PET Non-responders Research Articles

HER2DX Genomic Assay in HER2-Positive Early Breast Cancer Treated with Trastuzumab and Pertuzumab: A Correlative Analysis from the PHERGain Phase II Trial.

The purpose of this study was to assess the predictive capability of HER2DX assay following (neo)adjuvant trastuzumab-pertuzumab (HP)-based therapy in HER2-positive (HER2+) early breast cancer. HER2DX was analyzed in baseline pretreatment tumors from the PHERGain trial. Patients with stage I-IIIA HER2+ early breast cancer were randomized to group A [docetaxel, carboplatin, and HP (TCHP)] and group B (HP ± endocrine therapy). PET response was evaluated after two cycles. Group A received TCHP for six cycles regardless of PET response. Group B continued with HP ± endocrine therapy for six cycles (PET responders) or with TCHP for six cycles (PET nonresponders). The primary objective of this retrospective study was to associate the HER2DX pathologic complete response (pCR) score with pCR. The secondary objective was the association of the HER2DX risk score with 3-year invasive disease-free survival (iDFS). HER2DX was performed on 292 (82.0%) tumors. The overall pCR rate was 38.0%, with pCR rates of 56.4% in group A and 33.8% in group B. In multivariable analysis including treatment and clinicopathologic factors, the HER2DX pCR score (continuous variable) significantly correlated with pCR [OR, 1.29; 95% confidence interval (CI), 1.10-1.54; P < 0.001]. HER2DX-defined pCR-high, -med, and -low groups exhibited pCR rates of 50.4%, 35.8%, and 23.2%, respectively (pCR-high vs. pCR-low OR, 3.27; 95% CI, 1.54-7.09; P < 0.001). In patients with residual disease, the HER2DX high-risk group demonstrated numerically worse 3-year iDFS than the low-risk group (89.8% vs. 100%; HR, 2.70; 95% CI, 0.60-12.18; P = 0.197). HER2DX predicts pCR in the context of neoadjuvant HP-based therapy, regardless of chemotherapy addition, and might identify patients at higher risk of recurrence among patients with residual disease.

Quality of life (QOL) for patients with esophageal cancer receiving trimodality therapy with induction chemotherapy, chemoradiation, and surgery: Results from CALGB 80803 (Alliance).

283 Background: The randomized phase II CALGB 80803 trial evaluated use of PET imaging for early assessment of induction chemotherapy (iCT) responsiveness to tailor therapy for patients with esophageal and gastroesophageal junction adenocarcinomas (EC) undergoing trimodality therapy. The primary endpoint of improving pathologic complete response rates using PET-adapted therapy was met. A companion QOL study aimed to characterize patients’ experience through iCT, chemoradiation (CRT) and surgery (S). Methods: Between 11/2011 and 5/2015, 241 eligible patients were randomized to an iCT regimen: modified oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) or carboplatin/paclitaxel (CP), followed by PET scan then CRT, either continuing on the same CT for PET-responders (PET-R) or crossing over to the alternative CT for PET-nonresponders (PET-NR). We prospectively collected QOL domains and symptoms at baseline (T1), after iCT (T2), after CRT (T3), and 3- (T4) and 6- months (T5) after S using the EORTC QLQ-C30, The Esophageal Cancer subscale (EORTC OES18), FACT Neurotoxicity Scale (FACT-NTX), and 6 questions from the PRO-CTCAE. QOL scores were compared between iCT groups and between PET-R and PET-NR at each time point using mixed models. The association of QOL scores at enrollment with overall survival (OS) was tested using Cox regression. Results: 189 patients enrolled on the QOL sub-study, 92 received induction FOLFOX and 97 induction CP. Of those, 110 were PET-R and 79 were PET-NR. 97.9% went on to CRT, and 83.6% underwent S. Global QOL and symptoms statistically significantly worsened from T1 to T2 in 14 of 25 domains, and remained significantly worsened from T1 at: T3 for 19 of 25 domains, T4 for 17 of 25 domains, and T5 for 6 of 25 domains. Changes from T1 significantly favored iFOLFOX (vs iCP) for ability to eat (at T3 and T4), GI symptoms (at T3 and T4), and talking (at T5). Changes from T1 significantly favored iCP (vs iFOLFOX) for neuropathy (at T2, T3, and T4) and coughing (at T5). Proportion of patients reporting worsened PRO-CTCAE scores did not differ between PET-R or PET-NR groups . Multiple QOL domains and symptoms were associated with OS including role functioning, global health status/QOL, appetite loss, pain, dysphagia, and ability to eat (all p&lt;0.002). Conclusions: QOL was impacted most by CRT but returned to baseline 6 months after surgery for most domains. Observed symptom differences did not consistently favor one iCT regimen. Early interventions such as nutritional support and prehabilitation should be studied to improve QOL and OS. Clinical trial information: NCT01333033 .

Phase 1b/II study of durvalumab (D) and tremelimumab (T) plus PET-adjudicated chemoradiation (CRT) in patients (Pts) with esophageal adenocarcinoma.

355 Background: We previously evaluated adding D, an anti-PD-L1 antibody, to PET-directed CRT and found the combination to be safe and promising in terms of pathologic response and survival outcomes.1 Here, we add T to the combination. Methods: Pts with locally advanced esophageal/GEJ adenocarcinoma were enrolled. Pts received 2 cycles of mFOLFOX6 prior to repeat PET/CT. PET responders (≥35% reduction in SUV (PETr)) received 5-FU/capecitabine and oxaliplatin with RT, while induction PET non-responders (PETnr) received carboplatin/paclitaxel with RT. All Pts received T 300 mg ×1 and D 1,500 mg q4W ×2 starting 2 weeks prior to CRT. Esophagectomy was planned 6-8 weeks after CRT. Pts with R0 resections received adjuvant T 300 mg ×1 and D 1,500mg q4W ×6. The primary endpoint was the pathologic complete response (pCR) rate. Initially, 6 Pts were enrolled to evaluate for toxicity; they received RT to 50.4 Gy. Subsequently, RT was lowered to 41.4 Gy to decrease the length of preop treatment (tx). Results: 16 pts have been enrolled. All Pts had clinical ≥T3 and/or N+ disease. PD-L1 CPS was ≥1 in 9 (60%) of 15 tested. 1 Pt (6%) had a microsatellite unstable (MSI) tumor. 9 (56%) Pts were PETr; 3 Pts (19%) were PETnr but had improved clinical symptoms and other PET parameters (MTV/TLG) and also continued with 5-FU/capecitabine and oxaliplatin during RT. Significant tx-related adverse events (AEs) are shown in the Table. Immune-related AEs (irAEs) were: gd 3 enterocolitis (1 Pt), gd 3/4 colitis (2 Pts, 12%), gd 1 diarrhea (1 Pt), gd 2 pruritis (1 Pt), gd 1 and gd 3 dermatitis (1 Pt each) and gd 2 arthralgias in 1 Pt. 1 Pt died of aspiration pneumonia while being treated for gd 4 colitis during CRT; 1 Pt developed gd 3 enterocolitis and cholecystitis during CRT, achieved a clinical CR and did not undergo surgery. He developed local recurrence and had surgery off-study 16 months after start of tx; 1 Pt developed a bone metastasis after CRT. 4 Pts are awaiting restaging post-CRT. Of 9 Pts who had surgery, 4 achieved a pCR (44%, including the MSI Pt) and 3 (33%) had ypN0 tumors and ³90% tx response. All 9 Pts have initiated/completed adjuvant D+T. Conclusions: The addition of D+T to induction FOLFOX and PET-directed CRT prior to surgery is feasible, although irAEs seem numerically higher than in our prior study of D and CRT. Pathologic response data are promising. Accrual is ongoing and updated data will be presented. 1. Ann Surg 2023;278:e511. Clinical trial information: NCT02962063 . [Table: see text]

P53 Expression in Luminal Breast Cancer Correlates With TP53 Mutation and Primary Endocrine Resistance

TP53 mutation is associated with primary endocrine resistance in luminal breast cancer (BC). Nuclear accumulation of p53, as determined by immunohistochemistry (IHC), is a surrogate marker for TP53 mutation. The immunohistochemical p53 index that defines a p53-positive status is not well established. This study determined the optimal p53 index cutoff to identify luminal BCs harboring TP53 mutations. In total, 364 luminal BCs from the West German Study Group ADAPT trial (NCT01779206) were analyzed for TP53 mutations by next-generation sequencing and for p53 expression by IHC (DO-7 antibody). P53 indices were determined by automated image analysis. All tumors were from patients treated with short-term preoperative endocrine therapy (pET; tamoxifen or aromatase inhibitor) before tumor resection. IHC evaluation included needle biopsies before therapy (baseline) and resections specimens after therapy (post-pET). Optimal p53 index cutoffs were defined with Youden statistics. TP53 mutations were detected in 16.3% of BC cases. The median p53 indices were significantly higher in TP53-mutated BCs compared to BCs harboring wild-type TP53 (baseline: 47.0% vs 6.4%, P < .001; post-pET: 50.1% vs 1.1%, P < .001). Short-term pET decreased p53 indices in BCs harboring wild-type TP53 (P < .001) but not in TP53-mutated BCs (P = .102). For baseline biopsies, the optimal p53 index cutoff was ≥34.6% (specificity 0.92, sensitivity 0.63, Youden index 0.54, accuracy: 0.87). For post-pET specimens, the optimal cutoff was ≥25.3% (specificity 0.95, sensitivity 0.65, Youden index 0.60, accuracy: 0.90). Using these cutoffs to define the p53 status, p53-positive BCs were >2-fold more common in pET nonresponders compared to pET responders (baseline: 37/162, 22.8% vs 18/162, 11.1%, P = .007; post-pET: 36/179, 20.1% vs 16/179, 8.9%, P = .004). In summary, IHC for p53 identifies TP53-mutated luminal BCs with high specificity and accuracy. Optimal cutoffs are ≥35% and ≥25% for treatment-naïve and endocrine-pretreated patients, respectively.

PET-directed combined modality therapy for gastroesophageal junction cancer: Results of the multicentre prospective MEMORI trial of the German Cancer Consortium (DKTK)

BackgroundPositron emission tomography (PET) may differentiate responding and non-responding tumours early in the treatment of locally advanced gastroesophageal junction adenocarcinomas. Early PET non-responders (P-NR) after induction CTX might benefit from changing to chemoradiation (CRT). MethodsPatients underwent baseline 18F-FDG PET followed by 1 cycle of CTX. PET was repeated at day 14–21 and responders (P-R), defined as ≥35% decrease in SUVmean from baseline, continued with CTX. P-NR switched to CRT (CROSS). Patients underwent surgery 4–6 weeks post-CTX/CRT. The primary objective was an improvement in R0 resection rates in P-NR above a proportion of 70%. ResultsIn total, 160 patients with resectable gastroesophageal junction adenocarcinomas were prospectively investigated by PET scanning. Eighty-five patients (53%) were excluded. Seventy-five eligible patients were enrolled in the study. Based on PET criteria, 50 (67.6%)/24 (32.4%) were P-R and P-NR, respectively. Resection was performed on 46 responders, including one patient who withdrew the ICF, and 22 non-responders (per-protocol population). R0 resection rates were 95.6% (43/45) for P-R and 86.4% (19/22) for P-NR. No treatment related deaths occurred. With a median follow-up time of 24.5 months, estimated 18 months DFS was 75.4%/64.2% for P-R/P-NR, respectively. The estimated 18 months OS was 95.5% for P-R and 68.2% for P-NR. ConclusionThe primary endpoint of the study to increase the R0 resection rate in metabolic NR was not met. PET response after induction CTX is prognostic for outcome with a prolonged OS and DFS in PET responders. Trial registrationNCT 2014-000860-16.

Durvalumab (D) and PET-directed chemoradiation (CRT) after induction FOLFOX for esophageal adenocarcinoma: Final results.

4029 Background: Induction FOLFOX followed by PET-directed CRT prior to surgery demonstrated positive results in the CALGB 80803 study. We investigated the safety and efficacy of adding D, an anti-PD-L1 antibody, to PET-directed CRT. Methods: Patients (pts) with locally advanced esophageal/GEJ adenocarcinoma were enrolled. Pts received 2 cycles of mFOLFOX6 prior to repeat PET/CT. PET responders (≥35% reduction in SUV (PETr)) received 5-FU/capecitabine and oxaliplatin with RT to 50.4Gy, while induction PET non-responders (PETnr) received carboplatin/paclitaxel with RT. All Pts received D 1,500 mg q4W ×2 starting 2 weeks prior to CRT. Esophagectomy was planned 6-8 weeks after CRT. Pts with R0 resections received adjuvant D 1,500mg q4W ×6. The primary endpoint was the pathologic complete response (pCR) rate. Results: 36 pts were enrolled. Clinical ≥T3 disease was seen in 32 pts (88.9%, cT4 = 3) and ≥N1 in 23 (63.9%) pts. PD-L1 CPS was ≥1 in 25 (71.4%) of 35 tested with 14 (40%) ≥5. Microsatellite instability (MSI) was identified in 3 (8.3%) pts. 25 (70%) pts were PETr. Preop treatment was well tolerated with no new safety signals. Three pts had disease progression prior to surgery. pCR was identified in 8 (22.2%) pts and 22 (64.7%) had major pathologic response (MPR; ypTanyN0 + ≥90% response). Those with MSI tumors had ≥90% treatment response (1 pCR, 1: ypT1aN0 99% response, 1: ypT2N0, 90% response). 17 (73.9%) of 23 cN+ pts had ypN0 disease. MPR was associated with PD-L1 ≥1 (p = 0.03) and with a higher tumor mutational burden (TMB; p = 0.016) on MSK-IMPACT testing. Adjuvant D was commenced in 27 pts, with a median number of 6 cycles. Early discontinuation was due to risks of visits due to COVID19 (4, 15%), progressive disease (3, 11%), late surgical complications (2, 7%) and immune toxicity (1, 4%). With a median follow-up of 30 months, OS rates were 92% [95%CI: 83%-100%] and 85 % [95%CI: 74%-98%] at 12 and 24 months post induction. 12 and 24-month PFS rates were 81% [95%CI: 69%-95%] and 71% [95%CI: 58%-88%] respectively. In the 33 operated pts, 12 and 24-month disease free survival was 82% [95%CI: 70%-96%] and 78% [95%CI: 65%-94%], respectively. In addition to SUV on PET, total lesion glycolysis (TLG) was correlated with pathologic response. In cases with borderline change in SUV, TLG could predict response to treatment. One PETnr with 30.8% reduction in SUV had 88.1% reduction in TLG and pCR. Conversely, a PETr (-36.3%) who had an increase in TLG (39.3%) had only 40% treatment response on pathology. Conclusions: The addition of D to induction FOLFOX and PET-directed CRT prior to surgery is safe and appears effective with a high rate of pathologic response, as well as encouraging survival data. PD-L1 CPS≥1 and higher TMB may be associated with MPR. TLG is a novel PET variable that should be studied prospectively. Additional correlatives and comparison to a cohort treated with standard PET-directed CRT will be presented. Clinical trial information: NCT02962063.

Proceedings to the 7th Annual Conference of the Particle Therapy Cooperative Group North America (PTCOG-NA)

Proceedings to the 7th Annual Conference of the Particle Therapy Cooperative Group North America (PTCOG-NA)

Prognostic Value and Peripheral Immunologic Correlates of Early FDG PET Response Imaging in a Phase II Trial of Risk-Adaptive Chemoradiation for Unresectable NSCLC

<h3>Purpose/Objective(s)</h3> We hypothesized that FDG PET imaging during chemoradiation for unresectable non-small cell lung cancer (NSCLC) is prognostic for survival, and that PET response is correlated with systemic immune response to treatment, as characterized by peripheral immunologic correlates and tumor PD-L1 status. A prognostic test that could predict patient outcome would help better select patients who need additional therapies, and spare toxicity in patients who do not. <h3>Materials/Methods</h3> A total of 45 patients with AJCCv7 stage IIB-IIIB NSCLC enrolled on the phase II FLARE-RT trial and received platinum-doublet chemotherapy concurrent with 6 weeks of radiation (NCT02773238). FDG PET imaging was performed prior to treatment start and after 24 Gy of radiation (week 3). PET response status was prospectively defined by multifactor radiomics. PET responders received 60 Gy in 30 fractions, while non-responders received concomitant boosts to 74 Gy in 30 fractions. 22/45 patients received durvalumab post-chemoradiation. Peripheral blood was drawn synchronously with PET imaging, from which germline DNA sequencing, T-cell receptor (TCR) sequencing, and plasma cytokines analysis were performed. Overall survival (OS), progression-free survival (PFS), and locoregional control (LRC) were estimated by Kaplan-Meier. Unsupervised learning of germline DNA sequencing SNP genotypes was performed with hierarchical clustering and summarized with cumulative frequency distributions of rank ordered SNPs. Genotype associations to OS, PFS, and PET response status were characterized by logistic regression with Firth penalization for estimating odds ratios (OR). TCR diversity metric trends were estimated by Spearman rank correlation and pairwise changes by Wilcoxon signed rank testing. TCR diversity metric associations to OS and PFS were assessed by Permutation testing of Harrell's c-index. <h3>Results</h3> Median follow-up was 18.8 months, 1-year OS 82%, 1-year PFS 53%, and 1-year LRC 88%. Higher mid-treatment PET total lesion glycolysis was detrimental to OS (1-yr 87% vs. 63%, <i>P</i> < 0.001), PFS (1-yr 60% vs. 26%, <i>P</i> = 0.044) and LRC (1-yr 94% vs. 65%, <i>P</i> = 0.012), even after adjustment for clinical/treatment factors. Tumor PD-L1 expression was correlated with PET response (<i>P</i> = 0.017), with 6/6 patients with high PD-L1 TPS (> 50%) classified as PET responders and 4/5 patients with negative PD-L1 TPS (< 1%) classified as PET non-responders. Germline DNA alterations in immunologic pathways had an outsized effect on OS and PET response; of the top 30 SNPs ranked by association with PET response status (<i>P</i> < 0.016), a plurality (13/30) came from immunologic pathways. Higher TCR richness, higher clone distribution slope, and smaller decline in clone distribution slope was associated with improved OS (<i>P</i> = 0.018-0.05); clone distribution slope was correlated with PET response (<i>P</i> = 0.031). <h3>Conclusion</h3> Mid-chemoradiation PET imaging is prognostic for survival; PET response may be linked to tumor and peripheral immunologic biomarkers.

A DNA-damage immune response assay combined with PET biomarkers predicts response to neo-adjuvant chemotherapy and survival in oesophageal adenocarcinoma

18F-fluorodeoxyglucose PET-CT may guide treatment decisions in patients with oesophageal adenocarcinoma (OAC). This study evaluated the added value of maximum standardised uptake value (SUVmax) to a novel DNA-damage immune response (DDIR) assay to improve pathological response prediction. The diagnostic accuracy of PET response and the prognostic significance of PET metrics for recurrence-free survival (RFS) and overall survival (OS) were assessed. This was a retrospective, single-centre study of OAC patients treated with neo-adjuvant chemotherapy from 2003 to 2014. SUVmax was recorded from baseline and repeat PET-CT after completion of pre-operative chemotherapy. Logistic regression models tested the additional predictive value of PET metrics combined with the DDIR assay for pathological response. Cox regression models tested the prognostic significance of PET metrics for RFS and OS. In total, 113 patients were included; 25 (22.1%) were DDIR positive and 88 (77.9%) were DDIR negative. 69 (61.1%) were PET responders (SUVmax reduction of 35%) and 44 (38.9%) were PET non-responders. After adding PET metrics to DDIR status, post-chemotherapy SUVmax (hazard ratio (HR) 0.75, p = 0.02), SUVmax change (HR 1.04, p = 0.003) and an optimum SUVmax reduction of 46.5% (HR 4.36, p = 0.021) showed additional value for predicting pathological response. The optimised SUVmax threshold was independently significant for RFS (HR 0.47, 95% CI 0.26–0.85, p = 0.012) and OS (HR 0.51, 95% CI 0.26–0.99, p = 0.047). This study demonstrated the additional value of PET metrics, when combined with a novel DDIR assay, to predict pathological response in OAC patients treated with neo-adjuvant chemotherapy. Furthermore, an optimised SUVmax reduction threshold for pathological response was calculated and was independently significant for RFS and OS.

Durvalumab (D) and PET-directed chemoradiation (CRT) after induction FOLFOX for esophageal adenocarcinoma.

226 Background: Based on the positive results of the CALGB 80803 study (J Clin Oncol 2017;35:1 [abstr]), we have added D to induction FOLFOX and pre-op CRT. Methods: Patients (Pts) had TanyN+ or T3-4NanyM0 esophageal and Siewert Type I-III GEJ adenocarcinoma staged by EUS, PET/CT and CT. Pts received mFOLFOX6 ×2 prior to repeat PET/CT. PET responders (PETr) received 5-FU or capecitabine and oxaliplatin with RT to 50.4Gy, while induction PET non-responders (PETnr) received carboplatin/paclitaxel with RT. All Pts received D 1,500 mg q4W ×2 starting 2 wks prior to and during CRT. Esophagectomy was planned 6-8 weeks after CRT. Pts who had R0 resections received adjuvant D 1,500mg q4W ×6. Results: 36 Pts have been enrolled: 25 GEJ, 11 esophageal; 23 N+ and 32 T3/4. 26 of 36 Pts (72%) are PETr. 2 Pts developed metastatic disease after CRT and 9 Pts remain on preop treatment. 25 Pts have had surgery (Table). Pathologic complete response (pCR) was seen in 6 (24%); 5 Pts (20%) had ypT1N0 tumors with 99% response and 2 Pts (8%) had ypT0N1 with 99% response. 20 Pts (80%) had &gt;90% response. 3 Pts had MSI tumors (2 PETr; 1 pCR, 1 T1aN0 99% response, 1 ypT2N0 90% response). Notable grade (gd) 3/4 adverse events (AEs) observed were neutropenia in 8 Pts (22%), diarrhea and vomiting in 2 Pts each (6%). Notable gd 1/2 AEs in ≥20%: anemia (31 Pts), thrombocytopenia (29 Pts), nausea (21 Pts), fatigue (25 Pts), increased AST (20 Pts), constipation and diarrhea (9 Pts), diarrhea (8 Pts). Immune-related AEs noted were gd 2 dermatitis (2 Pts), gd 3 hepatitis and gd 1 hypothyroidism in 1 Pt each. Median length of post-op stay was 8 days, with 12% anastomotic complication rate, including 1 Pt who died of hematemesis 16 days after discharge from 55-day hospitalization. Conclusions: The addition of D to induction FOLFOX and PET-directed CRT is safe and feasible. pCR and near-pCR in ½ of operated Pts is encouraging and compares favorably to the pCR rate of 31% in CALGB 80803 Pts who received induction FOLFOX. The final pCR rate and correlatives for the fully accrued study will be presented. Clinical trial information: NCT02962063. [Table: see text]

Durvalumab (D) and PET-directed chemoradiation (CRT) after induction FOLFOX for esophageal adenocarcinoma.

394 Background: We previously presented safety data for the combination of D with carboplatin/paclitaxel (C/P) and RT for locally advanced esophageal cancer (J Clin Oncol 2018;36:172 [abstr]). Based on the positive results of the CALGB 80803 study (J Clin Oncol 2017;35:1 [abstr]), we amended the study to administer induction FOLFOX prior to PET assessment. Here, we present updated results. Methods: Patients (Pts) had TanyN+ or T3-4NanyM0 esophageal and Siewert Type I-III GEJ adenocarcinoma staged by EUS, PET/CT and CT. Pts received mFOLFOX6 ×2 prior to repeat PET/CT. PET responders (PETr) received 5-FU or capecitabine and oxaliplatin with RT to 50.4Gy, while PET non-responders (PETnr) received C/P with RT. All Pts received D 1,500 mg q4W ×2 starting 2 wks prior to and during CRT. Esophagectomy was planned 6-8 weeks after CRT. Pts who had R0 resections received adjuvant D 1,500mg q4W ×6. Results: 20 Pts have been enrolled: 16 GEJ, 4 esophageal; 3 T1-2N+, 8 T3-4N0, 1 T3Nx, 8 T3-4N+. 13 of 20 Pts (65%) are PETr. Of 13 Pts who have had surgery (8 PETr, all R0), pathologic complete response (pCR) was seen in 3 (23%; 2 PETr); 3 Pts (23%; all PETr) had ypT1bN0 tumors with 99% response and 1 Pt (8%; PETnr) had ypT0N1 (1/30 LN) with profound response in LN. 2 Pts had MSI tumors (1 PETr; 1 pCR, 1 ypT2N0 with 90% response). Notable gd 3/4 adverse events (AEs) observed were lymphopenia in 16 Pts (80%), neutropenia in 4 Pts (20%) and diarrhea and dysphagia in 1 Pt each (5%). Notable gd 1/2 AEs in ≥20%: thrombocytopenia (18 Pts), fatigue (13 Pts), anemia (12 Pts), increased AST (12 Pts), constipation (11 Pts), nausea (11 Pts), diarrhea (7 Pts) and odynophagia (7 Pts). Immune-related AEs noted were gd 3 hepatitis and gd 2 dermatitis in 1 Pt and gd 1 hypothyroidism in 1 Pt. Median length of post-op stay is 8 days, with 18% anastomotic complication rate. Conclusions: The addition of D to induction FOLFOX and PET-directed CRT is safe and feasible. pCR and near-pCR in ½ of Pts is encouraging and compares favorably to our historical pCR rate of 15% in PETr (Cancer 2016:122:2083) and pCR rate of 31% in CALGB 80803 Pts who received induction FOLFOX. Accrual to 36 Pts continues and updated outcomes and immune correlative data will be presented. Clinical trial information: NCT02962063.

Metabolic Tumor Volume Change Predicts Long-term Survival and Histological Response to Preoperative Chemotherapy in Locally Advanced Esophageal Cancer.

Here, we assess the ability of metabolic tumor volume (MTV) as measured by F-fluorodeoxyglucose-positron emission tomography/computed tomography (F-FDG PET/CT) to evaluate neoadjuvant chemotherapy response for patients with locally advanced esophageal cancer (EC). Optimal methods to evaluate treatment response for EC patients have not yet been established. Although previous studies have reported the value of standardized uptake value (SUV), the accuracy of predicting histological response or long-term survival in EC is limited. In all, 102 EC patients without distant metastasis who underwent F-FDG PET/CT both before and after the preoperative chemotherapy series were analyzed. The median primary tumor MTV values before and after preoperative chemotherapy were 22.55 (range 0.4-183.1) and 2.75 (0-52.9), respectively, and the median MVT reduction rate was 86.5%. We found the most significant difference in survival between PET responders and nonresponders with a cut-off value of 60% MTV reduction, using a 10% stepwise cut-off analysis [2-year progression-free survival (PFS): 79.2 vs 44.4%; hazard ratio (HR) 3.397; P < 0.0001). With this cut-off value, histological response (P = 0.0091), tumor location (P = 0.0102), pT (P = 0.0011), and pN (P = 0.0110) were significantly associated with PET response. Univariate analysis of PFS indicated a correlation between PFS and tumor size, cT, decrease of primary lesion by CT, SUVmax reduction rate, MTV reduction rate, pT, pN, and pM. Multivariate analysis further identified pM (HR 3.063; P = 0.0279) and MTV reduction rate (HR 2.471; P = 0.0263) to be independent prognostic predictors, but not decrease of primary lesion by CT or SUVmax reduction rate. MTV change is clinically useful in predicting both long-term survival and histological response to preoperative chemotherapy in EC patients, after determining the optimal cut-off value based on survival analysis.

PET-directed combined modality therapy for gastroesophageal junction cancer: First results of the prospective MEMORI trial.

4018 Background: We evaluated a PET-guided treatment stratification for improvement in obtaining negative surgical margins (R0) in resectable gastroesophageal junction (GEJ) adenocarcinoma. According to sequential 18F-FDG PET, only 40–50% of patients (pts) respond to neoadjuvant chemotherapy (CTX). Early PET non-responders (P-NR) after induction CTX might benefit from changing to chemoradiation (CRT). Methods: 75 pts with resectable GEJ adenocarcinomas were enrolled in this interventional, prospective, non-randomized multicenter trial. Pts underwent baseline 18F-FDG PET scan followed by 1 cycle of CTX (physicians’ choice, e.g. EOX, XP, mFOLFOX6). PET was repeated at day 14-21 and responders (P-R), defined as ≥ 35% decrease in SUVmax from baseline, continued with CTX. P-NR switched to CRT (41.4 Gy/23 fractions with weekly carboplatin/paclitaxel). Pts underwent surgery 4-6 weeks post-CTX/CRT. Primary objective was an improvement of R0 resection rates in P-NR above a proportion of 70% based on results from the MUNICON1/2 trials. Secondary endpoints include disease-free survival (DFS), overall survival (OS), measured from randomization to death from any cause, and translational endpoints. Results: Between 12/2014 and 07/ 2018 160 pts with resectable GEJ adenocarcinomas were prospectively screened with PET in three German university centers. Overall, 85 pts (53%) could not be included due to previously undetectable metastases (40/25%), no or too low FDG uptake of the primary tumor (21/13%), other reasons (24/15%). 75 eligible pts were enrolled in the study and 69 were evaluable. Based on PET criteria, 47 (68%) and 22 (32%) were P-R and P-NR, respectively. R0 resection rates were 94% (44/47) for P-R and 91% (20/22) for P-NR. Pathologic complete remission (pCR; &lt; 10% vital tumor cells), was 33% (15/46) in P-R and 55% (12/22) in P-NR. With a median follow-up time of 19 months (mo), estimated 18 mo DFS was 71%/61% for P-R/P-NR, respectively. Observed median 18 mo OS was 95% for P-R and 75% for P-NR. Conclusions: Alternative CRT for GEJ adenocarcinoma improved R0- and pCR rates among pts who were P-NR after induction CTX. PET response was prognostic for a prolonged OS and DFS. Clinical trial information: 2014-000860-16.

Relationship between PET response and pathologic response in distal esophageal/gastroesophageal junction cancers: A provincial population-based analysis.

e15506 Background: The utility of PET scans (PETs) to predict outcomes after neoadjuvant treatment of DE/GEJ cancers is unclear. We aimed to explore the relationship between PET response and pathologic/clinical outcomes in a real-world setting. Methods: Patients (pts) with DE/GEJ cancer treated with curative intent perioperative chemotherapy or neoadjuvant chemoradiation followed by surgery in British Columbia from 2009-2018 were included. Retrospective chart review was conducted; pts were stratified into PET responders (R, ≥ 35% decrease in max SUV) or PET non-responders (NR, &lt; 35%) groups. Chi-square and Kaplan Meier were used to test for associations between variables and outcomes. Results: Of 576 pts with locally advanced DE/GEJ cancers, 232 pts were eligible for analysis. Treatment regimens comprised of CROSS (72%), MAGIC (24%) and FLOT (4%). Median age was 66 (IQR 57-72), 85% male, 91% ECOG 0/1, 62% GEJ involvement, and 81% adenocarcinoma histology. Characteristics and treatment regimens were balanced between the PET-R and PET-NR groups (all p&gt;0.05). Median time from end of treatment to PETs was 30 days (IQR 22-36); 67% were PET-R. Pathologic complete response rates (14% vs 13%, p=0.079) were similar for PET-R vs PET-NR, respectively. Discordance rate was 34% between PET vs pathologic response (Table). Aborted surgery rate was higher in the PET-NR group (8% vs 3%, p=0.03); 70% of aborted cases were due to peritoneal involvement. Median overall survival was similar between the groups (PET-R 31.5 mo vs PET-NR 36.1 mo, p=0.616). Conclusions: In our population-based cohort, PET response did not demonstrate prognostic utility. PET-NR were more likely to have their surgeries aborted. The predictive ability of PET in determining surgical resectability should be further investigated to avoid unnecessary high morbidity surgeries.[Table: see text]

Early PET/CT Response Assessment for Selective FDG PET-Guided Dose Escalation in Locally Advanced NSCLC Patients Enrolled on the FLARE-RT Protocol

Dose escalation in unselected patients with locally advanced (LA) non-small cell lung cancer (NSCLC) was detrimental to survival in RTOG 0617, yet local failures persist. The phase II Functional Lung Avoidance & Response-adaptive Escalation (FLARE-RT) trial selects a resistant subset of LA-NSCLC patients for dose-escalation to FDG PET-avid regions at high failure risk, while simultaneously mitigating pneumonitis risk with functional lung avoidance in all patients. We report the ongoing trial results. Stage IIB-IIIB NSCLC patients receiving definitive chemoradiation underwent an early on-treatment PET/CT after 24Gy in 12 fractions. Patients were classified as responders (PET-R) and non-responders (PET-NR) based on early-RT changes in tumor glycolytic metabolism (SUVpeak and metabolic tumor volume MTV) and nuclear medicine diagnostic reads. PET-R received 60Gy in 30 fractions over 6 weeks while PET-NR received a concomitant 14Gy boost over the final 15 fractions (74Gy total) with heterogeneous escalation to FDG-avid regions. Patients were treated with a mix of IMRT/VMAT/Protons. Primary trial endpoint is 2-yr overall survival (superiority) relative to historical controls. Fisher’s Exact and Mann-Whitney tests of differences between PET-R and PET-NR subgroups were performed. FLARE-RT has recruited 22 patients to date. Due to a protocol-required PET/CT <30 days prior to RT, Stage IV progression was detected on short-interval repeat pre-treatment PET/CT in 2/22 patients (9%), while 1/22 withdrew. On early-RT PET/CT scans, Stage IV progression was detected in 2/19 patients (11%). We categorized 7/19 PET-NR (37%) and 12/19 PET-R (63%). SUVpeak decreased by 13% (8-23%) in PET-NR compared to 40% (32-48%) in PET-R (p<0.01). MTV decreased by 9% ([-5]-21%) in PET-NR compared to 40% (32-62%) in PET-R (p<0.01). 17 patients completed treatment per protocol, of whom 6 PET-NR received 74Gy to PTVmidtx and 89Gy (80-93Gy) to SUVpeak volumes. Esophageal, Lung-CTV, and heart doses were similar between PET-NR and PET-R (Table 1, all p>0.05). Grade 3 acute toxicity (CTCAE v4.0) was observed in 2/17 patients (12%) with no difference between PET-R and PET-NR (p=0.9). Tracking of sub-acute / chronic toxicities and outcomes are ongoing. FLARE-RT leverages a precision medicine trial design to escalate dose to FDG-avid regions in select LA-NSCLC patients without increasing toxicity risk. Short-interval FDG-PET/CT scans prior to and during the third week of RT significantly altered management in 18% of patients. Reports on safety and efficacy will be forthcoming.Abstract TU_32_3642; Table 1Dosimetry comparison of early-RT PET responders vs. PET non-responders on FLARE-RT trial.MedianEarly-RT PET category(n)PTV, vol. ccEso., Mean (Gy)Eso., V60 (%)Heart, V5 (%)Heart, Dmean (Gy)Lung- CTV, Dmean (Gy)Lung - CTV, V20 (%)PET-R(12)629.630.821.429.89.814.830.2PET-NR(6)417.215.29.033.54.28.622.9 Open table in a new tab

PET scan-directed chemoradiation (CRT) for esophageal squamous cell carcinoma (ESCC): No benefit for salvage chemo in PET non-responders (PETnr).

4055Background: Pre-operative or definitive CRT is standard for locally advanced (LA) ESCC. We previously showed that PET response after induction chemo and prior to CRT and surgery strongly predic...

Abstract OT1-03-01: Chemotherapy-free trastuzumab and pertuzumab in HER2 [+] breast cancer: FDG-PET response-adapted strategy. The PHERGain study

Abstract BACKGROUND: Several studies have confirmed that a significant subset of patients (pts) with early stage HER2[+]breast cancer (BC) achieve pathological complete response (pCR) with a dual HER2 neoadjuvant blockade without chemotherapy (chemo). Early metabolic evaluation using 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) might help to recognize those pts with a higher likelihood of obtaining a pCR and an excellent outcome with a chemo-free strategy. TRIAL DESIGN: This is a randomized, multicenter, non-comparative phase II trial. Pts age ≥ 18 years with centrally-confirmed, treatment-naïve, HER2 [+] operable BC will be randomized, in a 1:4 ratio, and stratified by HR status, to receive docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) (cohort A), or trastuzumab and pertuzumab (HP) ± endocrine therapy (ET) according to HR status (cohort B). Centrally-reviewed 18F-FDG PET/CT scans will be performed prior to randomization and after 2 cycles of therapy. Pts allocated into cohort A will continue with the same therapy for a total of 6 cycles regardless of 18F-FDG PET/CT results. Pts enrolled into cohort B showing at least a 40% reduction of the SUVmax on 18F-FDG PET/CT respect to baseline (PET responders) will continue with the same therapy for a total of 8 cycles. PET non-responders pts will receive 6 cycles of TCHP. After surgery, cohort B/PET responders pts who do not achieve a pCR will receive 6 cycles of TCHP. Moreover, all pts from cohorts A/B must complete 18 cycles of HP, along with adjuvant ET and radiotherapy (RT) according to HR status and institutional practices, respectively. Pts with subclinic metastases will be assigned to cohort C to receive 6 cycles of TCHP. Surgery and RT will be evaluated on a case-by-case basis on cohort C, and all pts will continue with HP for at least 12 additional cycles ± ET according to HR status. The first co-primary endpoint is to evaluate the rate of pCR defined as the absence of invasive disease in the breast and axilla (ypT0/isN0) achieved with HP ± ET in PET responders pts (cohort B/PET responders).The second co-primary endpoint is to evaluate 3-year (3-y) invasive disease-free survival (iDFS) rate defined as time from the first date of no disease to invasive recurrence, new invasive disease, or death by any cause in cohort B. Total accrual will be 400 pts. Considering a 10% and 25% of drop-out rates at the time of first and second co-primary analysis, the study will be positive if ≥41 pts achieved a pCR in cohort B/PET responders; or if we observe ≤14 events of 3-y iDFS in cohort B. Decisions will be based on one-sided, exact binomial test. With a 2.5% type I error rate (H0: pCR ≤20% and 3-y iDFS ≤89%) and 80% power (HA: pCR ≥30% and 3-y iDFS ≥95%). The secondary objectives are to evaluate other definitions of pCR, rates of breast-conserving surgery, tumor response by magnetic resonance imaging, optimal 18F-FDG PET cut-off for pCR and other 18F-FDG PET quantification parameters for pCR prediction, DFS, distant-DFS, overall survival, progression-free survival, and health-related quality of life. Translational sub-studies will analyze biomarkers that may be predictive of response to dual HER2 blockade with HP. Citation Format: Llombart-Cussac A, Curigliano G, Gebhart G, Gligorov J, Khaldoun K, Marmé F, Prat A, Schmid P, Cortes J, Perez J. Chemotherapy-free trastuzumab and pertuzumab in HER2 [+] breast cancer: FDG-PET response-adapted strategy. The PHERGain study [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 OT1-03-01.

Prognostic and Predictive Value of FDG-PET as an Aid in Oesophageal Cancer Management

18F-fluorodeoxyglucose positron emission tomography (FDG-PET) is widely used for cancer staging before treatment and detection of recurrence during post-treatment surveillance. It is increasingly being recognised that tumour FDG uptake values may not only be prognostic, but could have predictive value to assess for treatment response during and after neoadjuvant therapy in oesophageal cancer (OC). This review focusses on the available evidence concerning the prognostic or predictive role of FDG-PET and evaluates the potential value of FDG-PET in guiding treatment decisions in OC. The correlation between pretreatment maximum standardised uptake value (SUVmax) and prognosis has been demonstrated by multiple studies, although the results are inconsistent and sometimes conflicting. With regard to the predictive value for FDG-PET, post-SUVmax after neoadjuvant chemotherapy appears to hold better promise compared to chemoradiotherapy due to the confounding effect of radiation oesophagitis. Since a number of studies have demonstrated that FDG-PET can discriminate responders from non-responders to induction chemotherapy, the predictive value of FDG-PET imaging was evaluated prospectively and the initial results of CALGB 80803 suggested that changing chemotherapy regimen based on FDG-PET response to induction chemotherapy may improve pathologic complete response rate in PET non-responders when an alternative chemotherapy is used. Furthermore, additional research has suggested that FDG-PET response after induction chemotherapy or neoadjuvant chemotherapy may enrich a patient subset who may potentially avoid subsequent surgery after chemoradiotherapy. However, the majority of reports published on FDG-PET in OC are limited to small, retrospective, and single-institutional studies. Therefore, much of the current evidence-to-date is still hypothesis-generating and would require vigorous validation before FDG-PET could become part of routine clinical practice to direct treatment decisions.

Impact of early FDG-PET directed intervention on preoperative therapy for locally advanced gastric cancer: A Cooperative Group random assignment phase II study (Alliance A021302) Impac.

TPS4135 Background: Gastric cancer is a prevalent and morbid illness for which new treatment strategies are needed. Peri-operative therapy is a standard approach that is associated with only a 15% improvement in overall survival. Early FDG-PET scanning, performed prior to cycle 2, can distinguish patients (pts) responding to chemotherapy from those who are not. FDG-PET non-responding pts have poorer survival. This study addresses the question of salvage therapy in pts who are PET non-responders. Specifically, does salvage chemotherapy with docetaxel /irinotecan improve pt survival in FDG-PET-nonresponding pts with locally advanced gastric cancer. Methods: This is a multicenter, cooperative group, NCI supported, randomized phase II study of salvage chemotherapy + surgery versus surgery and post-operative chemoradiotherapy in pts who are FDG-PET non-responders (defined as a decrease in SUVmaxof the primary tumor of less than 35%). A total of 176 pts with locally advanced, resectable gastric cancer who were FDG-PET non-responders to cycle 1 of platinum/capecitabine based chemotherapy will be randomized in a 1:1 manner to receive either (Arm A) surgery followed by fluoropyrimidine-sensitized radiotherapy (4500 cGy), or (Arm B) salvage chemotherapy with docetaxel / irinotecan (DI) for 2 cycles followed by standard resection and 3 cycles DI post-operatively. DI is administered as D 30 mg/m2, I 50 mg/m2 given on D1, D8 of a 21 day cycle. 416 pts will be screened to yield 162 non-responders (81 FDG-PET non-responders per treatment group). With expected 120 events, the study will have 80% power to detect a hazard ratio of 0.625 for improved survival at the one-sided significant level of 0.15. Pts will be required to provide tissue at the time of resection, as well as whole blood prior to resection for correlative studies associated with platinum sensitivity, FDG avidity, and prognostic markers. This study is available through all cooperative groups (SWOG, ACRIN/ECOG, Alliance, and NRG) and the National Clinical Trials Network. Enrollment began in November 2015. Support: U10CA180821, U10CA180882; Clinical Trial Information: NCT02485834 .

18F-FDG PET Response After Induction Chemotherapy Can Predict Who Will Benefit from Subsequent Esophagectomy After Chemoradiotherapy for Esophageal Adenocarcinoma.

This study aimed to determine whether 18F-FDG PET response after induction chemotherapy before concurrent chemoradiotherapy can identify patients with esophageal adenocarcinoma who may benefit from subsequent esophagectomy. Methods: We identified and analyzed 220 patients with esophageal adenocarcinoma who had received induction chemotherapy before chemoradiotherapy, with or without surgery, with curative intent; all underwent 18F-FDG PET scanning before and after induction chemotherapy. 18F-FDG PET responders were defined as patients who achieved complete response (CR) after induction chemotherapy (maximum SUV ≤ 3.0). The predictive value of 18F-FDG PET response for patient outcomes was evaluated. Results: Overall, 86 patients had bimodality therapy (BMT; induction chemotherapy + chemoradiotherapy) and 134 had trimodality therapy (TMT; induction chemotherapy + chemoradiotherapy with surgery). Forty-eight patients (21.8%) achieved an 18F-FDG PET CR after induction chemotherapy. 18F-FDG PET CR was found to correlate with overall survival (OS) and progression-free survival (PFS) in BMT patients. For TMT patients, 18F-FDG PET CR predicted pathologic response (P = 0.003) but not survival. Among 18F-FDG PET nonresponders, TMT patients had significantly better survival than did BMT patients (P < 0.001). However, among 18F-FDG PET responders, BMT patients had OS (P = 0.201) and PFS (P = 0.269) similar to that of TMT patients. After propensity score-matched analysis, 18F-FDG PET responders treated with BMT versus TMT still had comparable OS and PFS, but TMT was associated with better locoregional control. Conclusion:18F-FDG PET response to induction chemotherapy could be a useful imaging biomarker to identify patients with esophageal adenocarcinoma who could benefit from subsequent esophagectomy after chemoradiotherapy. Compared with BMT, TMT can significantly improve survival in 18F-FDG PET nonresponders. However, outcomes for 18F-FDG PET responders were similar after either treatment (BMT or TMT). Prospective validation of these findings is warranted.