparable data among adult patients with secondary HLH. We conducted a retrospective study to assess the impact of etoposide-based therapy on outcomes in adult secondary HLH. The primary outcome was overall survival. The log-rank test was used to compare Kaplan-Meier distributions of time-to-event outcomes. Multivariable Cox proportional hazards modeling was used to estimate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs). Ninety adults with secondary HLH seen between January 1, 2009, and January 6, 2020, were included. Forty-two patients (47%) received etoposide-based therapy, while 48 (53%) received treatment only for their inciting proinflammatory condition. Thirty-three patients in the etoposide group (72%) and 32 in the no-etoposide group (67%) died during follow-up. Median survival in the etoposide and no-etoposide groups was 1.04 and 1.39 months, respectively. There was no significant difference in survival between the etoposide and no-etoposide groups (log-rank <i>p</i> = 0.4146). On multivariable analysis, there was no association between treatment with etoposide and survival (HR for death with etoposide = 1.067, 95% CI: 0.633–1.799, <i>p</i> = 0.8084). Use of etoposide-based therapy was not associated with improvement in outcomes in this large cohort of adult secondary HLH patients.


Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1109-1109
Author(s):  
Deborah L White ◽  
Verity A Saunders ◽  
Thea Kalebic ◽  
Timothy P Hughes

Abstract We have previously demonstrated significant interpatient variability in the IC50imatinib, a measure of the intrinsic sensitivity of a patient to imatinib induced kinase inhibition. Furthermore, this measure is predictive of the achievement of major molecular response (MMR &gt; 3 log reduction in BCR-ABL) in de-novo CML patients treated with imatinib (n=60)1. In an expanded patient pool (n=116) we now perform an evaluation of the IC50 as a predictor of response, and address the IC50imatinib as a guide to dose selection. Samples were obtained with informed consent from de novo CML patients enrolled to either the TIDEL (600mg imatinib) or TOPS (randomised 400mg vs 800mg imatinib) trials. Blood was collected pre therapy, and the IC50 was performed as previously1. Outcome data was assessed using Kaplan Meier Analysis and the log rank test was used to assess statistical significance. In our previous analysis the IC50imatinib was divided about the median value for the cohort (0.6μM) into low and high IC50, with a significantly greater proportion of patients with low IC50imatinib achieving MMR by 12 months. In this expanded patient pool, we confirm this finding (&lt;median of 0.7μM for this patient group) (low IC50 65% of patients achieve MMR by 12 mo vs high IC50 39% of patients p=0.014) Dividing the IC50’s into quartiles we now demonstrate that the IC50imatinib is a continuous variable with a greater proportion of patients in the lower quartile achieving MMR than those in the higher (Table 1 Total). Addressing the issue of dose we demonstrate that no patients with IC50&gt;0.95uM achieve MMR on 400mg, and that this is statistically significantly when compared to all other groups. At 600mg while there is no overall significant difference there is a statistically relevant difference between groups 1, 2 and 4 as indicated. In contrast, at 800 mg the effect of IC50imatinib is overcome. MMR by 12 months Total 400mg 600mg 800mg p value Group1 &lt;0.5μM 67% (27) 83% (12)* 50% (8)* 86% (7) 0.470 Group 2 &gt;0.5&lt;0.7μM 63% (30) 67% (6)* 53% (17)* 71% (7) 0.337 Group 3 &gt;0.7&lt;0.95μM 45% (31) 40%(5)* 30% (10) 56% (16) 0.139 Group 4&gt;0.95μM 32% (28) 0% (7)* 22% (9)* 58% (12) 0.016 P value 0.042 0.018 0.108 0.778 Table 1: Dividing the patients into quartile based on the IC50 imatinib and assessing the Impact of dose on the achievement of MMR by 12 month. *p value &lt;0.05 between groups (n). The failure to achieve a Complete Cytogenetic Response by 12 months is considered a suboptimal response. Assessing the molecular equivalent (≥2 log reduction in BCR-ABL) we demonstrate that a significantly greater proportion of patients with IC50imatinib&gt;0.7μM fail to achieve a 2 log reduction when treated with 400mg (IC50 &lt;0.7μM 11%: &gt;0.7μM 33% p=0.034), and 600mg (IC50 &lt;0.7μM 12%: &gt;0.7μM 22% p=0.036). However, there is no significant difference in the 800mg patient cohort (IC50 &lt;0.7μM 7%: &gt;0.7μM 14% p=0.79). This analysis confirms that the IC50imatinib, is predictive of imatinib response. Patients with an IC50imatinib &lt;0.7μM are likely to respond well to doses of 400mg imatinib, as suggested by evaluation of statistically relevant outcome benefit. In contrast patients with higher IC50imatinib (&gt;0.7μM) may benefit from higher dosing regimens (p=0.012). Thus, the accurate assessment of IC50imatinib could support dose optimization strategy for patients with a suboptimal response.


2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 629-629
Author(s):  
Andrea Fontana ◽  
Giacomo Allegrini ◽  
Mazhar al Zoubi ◽  
Paola Collecchi ◽  
Chiara Mazzanti ◽  
...  

629 Background: Currently, no biomarkers of trastuzumab (T) clinical resistance have been validated. The aim of this pilot study was to evaluate the impact of PIK3CA mutations and p95HER2 (pHER2 truncated form) expression on the efficacy of a T based-therapy in a HER2-positive metastatic breast cancer (MBC) patients (pts). Methods: 107 HER2-positive MBC pts, treated in the last 10 years, were evaluated. Median age was 54 years (25-79); ECOG performance status was 0 in 56% of pts; all pts received several lines of treatment including T; biomarkers molecular analysis was performed in 70 tumor specimens. The IHC expression of p95HER2 was evaluated by a monoclonal antibody that specifically recognizes only the HER2 external domain; the HER2 integrity was defined by the presence of a homogeneous membrane staining (moderate or intense) in at least 30% of the cells, otherwise the HER2 was defined as p95HER2 positive. PIK3CA mutations in exons 9 and 20 were detected by automated sequencing. The molecular data were correlated to Time to progression (TTP) of the first line treatment including T and the Overall Survival (OS) by using the Kaplan-Meir method and the log-rank-test. Results: p95HER2 positive pts and PIK3CA mutations in exon 9 or 20 were detected in 42% and 22% of tumor specimens, respectively. p95HER2 positive tumors showed a shorter TTP and OS that did not reach statistical significance; PIK3CA mutations correlated with a worse TTP (median 7,6 vs 11,3 months) and OS (median 20,1 vs 41,0 months, p= 0,046). Conclusions: These preliminary results suggest a possible role of PIK3CA mutational status in predicting the outcome of MBC pts treated with T.


2020 ◽  
Author(s):  
Gokce Askan ◽  
Ibrahim Halil Sahin ◽  
Joanne F. Chou ◽  
Aslihan Yavas ◽  
Marinela Capanu ◽  
...  

Abstract Background: Herein, we investigate the relationship between pancreatic stem cell markers (PCSC markers), CD44, and epithelial-specific antigen (ESA), tumor stroma, and the impact on recurrence outcomes in pancreatic ductal adenocarcinoma (PDAC) patients.Methods: PDAC patients who underwent surgical resection between 01/2012 -06/2014 were identified. CD44 and ESA expression was assessed by immunohistochemistry. Stroma was classified as loose, moderate, and dense based on fibroblast content. Overall survival (OS) and relapse-free survival (RFS) were estimated using the Kaplan-Meier method and compared between subgroups by log-rank test. The association between PCSC markers and stroma type was assessed by Fisher`s exact test. Results: N= 93 PDAC patients were identified. The number of PDAC patients with dense, moderate density, and loose stroma was 11 (12%), 51 (54%), and 31 (33%) respectively. PDAC with CD44+/ESA- had highest rate of loose stroma (63%) followed by PDAC CD44+/ESA+ (50%), PDAC CD44-/ESA+ (35%), CD44-/ESA- (9%) (p=0.0033). No local recurrence was observed in patients with dense stroma and 9 had distant recurrence. The highest rate of cumulative local recurrence observed in patients with loose stroma. No statistically significant difference in RFS and OS were observed among subgroups (P=0.089). Conclusions: These data indicate PCSCs may have an important role in stroma differentiation in PDAC. Although not reaching statistical significance, we observed more local recurrences in patients with loose stroma, and no local recurrence was seen in patients with dense stroma suggesting tumor stroma may influence the recurrence pattern in PDAC patients.


2004 ◽  
Vol 14 (2) ◽  
pp. 140-147 ◽  
Author(s):  
Christian Schreiber ◽  
Martin Kostolny ◽  
Joachim Weipert ◽  
Klaus Holper ◽  
Manfred Vogt ◽  
...  

Background:Creation of an extracardiac cavopulmonary connection has been proposed as a superior alternative to the lateral intracardiac tunnel for the completion of total cavopulmonary connection.Methods and results:We made a retrospective review of our experience with 125 patients undergoing a total cavopulmonary connection between June 1994 and January 2003. Our experience with the extracardiac connection for completion began in 1999. Since 1994, we have constructed an intracardiac tunnel in 50 patients, and an extracardiac connection in 75. Of the total number, 83 had undergone an earlier partial cavopulmonary connection. Additional intracardiac procedures were performed in 43 patients at time of completion, in 25 of those undergoing extracardiac completion, and in 18 of the patients having an intracardiac procedure. The mean size of the tube used for completion was 19 mm. The mean cross-clamp time for placement of the intracardiac tunnel was 77 min, with a median of 80.5 min, and a mean cardiopulmonary bypass time of 139 min, with a median of 131 min. For construction of the extracardiac connection, a mean cross-clamp time in 24 of the 75 patients was 54 min, with a median of 54 min. Mean cardiopulmonary bypass time for all the patients with an extracardiac connection was 100 min, with a median of 88 min. Reoperations were needed in 10 patients, 6 having intracardiac and 4 extracardiac procedures. Of these, 5 were early and 5 late, including one take down. None of the patients died after these interventions. Taken overall, 8 patients died, with 5 early deaths. In the multivariable analysis, cardiopulmonary bypass time of more than 120 min, atrioventricular valvar replacement, and banding of the pulmonary trunk prior to the total cavopulmonary connection, all reached statistical significance for early death, whereas only heterotaxy syndrome remained as the sole risk factor for late death. There was no significant difference in survival between the modifications used.Discussion:Whereas we could not identify any clinical superiority for the extracardiac approach in the short-term, the concept of extracardiac completion has helped to simplify the overall procedure. Longer follow-up will be required to elucidate any potential advantages.


Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3129-3129
Author(s):  
Karen Phekoo ◽  
Henrik Moller2 ◽  
Mike Richards ◽  
David Bevan3 ◽  
Don Gillett4 ◽  
...  

Abstract Haematological malignancies (HM) accounts for 7% of all cancers in England (DoH, 2003). However, concerns have been expressed regarding the quality of information from cancer registries (DoH, 2000, Haward, 2003) which sheds doubt on the validity of the data. Several initiatives have been undertaken to improve the quality of data (Cartwright et al., 1990, 1997, Clough et al., 1996, Taylor et al., 1998, Maynadie et al., 1996, Ong et al., 1997). These initiatives have been restricted in the range of diagnoses or have operated independently of national cancer registries (Phekoo et al., 2002). No studies have assessed the impact of incidence on survival rates. We present results of a collaboration designed to improve the quality of data and assess the impact on incidence and survival. A consensus dataset and database of HM was developed between the Thames Cancer Registry (TCR) and clinicians between 1999 and 2000 in South Thames (adult population 5.4 million). Clinicians identified and confirmed the diagnosis of patients whilst diagnostic data were collected by a dedicated team of data collectors. Clinicians validated their cases bi-annually. Incidence and survival of the study population for the period 1999–2000 following the collaboration were compared with the same population over the period 1994–1996 prior to the collaboration and with a control population (North Thames area, adult population 5.5 million), where TCR collected data but without any clinical collaboration, for the period 1999–2000. Statistical analyses: the statistical significance of the standardized rate ratio (SRR) was evaluated using the method of Jensen et al., (1991). The Kaplan-Meier survival curves were compared using the log-rank test. For the period 1994–1996 there were no differences in the SRR or survival estimates in any disorders between North and South Thames. A 43% increase in incidence occurred between 1994–1996 and 1999–2000 in South Thames compared to only 5% in North Thames over the same periods, mainly for CLL, MDS, PV, PT, IMF, MGUS and WM. Table I shows a statistically significant difference in the SRR between the North and South Thames during the period 1999–2000 for five conditions: CLL, MDS, PV, PT and WM. Three year survival for patients diagnosed between 1999 and 2000 were higher in South Thames than North Thames in four conditions: CLL (71% vs. 49%, p = 0.001), CML (50% vs. 30%, p = 0.001), MDS (45% vs. 27%, p &lt;0.001) and MM (39% vs. 28%, p &lt;0.001). No significant difference in incidence or survival were seen for acute leukaemia, NHL or HD. Table 1: Comparison of the age standardized rate between 1994–1996 and 1999–2000 in patients aged 16–85+ years 1994–1996 1999–2000 North Thames South Thames Comparison North Thames South Thames Comparison Subtypes ASR ASR SRR (95% CI) ASR ASR SRR (95% CI) CLL 4.28 4.76 0.89 (0.89–1.07) 3.78 6.58 0.57 (0.48–0.67) MDS 2.33 2.15 1.08 (0.80–1.46) 3.48 5.80 0.60 (0.50–0.71) PT 0.69 0.91 0.75 (0.50–1.13) 0.48 2.57 0.18 (0.13–0.26) PV 1.05 1.06 0.99 (0.69–1.41) 0.72 1.60 0.45 (0.31–0.63) WM 0.37 0.37 1.00 ( 0– 0) 0.33 0.98 0.33 (0.21–0.53) This study has shown that engaging clinicians have improved case ascertainment and that changes in incidence alone may affect outcome without significant differences in treatment. This study provides a benchmark of incidence and survival in the UK and a model for future collaborations.


2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 498-498
Author(s):  
Prantesh Jain ◽  
Gino Cioffi ◽  
Nirav Patil ◽  
Aman Opneja ◽  
Asrar Alahmadi ◽  
...  

498 Background: Primary liver angiosarcoma (LAS) is a rare and aggressive tumor of the liver. In this analysis of the national cancer database (NCDB) we sought the risk of mortality and factors associated with survival amongst patient diagnosed with LAS. Methods: Patients diagnosed with hepatocellular carcinoma (HCC) or LAS from 2004 – 2014 were identified in the NCDB. The Kaplan-Meier method with the log-rank test was used to calculate survival for HCC and LAS patients. Additional analyses were performed on the cohort with LAS to assess the impact of surgery, chemotherapy, radiation therapy (RT) and facility type on overall survival (OS). Multivariable analyses using cox proportional methods, adjusted for age, sex, Charlson/Deyo score, race, ethnicity, insurance status, facility location and type, surgery status, and chemotherapy status were performed to obtain adjusted hazard ratio (aHR). Results: Total of 118,066 patients with HCC and 346 patients with LAS were identified in the database. Median survival for HCC patients was 11.9 months (95% CI: 11.7-12.2) and 2.0 months for LAS patients (95% CI: 1.8 – 2.4). Risk of mortality was higher for patients with LAS compared to those with HCC (aHR (95% CI): 2.23 (1.97 - 2.53), p < .0001). Among the LAS patients, those who received surgery had a median survival of 8.6 months (95% CI: 5.6 - 17.3), and 1.8 months for those who did not (95% CI: 1.48 - 1.94). Risk of mortality was lower in patients who received surgery compared to those who did not (aHR (95% CI): 0.23 (0.15 - 0.37), p < .0001). Patients treated at and academic center had a higher median survival (3.3 months, 95% CI: 2.2 - 4.1) then those treated at a non-academic center (1.5 months, 95% CI: 1.2 - 1.8). Though, there was no significant difference in OS (aHR (95% CI): 0.48 (0.21 - 1.10), p = 0.082). A very small number of patients received chemotherapy or RT to conduct a meaningful analysis. Conclusions: Patients diagnosed with primary LAS have a worse OS compared to those with HCC. Amongst patients with primary LAS, surgical resection is associated with best survival outcomes. Treatment at an academic center is associated with better median survival, although OS did not reach statistical significance in our analysis.


Author(s):  
Natuya Zhuori ◽  
Yu Cai ◽  
Yan Yan ◽  
Yu Cui ◽  
Minjuan Zhao

As the trend of aging in rural China has intensified, research on the factors affecting the health of the elderly in rural areas has become a hot issue. However, the conclusions of existing studies are inconsistent and even contradictory, making it difficult to form constructive policies with practical value. To explore the reasons for the inconsistent conclusions drawn by relevant research, in this paper we constructed a meta-regression database based on 65 pieces of relevant literature published in the past 25 years. For more valid samples to reduce publication bias, we also set the statistical significance of social support to the health of the elderly in rural areas as a dependent variable. Finally, combined with multi-dimensional social support and its implications for the health of the elderly, meta-regression analysis was carried out on the results of 171 empirical studies. The results show that (1) subjective support rather than objective support can have a significant impact on the health of the elderly in rural areas, and there is no significant difference between other dimensions of social support and objective support; (2) the health status of the elderly in rural areas in samples involving western regions is more sensitive to social support than that in samples not involving the western regions; (3) among the elderly in rural areas, social support for the older male elderly is more likely to improve their health than that for the younger female elderly; and (4) besides this, both data sources and econometric models greatly affect the heterogeneity of the effect of social support on the health of the elderly in rural areas, but neither the published year nor the journal is significant. Finally, relevant policies and follow-up studies on the impact of social support on the health of the elderly in rural areas are discussed.


2021 ◽  
pp. 152660282199672
Author(s):  
Giovanni Tinelli ◽  
Marie Bonnet ◽  
Adrien Hertault ◽  
Simona Sica ◽  
Gian Luca Di Tanna ◽  
...  

Purpose: Evaluate the impact of hybrid operating room (HOR) guidance on the long-term clinical outcomes following fenestrated and branched endovascular repair (F-BEVAR) for complex aortic aneurysms. Materials and Methods: Prospectively collected registry data were retrospectively analyzed to compare the procedural, short- and long-term outcomes of consecutive F-BEVAR performed from January 2010 to December 2014 under standard mobile C-arm versus hybrid room guidance in a high-volume aortic center. Results: A total of 262 consecutive patients, including 133 patients treated with a mobile C-arm equipped operating room and 129 with a HOR guidance, were enrolled in this study. Patient radiation exposure and contrast media volume were significantly reduced in the HOR group. Short-term clinical outcomes were improved despite higher case complexity in the HOR group, with no statistical significance. At a median follow-up of 63.3 months (Q1 33.4, Q3 75.9) in the C-arm group, and 44.9 months (Q1 25.1, Q3 53.5, p=0.53) in the HOR group, there was no statistically significant difference in terms of target vessel occlusion and limb occlusion. When the endograft involved 3 or more fenestrations and/or branches (complex F-BEVAR), graft instability (36% vs 25%, p=0.035), reintervention on target vessels (20% vs 11%, p=0.019) and total reintervention rates (24% vs 15%, p=0.032) were significantly reduced in the HOR group. The multivariable Cox regression analysis did not show statistically significant differences for long-term death and aortic-related death between the 2 groups. Conclusion: Our study suggests that better long-term clinical outcomes could be observed when performing complex F-BEVAR in the latest generation HOR.


2021 ◽  
Vol 42 (Supplement_1) ◽  
pp. S162-S163
Author(s):  
Jennifer B Radics-Johnson ◽  
Daniel W Chacon ◽  
Li Zhang

Abstract Introduction Burn camps provide a unique environment and activities for children that have experienced a burn-injury. Positive outcomes from attending burn camp include increased self-esteem, decreased feelings of isolation and a greater sense of self-confidence. In a 3-year retrospective review of camper evaluations from one of the largest and longest running week-long burn camps in the nation for ages 5–17, we aimed to assess if a child’s gender, age, TBSA or ethnicity affected the impact that burn camp had on a child. Methods A 3-year retrospective review of a Burn Camp’s camper evaluation forms was conducted for campers that attended burn camp between 2017–2019. Camp rosters were reviewed to determine the camper gender, age, TBSA and ethnicity. Camper self-evaluation forms completed at the end of each camp session were reviewed to record camper responses to questions regarding their opinions on the impact camp had on them as well as how camp will impact their lives once they return home. Categorical variables were summarized as frequency and percentage, and continuous variables were described as median and range. To check the relationship between two categorical variables, Chi-square test was used. To compare the continuous variable among groups, Kruskal-Wallis ANOVA was used. Statistical significance was declared based on a p value&lt; 0.5. Results Within 2017–2019, there were 413 camper records. Participants’ demographic characteristics are summarized in Table 1. There were 208 males (50.3%) and 205 females (49.6%). The median age of campers were 11.86, 12.44 and 12.45 for 2017–2019, with the range from 5.16 years to 17.96 years. The median TBSA were 20, 20 and 18 for 2017–2019, with the range from 0.08 to 90. Collectively there were 47.7% Hispanic (n= 197); 24.2% Whites (n=100); 13.1% Black (n= 54); 4.6% Asian (n=19) and 7.7% Other (n=32). There were 395 camper self-evaluation forms submitted. Results of three questions there we were interested in are summarized collectively in Table 2. 57% of campers responded, “Yes, Definitely” to the question “After going to this event, will you feel more comfortable being around your classmates or friends?” 54% responded, “ Yes, Definitely” to the question “Do you feel more confidents in sharing your burn story with others when returning home?” and 51% responded “Yes, Definitely” to “Did you learn anything that will help you when you return home?” Conclusions In analyzing the camper responses, there was no statistically significant difference in responses comparing gender, age, TBSA or ethnicity.


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