The El Niño–Southern Oscillation (ENSO) is the most dominant natural variability in the Earth system, which represents seasonal-to-interannual variations of the surface equatorial Pacific Ocean temperatures and subsurface ocean interior. Impacting the physical upper ocean characteristics, ENSO exerts significant influences on the marine ecosystem, such as oxygen and phytoplankton concentrations via strong quasiperiodic oscillation between El Niño (warm phase) and La Niña (cold phase) events. The present study uses observational reanalysis and satellite data to investigate seasonal variations of ENSO and their impacts on marine biogeochemical processes. The results show that the oxygen and chlorophyll anomalies in the upper ocean exhibit different seasonal responses to ENSO. While both the summer and winter season biological responses significantly lag ENSO, the concentration of oxygen and phytoplankton during summer (winter) has no (large) concurrent covariability with ENSO. Given a strong negative correlation between chlorophyll-based indices and El Niño events, increasing mean ocean temperatures and ocean extreme events may induce lower upper-ocean oxygen levels, leading to possible risks in the ecosystem over the tropical Pacific Ocean.
83 Background: Absolute PSA change is an imperfect surrogate of clinical benefit; CTCs and PSA doubling time (DT) may also be used as a surrogate of progression (PD). Hormone therapy (HT) often leads to a rapid decline in PSA, however non-HT may be effective without causing a decline in absolute PSA or testosterone (T). SM-88, a non-HT novel combination Warburg effect therapy (amino acid analogue, CYP3a4 inducer, mTOR inhibitor and catalyst) does not affect T. We report outcomes leading to subsequent therapies of an ongoing PSA recurrent, non-metastatic PC trial. Methods: Prospective Phase II of rising PSA (per PCWG3), detectable CTCs, and no baseline lesions. Results: Since September 2016, 31 subjects enrolled with 17 on study for > 12 weeks. Mean age 68.9; BMI 28.7; 38% black and 62% post RT. Mean T increased 61 mg/dl from baseline 319 mg/dl (p=0.19). 82% (14/17) subjects experienced an improvement in PSA DT and 67% (10/15) experienced a decline in CTCs of >30%. Overall median PSA DT time on enrollment was 5.3 (1.4 – 37.6) and improved to 6.5 (Wilcoxon p=0.02) (see table). 3/4 subjects with PD failed to maintain a CTC drop >60% vs 2/17 without PD (p=.03); median time to nadir CTC was 3 cycles (1-7). Subjects avoiding subsequent therapy averaged a 50% CTC decline (15-100%). CTC and PSA DT effects were not correlated to T level. AEs possibly related to drug/unrelated were: No grade (G) 4 or 5; 0/1 G3; 1/7 G2; 13/19 G1. As reported elsewhere, typical HT-related side effects were not observed. Including all patients with >1 month of data, from initial diagnosis of PSA rise (median 9 months; 3-18), 96% (22/23) have remained metastases-free and 78% (18/23) remained free of additional HT (p<.05). Clinical trial information: NCT02796898. Conclusions: SM-88 may be a useful either before or as an additive to current PC treatments where normal T may be preferred. SM-88 might not worsen QOL parameters related to T level. An effect on PSA DT and CTCs were demonstrated even in an aggressive doubling time subgroup. Prospective trials are planned to confirm its utility.[Table: see text]
79 Background: Treatment for rising PSA non-metastatic prostate cancer (nmPC) includes multifaceted hormone therapies (HT) associated with increasing related toxicity; in aggregate the risk benefit ratio is not ideal. We report on the use before HT, of SM-88, a novel combination therapy (amino acid analogue, CYP3A4 inducer, mTOR inhibitor and catalyst) based on the Warburg effect without known hormone related toxicity. Methods: Prospective ongoing Phase II of SM-88 (230 mg po bid) in recurrent nmPC with rising PSA (PCWG3 definition), no radiographically identified metastases at baseline and detectable CTCs. Results: From Sept 2016 to Dec 2017, there have been 31 consented (34 planned) with 23 evaluable (completed > 1 cycle). Mean age 68.9; BMI 28.7; 38% black and 62% post RT. Mean testosterone (T) rose from 319 to 382 ng/dl (p=.19). Typical HT related side-effects were not observed: 96% of subjects reported no hot flashes, 91% no gynecomastia, 83% interest and 61% activity in sex, 78% excellent or nearly so overall health and 74% excellent QOL on at least 50% of their EORTC questionnaires; weight (-0.2 kg), hct (0%), glu (+2 mg/dl), urinary N telopeptide (-4.2 nmol), MAP (normotensives -2 mmHg, hypertensives -3 mmHg), heart rate (-2.4 beats/min), QTc (-3 ms) with no newly emergent >480 ms, serum Ca ++ (-0.006 mg/dL), LDH (+6.4 u/L), bsAlkPhos (+6.2 u/L), triglycerides (-5.2 mg/dL), total protein (0.05 g/dL) and albumin (0.02 g/dL). Neutrophil lymphocyte ratio decreased at the end of cycle 1 in 100% (n=5, median 2.4) of those who progressed to subsequent therapy vs 47% of those who did not (p=.05). AEs occurred in 16 subjects: 1 unrelated Grade (G) 3; 0 G 4; 14/26 G 1-2 possibly related to drug. No AEs were related to T levels. From initial diagnosis of PSA rise (median 9, 3-18 months), 96% (22/23) have remained metastases free and 78% (18/23) remained free of additional HT (p<.05). There were no skeletal or cardiovascular events. Conclusions: SM-88 may be useful in delaying the start of HT. While on SM88 subjects did not report any T or therapy related AEs >G2. SM88 may be useful in prostate cancer patients who are more sensitive or vulnerable to HT related toxicity while maintaining stable PSA values. Prospective trials are planned to confirm its utility. Clinical trial information: NCT02796898.
BackgroundGenomic changes that occur in breast cancer during the course of disease have been informed by sequencing of primary and metastatic tumor tissue. For patients with relapsed and metastatic disease, evolution of the breast cancer genome highlights the importance of using a recent sample for genomic profiling to guide clinical decision-making. Obtaining a metastatic tissue biopsy can be challenging, and analysis of circulating tumor DNA (ctDNA) from blood may provide a minimally invasive alternative.Patients and methodsHybrid capture-based genomic profiling was carried out on ctDNA from 254 female patients with estrogen receptor-positive breast cancer. Peripheral blood samples were submitted by clinicians in the course of routine clinical care between May 2016 and March 2017. Sequencing of 62 genes was carried out to a median unique coverage depth of 7503×. Genomic alterations (GAs) in ctDNA were evaluated and compared with matched tissue samples and genomic datasets of tissue from breast cancer.ResultsAt least 1 GA was reported in 78% of samples. Frequently altered genes were TP53 (38%), ESR1 (31%) and PIK3CA (31%). Temporally matched ctDNA and tissue samples were available for 14 patients; 89% of mutations detected in tissue were also detected in ctDNA. Diverse ESR1 GAs including mutation, rearrangement and amplification, were observed. Multiple concurrent ESR1 GAs were observed in 40% of ESR1-altered cases, suggesting polyclonal origin; ESR1 compound mutations were also observed in two cases. ESR1-altered cases harbored co-occurring GAs in PIK3CA (35%), FGFR1 (16%), ERBB2 (8%), BRCA1/2 (5%), and AKT1 (4%).ConclusionsGAs relevant to relapsed/metastatic breast cancer management were identified, including diverse ESR1 GAs. Genomic profiling of ctDNA demonstrated sensitive detection of mutations found in tissue. Detection of amplifications was associated with ctDNA fraction. Genomic profiling of ctDNA may provide a complementary and possibly alternative approach to tissue-based genomic testing for patients with estrogen receptor-positive metastatic breast cancer.
Response to neoadjuvant chemotherapy (NAC) in invasive breast cancer (IBC) is partly regulated by the immune microenvironment. We evaluated immune checkpoint PD-L1 expression, presence of CD68+ cells of macrophage/monocytic lineage and stromal tumor-infiltrating lymphocytes (TILs) in prechemotherapy biopsies and correlated with NAC response. We studied 76 cases of IBC. Prechemotherapy biopsies with >30% TILs were considered lymphocyte-rich IBC. We performed immunohistochemistry for PD-L1 and CD68. Prechemotherapy cores showing >1% PD-L1+ immune or tumor cells were considered positive. CD68 was positive if >40% of tumor stroma contained CD68+ cells or atleast 50% of tumor cells showed infiltration by CD68+ cells. Residual Cancer burden (RCB) Score of 0/I represented excellent response to NAC and RCB II or III unfavorable response. Thirty-five patients had RCB 0/I and 41 pts RCB II/ III. TILs>30% were present in prechemotherapy biopsies in 19 pts of whom 14 showed RCB 0/I (P=0.0075). Twenty-seven cases were PD-L1+ and 20 had an RCB 0/I (P=0.0003). Twenty-two cases were CD68+ of whom 18 showed RCB 0/I (P=<0.0001) There was a significant association between TILs>30%, PD-L1+ and CD68+ expression. Using atleast one of these immunologic parameters identified 26 of 35 patients with RCB 0/I and showed a higher sensitivity for response prediction than TILs alone (40% vs. 74.3%). In conclusion we demonstrate that high numbers of CD68+ monocytic/macrophage cells and PD-L1 expression in IBC shows significant association with NAC response. An immune biomarker profile including TILs, PD-LI and CD68 is more sensitive for NAC response prediction than TILs alone.
