Disease-free Survival Events Research Articles

Transanal Total Mesorectal Excision (TaTME) versus Laparoscopic Total Mesorectal Excision for Lower Rectal Cancer: A Propensity Score-Matched Analysis.

Simple SummaryTo treat locally advanced rectal cancer with a multimodality approach has led to improved oncological outcomes. Despite the trend of intensification of neoadjuvant therapy, surgery remains the mainstay treatment for rectal cancer. Transanal total mesorectal excision (TaTME) was shown to provide a better distal resection margin, less circumferential resection margin involvement, and a better short-term outcome than laparoscopic TME (LapTME) for mid-low rectal cancer. However, diverse oncological results were reported recently. We aimed to analyze the short- and long-term outcomes of TaTME compared with LapTME in patients with lower rectal cancer. Our results showed that TaTME had similar histopathological results and postoperative outcomes as LapTME, even in the learning curve. However, a better DFS (72% vs. 56.6%, p = 0.038) and fewer LR events (9.5% vs. 23.8%, p = 0.031) were observed after TaTME. Thus, TaTME can be considered a safe and feasible approach in patients with low rectal cancer.Studies have reported positive short-term and histopathological results of transanal total mesorectal excision (TaTME) for mid-low rectal cancer. The long-term oncological outcomes are diverse, and concerns regarding the high local recurrence (LR) rate of TaTME have recently increased. We retrospectively analyzed 298 consecutive patients who underwent Laparoscopic TME (LapTME) or TaTME between January 2015 and December 2019. Propensity score-matching (PSM) was performed with patients matched for demographics and stage. After PSM, 63 patients were included in each group. The TaTME group had a longer mean operative time (394 vs. 333 min, p < 0.001). The blood loss, diverting stoma rate, and conversion rate were similar. Postoperatively, TaTME and LapTME had compatible complications, recovery, and hospital stay. A similar specimen quality was detected in both groups. After a mean follow-up period of 41–47 months, TaTME had less LR than LapTME (9.5% vs. 23.8%, p = 0.031). The 3-year overall survival was 80.3% in the TaTME group and 73.6% in the LapTME group (p = 0.331). The 3-year disease-free survival (DFS) rate was 72.0% in the TaTME group and 56.6% in the LapTME group (p = 0.038). In conclusion, better DFS and fewer LR events were observed after TaTME; thus, TaTME can be considered a safe and feasible approach in patients with low rectal cancer.

Postoperative Adjuvant Chemoradiotherapy on the Survival of Stage III Gastric Cancer.

Objective Although adjuvant therapy has been shown to be beneficial in gastric cancer, the use of adjuvant chemoradiotherapy remains controversial. This paper investigated the effects of postoperative adjuvant chemoradiotherapy on the survival of patients with stage III gastric cancer. Methods In total, the data of 72 stage III gastric cancer patients treated at our hospital from January 2014 to December 2019 were retrieved and assessed. They were categorized into a chemotherapy group (CT group) and a radiochemotherapy group (RCT group) according to their given treatment regimens. A 3-year follow-up was conducted to record their incidence of disease-free survival (DFS), overall survival (OS), and adverse events. Results For the CT and RCT groups, DFS was 86.4% and 92.6% in the first year, decreasing to 55.1% and 73.7% in the second year, and 41.3% and 69.1% in the third year. There was no significant difference in DFS between the two groups during the three-year follow-up. Additionally, for the CT and RCT groups, their respective 1-year, 2-year, and 3-year OS were 95.6% and 96.3%, 75.1% and 87.9%, and 50.3% and 74.2%, indicating that the OS of patients in the RCT group was significantly higher than that in the CT group during 3 years of follow-up. Further, no significant difference in the incidence of adverse events was found between the two treatment groups. Conclusions Collectively, adjuvant radiochemotherapy after radical gastrectomy for stage III gastric cancer was associated with better survival outcomes than chemotherapy, without increase in adverse events.

Quantifying the absolute benefit of neoadjuvant chemotherapy followed by definitive therapy in patients with muscle-invasive bladder cancer: A systematic review and meta-analysis.

4594 Background: Cisplatin based neoadjuvant chemotherapy (NAC) followed by definitive therapy improves survival in patients with muscle invasive bladder cancer (MIBC). However, the clinical benefit of NAC might vary with the choice of definitive therapy. Therefore, we assessed the absolute benefit of NAC followed by radical cystectomy or radical radiotherapy separately using the totality of evidence. Methods: MEDLINE and EMBASE were systematically searched to identify randomized trials assessing cisplatin based neoadjuvant chemotherapy followed by either radical cystectomy or definitive radiotherapy in patients with MIBC. Outcomes of interest included overall survival (OS) and disease-free survival (DFS). Treatment effects were expressed as hazard ratios (HR) with 95% confidence interval (CI). Incidence rate ratios were calculated to estimate time to event outcomes for trials not reporting HR. A random-effects DerSimonian-Laird meta-analysis was conducted. Absolute effects were then obtained using baseline risks from the control arm of RCTs. Results: Of 4887 studies identified, 13 trials with 2529 patients were included in this meta-analysis. Most trials included patients with T2-4 and N0 patients and only 3 trials included patients with node positive disease. Total of 180 (47%) DFS events were observed with NAC+RC compared to 213 (56%) events in RC alone (HR: 0.72; 95% CI: 0.59-0.89) and 346 (58%) OS events were observed with NAC+ RC compared to 385 (52%) events in RC alone (HR: 0.80; 95% CI: 0.69-0.92). Total of 186 (70%) DFS events were observed with NAC + radiotherapy compared to 205 (71%) events in radiotherapy alone (HR: 0.91; 95% CI: 0.74-1.12) and 263 (58%) OS events were observed with NAC+ radiotherapy compared to 294 (61%) events in radiotherapy alone (HR:0.93; 95% CI: 0.79-1.08). Conclusions: The choice of definitive therapy after cisplatin-based NAC impacts survival in patients with MIBC. RC after NAC improved DFS (114 fewer events per 1000 events) and OS (76 fewer per 1000 events) whereas radiotherapy after NAC showed no survival benefit. [Table: see text]

Long-term outcomes of adjuvant denosumab in breast cancer: Fracture reduction and survival results from 3,425 patients in the randomised, double-blind, placebo-controlled ABCSG-18 trial.

507 Background: State-of-the-art adjuvant endocrine therapy with aromatase inhibitors (AI) compromises bone health in postmenopausal patients with hormone receptor-positive (HR+) breast cancer, increasing fracture incidence. Adjuvant treatment with the anti-RANK ligand denosumab (Dmab) counteracts these side effects and may improve outcomes. We here report the final long-term outcomes of the ABCSG-18 trial (ClinicalTrials.gov NCT00556374). Methods: In this prospective, double-blind, placebo-controlled, phase 3 trial, 3,425 postmenopausal patients with early HR+ breast cancer on AI therapy were randomised in 58 trial centers between 2006 and 2013 to receive either Dmab 60 mg or placebo s.c. every 6 months (q6m). The primary endpoint was time to first clinical fracture, secondary disease outcome-related endpoints were disease-free survival (DFS), bone-metastasis free survival (BMFS), and overall survival (OS). In addition to the main endpoint analyses reported previously, exploratory long-term follow-up was conducted in ABCSG-18. Main time-to-event analyses were based on stratified Cox models. Sensitivity analyses accounting for treatment cross-over associated with a late Dmab open-label phase, as well as for receiving any anti-resorptive agents were performed. Results: For this final protocol-defined analysis, median follow-up is 8 years (Q1,3: 6, 9.6), and all patients had ended their randomly assigned double-blind treatment (Dmab 60mg s.c. q6m n = 1711; placebo s.c. q6m n = 1709) for a median of 5 years. DFS was improved in the Dmab group versus the placebo group (309 versus 368 DFS events, hazard ratio (HR) 0.83, 95% CI 0.71-0.97, p = 0.016), resulting in an absolute 9-year DFS difference of 3.5% (79.4% vs 75.9%, respectively). When censoring for late cross-over and use of anti-resorptive agents, the DFS difference was confirmed (HR 0.82, p = 0.010). BMFS was improved by 19 per cent (HR 0.81, 95% CI 0.65-1.00, p = 0.047) in the Dmab group, and OS was improved by 20 per cent in the uncensored analysis (127 versus 158 OS events, HR 0.80, 95% CI 0.64-1.01, p = 0.065), and 26 per cent after censoring (HR 0.74, 95% CI 0.58-0.94, p = 0.013). The previously reported marked reduction in clinical fractures persisted even long-term, with 201 fractures in the Dmab and 255 fractures in the placebo group (HR 0.76, 95% CI 0.63-0.92, p = 0.004). No new toxicities for this (low) bone-protective dose of adjuvant Dmab were reported, particularly no ONJ occured.. Conclusions: Adjuvant Dmab 60mg every 6 months during AI therapy is safe, and markedly reduces treatment-induced clinical fractures even in the long-term. DFS, BMFS, and OS are improved in this descriptive final long-term analysis of ABCSG-18. Adjuvant denosumab should be considered for routine clinical use in postmenopausal patients with HR+ breast cancer. Clinical trial information: NCT00556374.

Historical early treatment effects of adjuvant endocrine therapy for breast cancer in high-risk subgroups: Reanalysis of BIG 1-98, SOFT and TEXT.

508 Background: Clinical trials testing adjuvant endocrine therapy (ET) have not historically limited enrollment to patients with clinically high-risk breast cancer (BC), nor estimated treatment (trt) effects prior to 5 yrs. In light of recent trial results for adjuvant CDK4/6 inhibitors, we estimated early relative and absolute trt effects of aromatase inhibitor (AI) vs tamoxifen (T), with ovarian suppression (OFS) if premenopausal, in high risk subgroups. Methods: From pts enrolled in adjuvant phase 3 randomized clinical trials BIG 1-98 (postmenopausal, 5yr AI v T), TEXT (5yr AI+OFS v T+OFS) and SOFT (5yr AI+OFS v T+OFS v T), we identified subgroups with HR+/HER2- BC and high risk features (≥4 pLN; or 1-3 pLN with grade 3, pT≥5 cm and/or Ki-67≥20% [retrospectively centrally assessed]). TEXT randomized at start of adjuvant trt; BIG 1-98 and SOFT after chemotherapy. Disease-free survival (DFS) was defined from randomization to invasive recurrence at local, regional, distant or contralateral breast, second non-breast malignancy or death. We estimated trt effects as differences in 2, 3 and 5yr DFS Kaplan-Meier estimates (KM diffs at t yrs) and hazard ratios over time intervals of 0-2, 0-3 and 0-5 yrs (HRs over 0 to t yrs) to approximate the maturity of trial results with increasing follow-up. Results: The high-risk HR+/HER2- subgroups were 695/4922, 707/2660 and 526/3047 pts in BIG 1-98, TEXT and SOFT with 202, 122, 142 DFS events observed by 5 yrs since randomization. 60%, 46% and 44% of pts had ≥4 pLNs; 42%, 90% and 92% had chemotherapy. The table summarizes results. Conclusions: In re-analysis of clinical high risk HR+/HER2- subgroups of 3 trials each ̃700 pts, 5 yrs AI vs T had similar magnitude of early trt effects after 2-3 yrs follow-up of all pts vs trt effects observed after 27 mos median follow-up in monarchE trial (HR=0.70; KM diffs 2.7% at 2 yrs, 5.4% at 3 yrs; n=5637). Relative and absolute trt effects sometimes diminished when estimated over 5 yrs rather than over 2 yrs, but meaningful absolute differences remained at 5 yrs in contrast to Penelope-B trial results. Design and interpretation of high risk HR+/HER2- early BC trials may depend on timing of randomization and selection of backbone adjuvant trts; follow-up &gt;5 yrs must remain standard. [Table: see text]

Adding ovarian function suppression to tamoxifen in young women with hormone-sensitive breast cancer who remain premenopausal or resume menstruation after chemotherapy: 8-year follow-up of the randomized ASTRRA trial.

506 Background: Addition of Ovarian Suppression to Tamoxifen in Young Women With Hormone-Sensitive Breast Cancer Who Remain Premenopausal or Regain Vaginal Bleeding After Chemotherapy (ASTRRA) trial, at 63 months median follow-up, showed that the addition of 2 years of ovarian function suppression (OFS) to Tamoxifen (TAM) significantly improved disease-free survival (DFS) compared with TAM alone in patients with hormone receptor–positive breast cancer who remain in a premenopausal state or resume ovarian function after chemotherapy. We report updated long-term outcomes from ASTRRA trial with 106.4 months median follow-up. Methods: This study is a post-trial follow-up of the ASTRRA trial, which randomly assigned 1,298 patients with breast cancer in a 1:1 ratio to receive TAM only (n = 647) or TAM + OFS (n = 635). The primary endpoint was DFS and secondary endpoint was overall survival (OS). We used Kaplan-Meier estimates for time to event endpoints and hazard ratios (HR) with 95% confidence interval (CI) from Cox-regression model. Results: At 106.4 months of median follow-up, there continues to be a statistically significant reduction in DFS event rate in favor of the TAM+OFS group. The estimated 8-year DFS rate was 85.4% in the TAM + OFS group and 80.2% in the TAM-only group (HR 0.67; 95% CI, 0.51 to 0.87). There were no significant differences in OS between two groups. The estimated 8-year OS rate was 96.5% in the TAM + OFS group and 95.3% in the TAM-only group (HR, 0.78; 95% CI, 0.49 to 1.25). The results of DFS and OS between the two groups defined from the time of random assignment to the time of events were also similar. Conclusions: These data demonstrate consistent survival advantages of adding OFS 2 years to TAM treatment over time, with the long-term follow-up reported to date. This study finding suggest that adding OFS to TAM should be considered for those who remain in a premenopausal state or resume ovarian function after chemotherapy. Longer follow-up is needed to fully evaluate the OS benefit.

Dose-dense sequential adjuvant chemotherapy in the trastuzumab era: final long-term results of the Hellenic Cooperative Oncology Group Phase III HE10/05 Trial.

Dose-dense sequential chemotherapy with anthracyclines and taxanes achieved an 18% reduction of recurrence risk in early breast cancer (BC). The optimal chemotherapy schedule and interval between cycles remain under investigation. Overall, 990 patients were randomised to receive either three cycles of epirubicin (E, 110 mg/m2) every 2 weeks followed by 3 cycles of paclitaxel (T, 200 mg/m2) every 2 weeks followed by three cycles of intensified CMF (Control Arm A, E-T-CMF) that was previously used in BC or three cycles of epirubicin followed by three cycles of CMF followed by nine consecutive weekly cycles of docetaxel (wD) 35 mg/m2 (Arm B, E-CMF-wD) or nine consecutive weekly cycles of paclitaxel (wT) 80 mg/m2 (Arm C, E-CMF-wT). Trastuzumab was administered for HER2-positive disease. At a median follow-up of 13.3 years, 330 disease-free survival (DFS) events (33.3%) were reported. DFS and overall survival (OS) did not differ between patients in the combined B and C arms versus arm A either in the entire cohort (HR = 0.90, P = 0.38 and HR = 0.85, P = 0.20) or among trastuzumab-treated patients (HR = 0.69, P = 0.13 and HR = 0.67, P = 0.13). Thirty-four patients (3.4%) developed secondary neoplasms. Overall, no significant differences in survival were found amongst the studied regimens after a long-term observational period. Australian New Zealand Clinical Trials Registry ACTRN12610000151033.

Effect of Metformin vs Placebo on Invasive Disease–Free Survival in Patients With Breast Cancer

Metformin, a biguanide commonly used to treat type 2 diabetes, has been associated with potential beneficial effects across breast cancer subtypes in observational and preclinical studies. To determine whether the administration of adjuvant metformin (vs placebo) to patients with breast cancer without diabetes improves outcomes. MA.32, a phase 3 randomized, placebo-controlled, double-blind trial, conducted in Canada, Switzerland, US, and UK, enrolled 3649 patients with high-risk nonmetastatic breast cancer receiving standard therapy between August 2010 and March 2013, with follow-up to October 2020. Patients were randomized (stratified for hormone receptor [estrogen receptor and/or progesterone receptor {ER/PgR}] status, positive vs negative; body mass index, ≤30 vs >30; human epidermal growth factor receptor 2 [ERBB2, formerly HER2 or HER2/neu], positive vs negative; and any vs no chemotherapy) to 850 mg of oral metformin twice a day (n = 1824) or oral placebo twice a day (n = 1825) for 5 years. The primary outcome was invasive disease-free survival in hormone receptor-positive breast cancer. Of the 8 secondary outcomes, overall survival, distant relapse-free survival, and breast cancer-free interval were analyzed. Of the 3649 randomized patients (mean age, 52.4 years; 3643 women [99.8%]), all (100%) were included in analyses. After a second interim analysis, futility was declared for patients who were ER/PgR-, so the primary analysis was conducted for 2533 patients who were ER/PgR+. The median duration of follow-up in the ER/PgR+ group was 96.2 months (range, 0.2-121 months). Invasive disease-free survival events occurred in 465 patients who were ER/PgR+. The incidence rates for invasive disease-free survival events were 2.78 per 100 patient-years in the metformin group vs 2.74 per 100 patient-years in the placebo group (hazard ratio [HR], 1.01; 95% CI, 0.84-1.21; P = .93), and the incidence rates for death were 1.46 per 100 patient-years in the metformin group vs 1.32 per 100 patient-years in the placebo group (HR, 1.10; 95% CI, 0.86-1.41; P = .47). Among patients who were ER/PgR-, followed up for a median of 94.1 months, incidence of invasive disease-free survival events was 3.58 vs 3.60 per 100 patient-years, respectively (HR, 1.01; 95% CI, 0.79-1.30; P = .92). None of the 3 secondary outcomes analyzed in the ER/PgR+ group had statistically significant differences. Grade 3 nonhematological toxic events occurred more frequently in patients taking metformin than in patients taking placebo (21.5% vs 17.5%, respectively, P = .003). The most common grade 3 or higher adverse events in the metformin vs placebo groups were hypertension (2.4% vs 1.9%), irregular menses (1.5% vs 1.4%), and diarrhea (1.9% vs 7.0%). Among patients with high-risk operable breast cancer without diabetes, the addition of metformin vs placebo to standard breast cancer treatment did not significantly improve invasive disease-free survival. ClinicalTrials.gov Identifier: NCT01101438.

A retrospective analysis of changes in distant and breast cancer related disease-free survival events in adjuvant breast cancer trials over time

Disease-free survival (DFS) comprises both breast cancer and non-breast cancer events. DFS has not been validated as a surrogate endpoint for overall survival (OS) in most breast cancer subtypes. We assessed changes to the type of events contributing to DFS over time. We identified adjuvant studies in breast cancer (BC) from 2000 to 2020 where the endpoint was DFS. We examined change in distant DFS events and the BC-related DFS using univariable and multivariable linear regression. Data were reported quantitatively using the Burnand criteria irrespective of statistical significance. We included 84 studies (88 cohorts), comprising 212,191 participants, 41,604 DFS events and 23,205 distant DFS events. The DFS event rate/100 participants/year has declined modestly over time (ß − 0.34, p = 0.001). Start year was negatively associated with distant DFS events (ß − 0.58, p < 0.0001); however, the effect was lost after adjusting for follow-up time (ß − 0.18, p = 0.096). The average number of BC-related events/100 participants/year also declined over time (ß − 0.28, p = 0.009). In multivariable analysis, start year and ER expression were quantitatively associated with distant DFS events and BC-related DFS events. DFS events have declined over time driven by a reduction in BC related events. As DFS events are increasingly defined by non-BC events, there will be limited surrogacy between DFS and OS.

The Efficacy of Adjuvant Targeted Therapy in Patients with Advanced Renal Cell Carcinoma: A Systematic Review and Meta-Analysis.

Background The aim of this systematic evaluation and meta-analysis was to analyze the efficacy and adverse effects of adjuvant targeted therapy regimens in advanced or metastatic renal cell carcinoma (RCC). Methods Studies eligible for the efficacy of adjuvant targeted therapy regimens in advanced or metastatic RCC published before December 2021 in PubMed, Embase, Cochrane Clinical Trials Database (CENTRAL), and Web of Science were searched for (1) patients with locally advanced renal cell carcinoma (RCC) who received adjuvant postoperative targeted therapy versus those not receiving active treatment; (2) primary endpoint outcomes of disease-free survival (DFS), overall survival (OS), and adverse events (AEs); and (3) design: randomized controlled trial (RCT) as inclusion criteria. Data on DFS and OS were extracted or recalculated by meta-analysis as hazard ratios (HRs), and AEs were compared using a dominance ratio (OR). Result This systematic evaluation will provide evidence on the effectiveness and adverse effects of adjuvant targeted therapy in patients with advanced RCC. The results of meta-analysis showed that all of the three adjuvant targeted therapeutic drugs (sorafenib, sunitinib, and pazopanib) did not benefit from the adjuvant targeted therapy for DFS and OS and even increase the incidence of AEs compared to the placebo. Conclusions The aim of this study was to summarize data on DFS, OS, and AEs in patients with advanced RCC treated with targeted therapies. The evidence provided by this systematic evaluation and meta-analysis will help guide clinical decision-making and provide insight into the future management of patients with advanced RCC.

Abstract PD13-09: Primary analysis from NEOS trial: A randomized phase III study that assessed the long-term prognosis of estrogen receptor positive (ER+) primary breast cancer (PBC) pts who received neoadjuvant endocrine therapy (NET) with/without adjuvant chemotherapy (CT)

Abstract Background: NET is one of option in postmenopausal PBC with ER+ and molecular signature is useful tool to determine with/without CT after surgery. We presented a relationship between molecular signature and response of NET in this study cohort (BCRT; 2018). Here we report the primary analysis of NEOS trial, a Phase III study that evaluated long-term prognosis with/without CT in ER+ PBC who received NET. Methods: Postmenopausal BC pts with ER +/HER2 negative, T1c-2, clinically node negative, under 76 years old were enrolled at primary registration. Pts were treated by letrozole (LET) in weeks 24-28 after primary enrollment. Pts experienced progression disease (PD) during neoadjuvant phase or with more than 4 positive lymph nodes in pathological findings after surgery were excluded at randomization and received any systemic therapy driven by investigators before or after surgery. Pts who met eligibility criteria were randomized 1:1 to LET for 4.5-5 years after CT or LET alone for 4.5-5 years without CT after surgery. Primary endpoint is disease-free survival (DFS) with/without adjuvant CT. Secondary endpoints include distant DFS (DDFS), overall survival (OS), DFS/DDFS/OS according clinical response of NET and QoL. Statistical analysis plan is as follow. The Hazard ratio (HR) will be compared with the threshold HRs obtained in a pre-study questionnaire survey to reach a conclusion about the choice between LET plus chemotherapy or LET alone. Based on these survey results, the HR thresholds used to choose between the two treatments were set at 0.9 and 0.6. After amendment, the selection probability was finally set as 80-85%. About 170 events were required for both arms. Results: Between May 2008 and June 2013, 904 patients were enrolled at primary registration from 100 institutions in Japan and 21 pts were withdrawn before neoadjuvant phase. 42pts were excluded by PD during NET. 172pts were not randomized because of non-eligible for second enrolled criteria after surgery and patient’s preference. 669pts were randomized (1:1) to adjuvant CT + ET (333pts) or ET alone (336pts). Patients’ characteristics (age, tumor size, progesterone receptor(PgR) status, nuclear grade (NG), clinical and pathological response of NET and a number of Ax LN metastasis) were well balance among two arms. Median follow up is 7.8 years. Primary endpoint (DFS) was not able to evaluated for necessity of chemotherapy because DFS events (CT+ET:46, ET alone:61) was lower compared with planned numbers (HR:0.74 (95%CI; 0.51, 1.09), P=0.13). DDFS was also not able to evaluated similar with DFS (HR:0.79 (95%CI; 0.46, 1.35) P=0.39). DFS/DDFS rate at 8Y were 85.6%/93.1% and 82.7%/91.7% in CT+ ET and ET alone, respectively. OS was not difference between two arms (HR 0.46 (95%CI; 0.20, 1.07) P=0.072). Both DDFS and locoregional events were lower in CT+ET than ET alone arm. A number of any secondary cancers was higher than DDFS events among both arms. DFS was statistically significant better in CT+ET arm than ET alone arm among any subgroups who &amp;lt; 60 years (HR:0.30, p=0.003, clinical T2 (HR:0.56, p=0.012) and ki67 &amp;gt;20% cases (HR:0.49, P=0.026) at baseline characteristics. No statistically significant difference of DFS between two arms according to response of NET (HR:0.76, P=0.35 in CR and PR group, HR:0.70, p=0.19 in SD group). PgR status, NG, a number of Ax LN metastasis were also not predictive factors about the difference of DFS between CT+ET and ET alone. Conclusion: The decision to use adjuvant chemotherapy could not be based solely on clinical response of NET. Adjuvant chemotherapy should be selected by any clinical factors and genomic tool regardless of response by NET for ER+ PBC. UMIN000001090 Citation Format: Hiroji Iwata, Tatsuya Toyama, Naruto Taira, Norikazu Masuda, Yutaka Yamamoto, Tomomi Fujisawa, Shoichiro Ohtani, Masahiro Kashiwaba, Takehiko Sakai, Yoshie Hasegawa, Rikiya Nakamura, Hiromitsu Akabane, Yukiko Shibahara, Hironobu Sasano, Takuhiro Yamaguchi. Primary analysis from NEOS trial: A randomized phase III study that assessed the long-term prognosis of estrogen receptor positive (ER+) primary breast cancer (PBC) pts who received neoadjuvant endocrine therapy (NET) with/without adjuvant chemotherapy (CT) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD13-09.

Abstract PD5-06: Safety of assisted reproductive technologies (ART) following treatment completion in young women with germline BRCA pathogenic variants having a pregnancy after breast cancer

Abstract BACKGROUND: Young breast cancer (BC) survivors are at risk of infertility. Ovarian stimulation for fertility preservation before (neo)adjuvant chemotherapy is standard of care. Research efforts have shown no negative prognostic effect of pregnancy following BC therapy, also among BRCA carriers. Currently, poor evidence is available on the safety to undergo ART following BC treatment, with no data in carriers of germline BRCA pathogenic variants. To provide evidence on the safety of fertility treatments in this specific population, we assessed the outcomes of a cohort of BRCA-mutated BC survivors who had a pregnancy after prior BC history by comparing the group of patients who underwent ART to achieve pregnancy to the group with spontaneous pregnancy. METHODS: We conducted a multicenter retrospective cohort study across 30 centers worldwide including women diagnosed at ≤ 40 years with stage I-III BC, between January 2000 and December 2012, bearing germline BRCA1/2 pathogenic variants. Survivors with a pregnancy (any outcome) after BC, with no disease-free survival (DFS) event before pregnancy, were assigned to the ART and non-ART group if their pregnancy was achieved through ART or spontaneously, respectively. ART procedures included ovulation induction, ovarian stimulation for in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI), and embryo transfer under hormonal replacement therapy (HRT). RESULTS: Of 1,424 patients registered in the study, 168 with a pregnancy after BC were included in the present analysis. A total of 22 patients were included in the ART group and 146 in the non-ART group. Before BC diagnosis, 18.2% patients in the ART group had at least one child, compared to 38.4% in the non-ART group (P=0.030). Patients had a median age at BC diagnosis of 33.0 vs 30.2 years old in the ART group and in the non-ART group, respectively (P=0.004); 45.4% and 17.1% had grade 1-2 tumors, respectively (P=0.008), and 59.1% vs 31.5% had hormone receptor-positive tumors, respectively (P=0.016). Both cohorts had similar tumor size and nodal stage characteristics. Type and duration of endocrine therapy were comparable between groups. The type of ART was not specified in 5 survivors (22.7%). Ovulation induction was used in 1 patient (4.5%), ovarian stimulation in 7 patients (31.8%), embryo transfer under HRT following oocyte donation in 5 patients (22.7%), and embryo transfer under HRT following oocyte and/or embryo cryopreservation for fertility preservation in 4 patients (18.2%). Median age at conception among survivors was 39.7 years in the ART group versus 35.4 years in the non-ART group (P&amp;lt;0.001). Overall, no differences in obstetrical outcomes were observed between groups, although there were more delivery complications in the ART group vs the non-ART group (22.1% vs 4.1%, respectively, P=0.011). Median follow-up from pregnancy was 3.4 years (range: 0.8-8.6) for patients in the ART group vs 5.0 years (range: 0.8-17.6) in the non-ART group (P=0.009). In the ART group, 2 patients (9.1%) experienced a DFS event (both were loco-regional recurrences) as compared to 40 patients (27.4%) in the non-ART group (P=0.182). No patients died in the ART group compared to 10 patients (6.9%) in the non-ART group. CONCLUSIONS: To our knowledge, this is the first study assessing the safety of ART in BC survivors bearing germline BRCA pathogenic variants. Even though the exposed cohort was small, results showed that the use of ART does not appear to increase the relapse risk at short-term follow-up. Further reproductive studies in BRCA-mutated BC patients are warranted. Citation Format: Margherita Condorelli, Marco Bruzzone, Marcello Ceppi, Alberta Ferrari, Albert Grinshpun, Anne-Sophie Hamy, Evandro de Azambuja, Estela Carrasco, Fedro A. Peccatori, Antonio Di Meglio, Shani Paluch-Shimon, Philip D. Poorvu, Marta Venturelli, Christine Rousset-Jablonski, Claire Senechal, Luca Livraghi, Riccardo Ponzone, Laura De Marchis, Katarzyna Pogoda, Amir Sonnenblick, Cynthia Villarreal-Garza, Octavi Córdoba, Luis Teixeira, Florian Clatot, Kevin Punie, Rossella Graffeo Galbiati, Maria Vittoria Dieci, Alejandro Pérez-Fidalgo, Francois P. Duhoux, Fabio Puglisi, Arlindo R. Ferreira, Eva Blondeaux, Tamar Peretz-Yablonski, Olivier Caron, Claire Saule, Lieveke Ameye, Judith Balmaña, Ann H. Partridge, Hatem A. Azim, Jr, Isabelle Demeestere, Matteo Lambertini. Safety of assisted reproductive technologies (ART) following treatment completion in young women with germline BRCA pathogenic variants having a pregnancy after breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD5-06.

Abstract P1-12-01: Dose-dense sequential adjuvant chemotherapy in the trastuzumab era: Final long-term results of the hellenic cooperative oncology group phase III HE10/05 trial

Abstract Background: Dose-dense sequential chemotherapy based on anthracyclines and taxanes has achieved an 18% reduction of recurrence risk in the adjuvant setting of early breast cancer (BC). However, the optimal chemotherapy schedule and the preferable interval between cycles are still under investigation. Methods: A total of 990 eligible BC patients were randomized to receive either 3 cycles of epirubicin (E,110 mg/m2) every 2 weeks followed by 3 cycles of paclitaxel (T, 200 mg/m2) every 2 weeks followed by 3 cycles of intensified CMF (Control Arm A, E-T-CMF; 333 patients) or three cycles of epirubicin followed by 3 cycles of CMF followed by 9 consecutive weekly cycles of docetaxel (wD) 35 mg/m2 (Experimental Arm B, E-CMF-wD; 331) or 9 consecutive weekly cycles of paclitaxel (wT) 80 mg/m2 (Experimental Arm C, E-CMF-wT; 326). Trastuzumab was administered for HER2-positive disease. The primary endpoint was disease-free survival (DFS). Results: At a median follow-up of 13.3 years, 330 DFS events (33.3%) had been reported. DFS and overall survival (OS) did not differ between patients in the combined B and C arms versus control arm A either in the entire cohort (HR=0.90, p=0.38 and HR=0.85, p=0.20) or among HER2-positive, trastuzumab-treated patients (HR=0.69, p=0.13 and HR=0.67, p=0.13). Thirty-four patients (3.4%) developed secondary neoplasms. Conclusions: Overall, no significant differences in DFS or OS were found amongst the studied regimens after a long-term observational period. Trial registration: Australian New Zealand Clinical Trials Registry ACTRN12610000151033 Citation Format: Flora Zagouri, Georgia-Angeliki Koliou, Foteinos Dimitrakopoulos, Christos Papadimitriou, Ioannis Binas, Angelos Koutras, Pavlos Papakostas, Christos Markopoulos, Vasileios Venizelos, Grigorios Xepapadakis, Charisios Karanikiotis, Amanda Psyrri, Dimitrios Bafaloukos, Paris Kosmidis, Gerasimos Aravantinos, Eleni Res, Davide Mauri, Anna Koumarianou, Kalliopi Petraki, Anna Tsipoura, Dimitrios Pectasides, Helen Gogas, George Fountzilas. Dose-dense sequential adjuvant chemotherapy in the trastuzumab era: Final long-term results of the hellenic cooperative oncology group phase III HE10/05 trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-12-01.

Abstract GS2-05: Randomized comparison of adjuvant aromatase inhibitor exemestane (E) plus ovarian function suppression (OFS) vs tamoxifen (T) plus OFS in premenopausal women with hormone receptor-positive (HR+) early breast cancer (BC): update of the combined TEXT and SOFT trials

Abstract Background The updated combined SOFT+TEXT analysis, after 9 years median follow-up (MFU), revealed that adjuvant E+OFS vs T+OFS significantly improved disease-free survival (DFS) and distant recurrence-free interval (DRFI) but not overall survival (OS) in premenopausal women with HR+ early BC (Francis et al NEJM 2018). Given the high rate of OS in both arms and the long-term risk of relapse in HR+ BC, continued follow-up is key to assessing treatment benefit. We report a planned update analysis including OS with database lock of May 2021, after 13 years MFU.. Methods TEXT and SOFT enrolled premenopausal women with HR+ early BC from November 2003 to April 2011 (2660 in TEXT, 3047 in SOFT intention-to-treat (ITT) populations). TEXT randomized women within 12 weeks of surgery to 5 years E+OFS vs T+OFS; chemotherapy (CT) was optional and concurrent with OFS. SOFT randomized women to 5 years E+OFS vs T+OFS vs T alone, within 12 weeks of surgery if no CT planned, or within 8 months of completing (neo)adjuvant CT. Both trials were stratified by CT use. For the combined analysis of E+OFS vs T+OFS, the primary endpoint was DFS defined as invasive local, regional, distant recurrence, contralateral BC, second malignancy, death. Secondary endpoints included invasive breast cancer-free interval (BCFI), DRFI and OS.. Results: At database lock there were 953 DFS events and 473 deaths among 4690 pts assigned to T+OFS or E+OFS. In the ITT population, DFS, BCFI and DRFI outcomes for pts assigned E+OFS (n=2346) continued to be significantly improved over T+OFS (n=2344). 12-yr DFS was 80.5% vs. 75.9% (4.6% absolute improvement; HR 0.79 95% CI 0.70-0.90), 12-yr BCFI was improved by 4.1% and 12-yr DRFI by 1.8%. At 12 years OS was excellent in both groups, 90.1% in pts assigned E+OFS vs 89.1% in pts assigned T+OFS (HR 0.93; 95% CI, 0.78-1.11). There was heterogeneity of relative treatment effect according to HER2 status. When enrollment commenced, anti-HER2 adjuvant therapy was not standard; 53% of 583 pts with HER2+ tumors received HER2-targeted therapy. Below are Kaplan-Meier 12-yr estimates for patients with HER2 negative tumors by trial and chemotherapy stratum and for those with high-grade tumours, as an example of high-risk feature (Table). There is an emerging OS benefit for E+OFS vs T+OFS in pts with HER2 negative tumors who received chemotherapy in both trials.In pts with HER2-negative tumors, clinically-relevant outcome benefits were also seen in other high-risk subgroups: 12-yr DFS and OS were improved by 7.4% and 2.7%, respectively, in pts with pN1a disease, and by 10.6% and 4.5%, respectively, in those with tumors &amp;gt;2cm. Conclusions After 13 years MFU, adjuvant E+OFS, as compared with T+OFS, shows a sustained reduction in the risk of recurrence, more consistent in HER2 negative patients and in those with high-risk disease features, e.g., indication for adjuvant chemotherapy and G3 tumors. Oncologists may use this information to discuss potential benefits of E+OFS with individual patients. Follow-up continues for 5 additional years. Chemotherapy HER2-negativeSOFTT+OFS (n=424)E+OFS (n=411)Absolute difference12-yr DFS67.4%74.1%6.7%12-yr OS81.1%84.4%3.3%TEXTT+OFS (n=656)E+OFS (n=661)Absolute difference12-yr DFS71.0%78.4%7.4%12-yr OS83.5%86.8%3.3%No chemotherapy HER2-negativeSOFTT+OFS (n=445)E+OFS (n=447)Absolute difference12-yr DFS82.9%88.2%5.3%12-yr OS96.1%96.9%0.9%TEXTT+OFS (n=499)E+OFS (n=492)Absolute difference12-yr DFS80.2%86.7%6.5%12-yr OS95.9%96.2%0.2%G3 HER2-negativeT+OFS (n=423)E+OFS (n=405)Absolute difference12-yr DFS62.7%73.0%10.3%12-yr OS78.1%83.6%5.5% Citation Format: Meredith M Regan, Barbara A Walley, Gini F Fleming, Prudence A Francis, Marco A Colleoni, István Láng, Henry L Gómez, Carlo A Tondini, Harold J Burstein, Matthew P Goetz, Eva M Ciruelos, Vered Stearns, Hervé R Bonnefoi, Silvana Martino, Charles E Geyer, Jr, Claudio Chini, Alessandro M Minisini, Simon Spazzapan, Thomas Ruhstaller, Eric P Winer, Barbara Ruepp, Sherene Loi, Alan S Coates, Aron Goldhirsch, Richard D Gelber, Olivia Pagani. Randomized comparison of adjuvant aromatase inhibitor exemestane (E) plus ovarian function suppression (OFS) vs tamoxifen (T) plus OFS in premenopausal women with hormone receptor-positive (HR+) early breast cancer (BC): update of the combined TEXT and SOFT trials [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS2-05.

Abstract P1-08-35: Stromal tumor infiltrating lymphocytes analysis by race and ethnicity in triple negative breast cancers from 2 phase III randomized adjuvant breast cancer trials: ECOG-ACRIN E2197 and E1199

Abstract Background: Black patients with triple negative breast cancer (TNBC) have worse survival outcomes, even after adjusting for stage at diagnosis, income, insurance status and other socioeconomic factors. Little is known regarding anti-tumor immune responses in Black patients and how these differences affect responses to treatment in TNBC. Limited data exists regarding the stromal tumor infiltrating lymphocytes (sTILs, which are strongly prognostic in TNBC) distribution based on race and ethnicity. Here we evaluate the prevalence, distribution, and prognostic impact of sTILs in TNBC by race/ethnicity from 2 prospective clinical trials of adjuvant anthracycline/taxane-based chemotherapy (E2197 and E1199). Methods: Full-face hematoxylin and eosin-stained sections of 481 tumors from ECOG-ACRIN trials E2197 and E1199 were previously evaluated for density of sTILs and shown to be associated with disease-free survival (DFS), distant recurrence-free interval (DRFI), and overall survival (OS) (Adams, et al JCO 2014). Further analyses were undertaken to evaluate the impact of race/ethnicity. Results: The majority of the 481 TNBC were from White patients (82.3%, n=403); with 12.3% (n=59) Black patients, 1.6% (n=14) other (9 Hispanic, 3 Asian, 2 Other), and 0.5% (n=5) unknown race. Age distribution (mean 49.2 for White and 49.2 for Black) and node negative disease (White 68/403 (42%), Black 24/59 (41%)) were similar. However, tumor size ≤2cm was seen more commonly in White patients (34%, 137/403) compared with Black patients (20%, 12/59). Black patients had a higher proportion of high sTILs (≥30%) with 23.7% (14/59) compared to White patients (11.4%, 46/403). The association of continuous stromal TILs with DFS (hazard ratio for a 10-point difference) was 0.84 (95% CI 0.72, 0.98) for White patients and 0.94 (95% CI 0.73, 1.20) for Black patients [159 DFS events for Whites, 26 DFS events for Blacks]. Conclusions: This is the first dataset from prospective clinical trials evaluating sTILs in TNBC in Black patients. Prevalence of high sTILs was greater in Black patients compared to White patients. The association between increasing sTILs and improved invasive disease-free survival across racial/ethnic groups must be investigated in larger datasets. Table 1.Race/EthnicityTotal (n=481)White (n=403)Black (n=59)Other (n=19)Mean age49.049.249.245.6T1 (tumor &amp;lt;=2cm)157(32.6%)137 (34.0%)12 (20.3%)8 (42.1%)T2 (tumor &amp;gt;2 and &amp;lt;=5cm)283(58.8%)232 (57.6%)41 (69.5%)10 (52.6%)T3 and T441 (8.5%)34 (8.4%)6 (10.2%)1 (5.3%)Node negative197 (41.0%)168 (41.7%)24 (40.7%)5 (26.3%)Median sTILs (Quartiles)10 (10, 20)10 (10, 20)10 (10,20)20 (10, 30)sTILs = 095 (19.8%)83 (20.6%)10 (16.9%)2 (10.5%)sTILs 10-29%319 (66.3%)274 (68.0%)35 (59.3%)10 (52.6%)sTILs ≥30%67 (13.9%)46 (11.4%)14 (23.7%)7 (36.8%)—sTIL 30-49%,46 (9.6%)32 (7.9%)11 (18.6%)3 (15.8%)—sTIL 50-74%,17 (3.5%)11 (2.7%)3 (5.1%)3 (15.8%)—sTIL 75-100%4 (0.8%)3 (0.7%)01 (5.2%)iDFS (HR for 10% sTIL increase)0.86 (95% CI 0.76, 0.98)0.84 (95% CI 0.72, 0.98)0.94 (95% CI 0.73, 1.20)0.97 (95% CI 0.68, 1.40)DRFI (HR for 10% sTIL increase)0.82 (95% CI 0.68, 0.99)0.79 (95% CI 0.63, 1.00)1.08 (95% CI 0.82, 1.44)0.54 (95% CI 0.32, 0.90)OS (HR for 10% sTIL increase)0.81 (95% CI 0.69, 0.95)0.76 (95% CI 0.62, 0.94)1.01 (95% CI 0.76, 1.35)0.83 (95% CI 0.54, 1.29) Citation Format: Natalie Klar, Robert J Gray, Sylvia Adams, Joseph A Sparano, Lori J Goldstein, Angela M DeMichele, Antonio C Wolff, Nancy E Davidson, George W Sledge, Sunil S Badve. Stromal tumor infiltrating lymphocytes analysis by race and ethnicity in triple negative breast cancers from 2 phase III randomized adjuvant breast cancer trials: ECOG-ACRIN E2197 and E1199 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-08-35.

Abstract P1-08-14: Differences in Recurrence Score (RS) results between primary and second primary breast cancer (BC): Exploratory analysis of the Clalit Health Services (CHS) registry

Abstract Background: The first invasive disease-free survival event in patients (pts) with estrogen receptor (ER)+ early-stage breast cancer (BC) is often contralateral BC, as reflected in the TAILORx data. We analyzed the CHS registry to study differences in RS results and clinicopathological characteristics between the primary and second primary BC. Methods: This exploratory analysis included all ER+ HER2-negative BC pts who underwent RS testing through CHS between 1/2006 and 12/2020 and for whom ≥2 RS results were identified which were &amp;gt;1 year apart. Results: In this timeframe, 11,040 RS assays were ordered through CHS for 10,659 unique patients. The current analysis included 62 pts for whom multiple RS assays were performed &amp;gt;1 year apart. All 62 pts were females; their median (interquartile [IQR]) age at diagnosis was 56 (44-63) yrs, and 77% were initially diagnosed with node-negative disease. The median (IQR) time between the first and the latest RS assay was 5.3 (3.1-7.6) yrs. Tumor characteristics for the first and subsequent (second/third) primary BC tumors are presented (Table). Clinicopathologic characteristics were overall similar between the first and second/third primary BC tumors. The RS results, however, were statistically significantly higher in the second/third primary BC (P=0.0002), and the RS distribution was also significantly different with more tumors in the RS 26-100 category in the second/third primary BC (P=0.0036) (Table). The median (IQR) difference in the RS results between the first and latest RS assay for all 62 pts was 6 (-0.25-11.25). In 46 pts, (74%), the latest BC tumor had higher RS (a median [IQR] difference of 9 [5-13]) compared to the first BC tumor, and in 15 pts (24%) it had lower RS (a median [IQR] difference of -6 [-10 to -3]). One pt (2%) had the same RS result in both tumors. In 42 pts (68%), the latest primary BC was ipsilateral and in 20 pts (32%), it was contralateral. A higher RS result was observed in 33/42 (79%) of pts with ipsilateral second primary BC, and in 13/20 (65%) of pts with contralateral second primary BC (P=NS, Chi-square test). Conclusions: In ER+ HER2-negative BC pts, the characteristics of the first and second/third primary BC tumors were overall similar except for the RS result which was generally higher in the second/third primary BC. First BC; 62 tumorsSecond/third BC; 65 tumorsMedian (IQR) tumor size in the greatest dimension, cm1.55 (1.0-2.2)1.5 (1.0-1.95)Tumor size category, n (%)≤1 cm16 (25.8%)18 (27.7%)&amp;gt;1 - 2 cm28 (45.2%)33 (50.8%)&amp;gt;218 (29.0%)10 (15.4%)Unknown0 (0%)4 (6.2%)Tumor grade category, n (%)Grade 19 (14.5%)6 (9.2%)Grade 232 (51.6%)39 (60.0%)Grade 311 (17.7%)10 (15.4%)Not applicable/Unknown10 (16.1%)10 (15.4%)Histology, n (%)Invasive ductal carcinoma49 (79.0%)51 (78.5%)Invasive lobular carcinoma8 (12.9%)11 (16.9%)Mucinous/colloid/papillary2 (3.2%)2 (3.1%)Other/unknown3 (4.8%)1 (1.5%)Recurrence Score Mean (SD)a 18 (10)24 (12)Median (IQR)17 (13-22)23 (17-30)RS categoryb, n (%)0-1525 (40.3%)13 (20.0%)16-2528 (45.2%)27 (41.5%)26-1009 (14.5%)25 (38.5%)aP = 0.0002 (Mann–Whitney test); bP = 0.0036 (Chi-square test) Citation Format: Shlomit Strulov Shachar, Michelle Leviov, Rinat Yerushalmi, Karen Drumea, Margarita Tokar, Lior Soussan-Gutman, Avital Bareket-Samish, Amir Sonnenblick, Noa Efrat Ben-Baruch, Shani Paluch-Shimon, Gil Bar Sela, Salomon M Stemmer. Differences in Recurrence Score (RS) results between primary and second primary breast cancer (BC): Exploratory analysis of the Clalit Health Services (CHS) registry [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-08-14.

Diet- and Lifestyle-Based Prediction Models to Estimate Cancer Recurrence and Death in Patients With Stage III Colon Cancer (CALGB 89803/Alliance).

Current tools in predicting survival outcomes for patients with colon cancer predominantly rely on clinical and pathologic characteristics, but increasing evidence suggests that diet and lifestyle habits are associated with patient outcomes and should be considered to enhance model accuracy. Using an adjuvant chemotherapy trial for stage III colon cancer (CALGB 89803), we developed prediction models of disease-free survival (DFS) and overall survival by additionally incorporating self-reported nine diet and lifestyle factors. Both models were assessed by multivariable Cox proportional hazards regression and externally validated using another trial for stage III colon cancer (CALGB/SWOG 80702), and visual nomograms of prediction models were constructed accordingly. We also proposed three hypothetical scenarios for patients with (1) good-risk, (2) average-risk, and (3) poor-risk clinical and pathologic features, and estimated their predictive survival by considering clinical and pathologic features with or without adding self-reported diet and lifestyle factors. Among 1,024 patients (median age 60.0 years, 43.8% female), we observed 394 DFS events and 311 deaths after median follow-up of 7.3 years. Adding self-reported diet and lifestyle factors to clinical and pathologic characteristics meaningfully improved performance of prediction models (c-index from 0.64 [95% CI, 0.62 to 0.67] to 0.69 [95% CI, 0.67 to 0.72] for DFS, and from 0.67 [95% CI, 0.64 to 0.70] to 0.71 [95% CI, 0.69 to 0.75] for overall survival). External validation also indicated good performance of discrimination and calibration. Adding most self-reported favorable diet and lifestyle exposures to multivariate modeling improved 5-year DFS of all patients and by 6.3% for good-risk, 21.4% for average-risk, and 42.6% for poor-risk clinical and pathologic features. Diet and lifestyle factors further inform current recurrence and survival prediction models for patients with stage III colon cancer.

Pembrolizumab outperforms tyrosine kinase inhibitors as adjuvant treatment in patients with high-risk renal cell carcinoma after nephrectomy

We determined the oncologic outcomes and safety profiles of adjuvant immune checkpoint inhibitors (ICIs) compared to adjuvant tyrosine kinase inhibitors (TKIs) in patients at high risk after nephrectomy for clinically nonmetastatic renal cell carcinoma (RCC). Network meta-analyses were conducted for disease-free survival (DFS), overall survival (OS), and adverse events (AEs) with placebo as the common comparator arm. Six trials (KEYNOTE-564, S-TRAC, ASSURE, PROTECT, ATLAS, and SORCE) were included in our analysis. Compared to placebo, both pembrolizumab (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.51–0.92) and pazopanib 800 mg (HR 0.69, 95% CI 0.49–0.97) were significantly associated with better DFS. Adjuvant pembrolizumab (HR 0.54, 95% CI 0.30–0.97) was significantly associated with better OS compared to TKIs (HR 0.93, 95% CI 0.83–1.04). Analysis of treatment ranking revealed that pembrolizumab was the best treatment with regard to both DFS and OS and had the lowest likelihood of any-grade and high-grade AEs in comparison to TKIs. The superior oncologic benefit of pembrolizumab and its better toxicity profile support it as the new standard of care in the adjuvant setting for nephrectomy patients at high risk of RCC relapse. Patient summaryFor patients with kidney cancer at high risk of relapse after surgical removal of their kidney, postoperative therapy with the immune checkpoint inhibitor pembrolizumab offers the best risk/benefit ratio.

Local Therapy Outcomes and Toxicity From the ATEMPT Trial (TBCRC 033): A Phase II Randomized Trial of Adjuvant Trastuzumab Emtansine Versus Paclitaxel in Combination With Trastuzumab in Women With Stage I HER2-Positive Breast Cancer

Human epidermal growth factor receptor 2 (HER2)-directed therapy improves local control among women with HER2-positive breast cancer. This retrospective analysis evaluates the safety and efficacy of radiation therapy (RT) among patients receiving adjuvant trastuzumab emtansine (T-DM1) or paclitaxel (T) plus trastuzumab (H) in the ATEMPT (Adjuvant Trastuzumab Emtansine Versus Paclitaxel in Combination With Trastuzumab) trial; Translational Breast Cancer Research Consortium (TBCRC) 033. Patients with stage I HER2-positive breast cancer were randomized 3:1 to receive adjuvant T-DM1 or TH after mastectomy or breast-conserving surgery (BCS). Breast RT was required after BCS and permitted after mastectomy. Patients receiving T-DM1 began RT after 12 weeks of therapy and received RT concurrently with T-DM1. Patients receiving TH began RT after paclitaxel, but concurrent with trastuzumab. RT records were retrospectively reviewed to determine details of radiation delivery and acute RT-related toxicity. Protocol therapy was initiated by 497 patients. Among the 299 BCS patients, 289 received whole breast RT (WBRT) and 10 partial breast. Among WBRT patients, 40.2% in the T-DM1 arm and 41.5% of TH patients received hypofractionated (≥2.5 Gy/fraction) RT. Eight mastectomy patients received RT, all conventional fractionation. Skin toxicity (grade ≥2) was seen in 33.9% of patients in the T-DM1 arm and 23.2% in the TH arm (P = .11). In conventionally fractionated WBRT patients, 44.7% had a grade ≥2 skin toxicity compared with 17.9% of patients receiving hypofractionation (P < .001). Five patients experienced pneumonitis after RT (T-DM1: n = 4, 1.0%; TH: n = 1, 0.9%). Three-year invasive disease-free survival was 97.8% for T-DM1 (95% confidence interval, 96.3-99.3) and 93.4% for TH (95% confidence interval, 88.7-98.2). Among the 18 invasive disease-free survival events, 7 were isolated locoregional recurrences (2, T-DM1; 5, TH). RT was well-tolerated when given concurrently with either T-DM1 or TH. Among BCS patients, hypofractionation resulted in lower grade ≥2 acute skin toxicity even with concurrent anti-HER2 therapy. Although follow-up was short, local recurrences were uncommon, attesting to the efficacy of HER2-directed therapy combined with RT.

Survival analysis of the randomised phase III GeparOcto trial comparing neoadjuvant chemotherapy of intense dose-dense epirubicin, paclitaxel, cyclophosphamide versus weekly paclitaxel, liposomal doxorubicin (plus carboplatin in triple-negative breast cancer) for patients with high-risk early breast cancer

BackgroundGeparOcto demonstrated that pathological complete response (pCR) of intense dose-dense epirubicin, paclitaxel and cyclophosphamide (iddEPC) was comparable to weekly paclitaxel/non-pegylated liposomal doxorubicin (plus carboplatin (PM(Cb) in triple-negative breast cancer [TNBC]) in high-risk early breast cancer (BC). Here, we report time-to-event secondary end-points. Patients and methodsPatients were randomised to receive 18 weeks of E (150 mg/m2) followed by P (225 mg/m2) followed by C (2000 mg/m2), each q2w or weekly P (80 mg/m2) plus M (20 mg/m2) plus, in TNBC, Cb (AUC 1.5). Patients with human epidermal growth factor receptor 2-positive (HER2+)BC received trastuzumab (6[loading dose 8]mg/kg q3w) and pertuzumab (420[840]mg q3w) with P and C cycles. Results945 patients started treatment (iddEPC n = 470; PM(Cb) n = 475). After a median follow-up of 47.0 (range 1.6–61.5) months, 162 (75 in iddEPC; 87 in PM(Cb)) invasive disease-free survival (iDFS) events and 79 (41 in iddEPC; 38 in PM(Cb)) deaths were reported. No significant difference was observed in 4-year iDFS (81.9% iddEPC versus 79.7% PM(Cb), HR = 1.16 [95%CI 0.85–1.59], log-rank p = 0.334) or 4-year overall survival (OS) (90.3% iddEPC versus 90.6% PM(Cb), HR = 0.90 [95%CI 0.58–1.40], log-rank p = 0.637) overall and in HER2+ and TNBC subgroups. HR+/HER2- BC patients, however, had significantly better 4-year iDFS (77.9% iddEPC versus 62.5% PM, HR = 2.11 [95%CI 1.08–4.10], log-rank p = 0.025) and 4-year OS with iddEPC (94.7% iddEPC versus 80.1% PM, HR = 3.26 [95%CI 1.06–10.00], log-rank p = 0.029). ConclusionWhile there was no difference in survival for the entire cohort, the HR+/HER2-subgroup significantly benefits from iddEPC. This supports the concept of an additional effect of NACT beyond pCR in patients with HR+/HER2- BC. ClinicalTrials.gov identifierNCT02125344.