Long-term risk of subsequent ipsilateral lesions after surgery with or without radiotherapy for ductal carcinoma in situ of the breast

Background Radiotherapy (RT) following breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS) reduces ipsilateral breast event rates in clinical trials. This study assessed the impact of DCIS treatment on a 20-year risk of ipsilateral DCIS (iDCIS) and ipsilateral invasive breast cancer (iIBC) in a population-based cohort.Methods The cohort comprised all women diagnosed with DCIS in the Netherlands during 1989–2004 with follow-up until 2017. Cumulative incidence of iDCIS and iIBC following BCS and BCS + RT were assessed. Associations of DCIS treatment with iDCIS and iIBC risk were estimated in multivariable Cox models.Results The 20-year cumulative incidence of any ipsilateral breast event was 30.6% (95% confidence interval (CI): 28.9–32.6) after BCS compared to 18.2% (95% CI 16.3–20.3) following BCS  +  RT. Women treated with BCS compared to BCS + RT had higher risk of developing iDCIS and iIBC within 5 years after DCIS diagnosis (for iDCIS: hazard ratio (HR)_age < 50 3.2 (95% CI 1.6–6.6); HR_{age ≥ 50} 3.6 (95% CI 2.6–4.8) and for iIBC: HR_age<50 2.1 (95% CI 1.4–3.2); HR_{age ≥ 50} 4.3 (95% CI 3.0–6.0)). After 10 years, the risk of iDCIS and iIBC no longer differed for BCS versus BCS + RT (for iDCIS: HR_age < 50 0.7 (95% CI 0.3–1.5); HR_{age ≥ 50} 0.7 (95% CI 0.4–1.3) and for iIBC: HR_age < 50 0.6 (95% CI 0.4–0.9); HR_{age ≥ 50} 1.2 (95% CI 0.9–1.6)).Conclusion RT is associated with lower iDCIS and iIBC risk up to 10 years after BCS, but this effect wanes thereafter.Subject terms: Radiotherapy, Outcomes research, Breast cancer, Cancer epidemiology     

Impact of timing of adjuvant chemotherapy for early breast cancer: the Royal Marsden Hospital experience

Background The optimal time to deliver adjuvant chemotherapy has not been defined.Methods A retrospective study of consecutive patients receiving adjuvant anthracycline and/or taxane 1993–2010. Primary endpoint included 5-year disease-free survival (DFS) in patients commencing chemotherapy <31 versus ≥31 days after surgery. Secondary endpoints included 5-year overall survival (OS) and sub-group analysis by receptor status.Results We identified 2003 eligible patients: 1102 commenced chemotherapy <31 days and 901 ≥31 days after surgery. After a median follow-up of 115 months, there was no difference in 5-year DFS rate with chemotherapy <31 compared to ≥31 days after surgery in the overall population (81 versus 82% hazard ratio (HR) 1.15, 95% confidence interval (95% CI) 0.92–1.43, p = 0.230). The 5-year OS rate was similar in patients who received chemotherapy <31 or ≥31 days after surgery (90 versus 91%, (HR 1.21, 95% CI 0.89–1.64, p = 0.228). For 250 patients with triple-negative breast cancer OS was significantly worse in patients who received chemotherapy ≥31 versus <31 days (HR = 2.18, 95% CI 1.11–4.30, p = 0.02).Discussion Although adjuvant chemotherapy ≥31 days after surgery did not affect DFS or OS in the whole study population, in TN patients, chemotherapy ≥31 days after surgery significantly reduced 5-year OS; therefore, delays beyond 30 days in this sub-group should be avoided.Subject terms: Chemotherapy, Breast cancer     

Using drug scheduling to manage adverse events associated with hedgehog pathway inhibitors for basal cell carcinoma

Basal cell carcinoma (BCC) is the most common malignancy and form of skin cancer worldwide; advanced BCC, either as locally advanced BCC (laBCC) or metastatic BCC (mBCC), can cause substantial tissue invasion and morbidity. Until the recent availability of the hedgehog pathway inhibitors (HHIs) sonidegib and vismodegib, treatment options for advanced BCC were limited. These agents demonstrate efficacy in patients with laBCC and mBCC; however, the adverse events (AEs) associated with these agents can lead to treatment interruption or discontinuation and reduced quality of life, all of which significantly impact long-term adherence to therapy, which might affect clinical outcome. Given that most AEs are class-related effects, switching HHIs does not appear to lead to a significantly different AE profile, underscoring the importance of maintaining patients on their first HHI. Interrupting treatment of sonidegib and vismodegib does not appear to undermine the efficacy of these agents and is therefore a practical option to manage AEs in order to maintain continued treatment and disease control.     

Adenoma characteristics associated with post-polypectomy proximal colon cancer incidence: a retrospective cohort study

Background Colorectal cancer (CRC) screening is less effective at reducing cancer incidence in the proximal colon compared to the distal colorectum. We aimed to identify adenoma characteristics associated with proximal colon cancer (PCC).Methods Endoscopy and pathology data for patients with ≥1 adenoma detected at baseline colonoscopy were obtained from 17 UK hospitals between 2001 and 2010. Multivariable Cox regression models were used to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for PCC, and, for comparison, distal CRC incidence, by adenoma characteristics.Results Among 18,431 patients, 152 and 105 developed PCC and distal CRC, respectively, over a median follow-up of 9.8 years. Baseline adenoma characteristics positively associated with PCC incidence included number (≥3 vs. < 3: aHR 2.10, 95% CI: 1.42–3.09), histology (tubulovillous/villous vs. tubular: aHR 1.61, 95% CI: 1.10–2.35) and location (any proximal vs. distal only: aHR 1.70, 95% CI: 1.20–2.42), for which there was borderline evidence of heterogeneity by subsite (p = 0.055). Adenoma dysplasia (high vs. low grade) was associated with distal CRC (aHR 2.42, 95% CI: 1.44–4.04), but not PCC (p-heterogeneity = 0.023).Conclusions Baseline adenoma number, histology and proximal location were independently associated with PCC and may be important to identify patients at higher risk for post-polypectomy PCC.Subject terms: Epidemiology, Cancer epidemiology, Cancer screening, Colorectal cancer, Cancer prevention     

β-blockers and breast cancer survival by molecular subtypes: a population-based cohort study and meta-analysis

Background The association between use of β-blockers and breast cancer (BC) prognosis has been investigated in several observational studies, with conflicting results. We performed a nationwide cohort study and a meta-analysis to investigate the association, and assess if it varied between molecular subtypes of BC.Methods We identified women aged ≥50 years with BC diagnosed between 2004 and 2018 in Norway. We used Cox regression models to estimate the association between β-blocker use at diagnosis and BC-specific survival, overall and by molecular subtype. We performed a meta-analysis of observational studies that reported molecular subtype-specific estimates of this association.Results We included 30,060 women, of which 4461 (15%) used β-blockers. After a median follow-up of 5.1 years, 2826 (9%) died of BC. Overall, β-blocker use was not associated with BC-specific survival (hazard ratio [HR] = 1.07; 95% confidence interval [CI]: 0.97–1.19). We found an association only in triple-negative BC (TNBC) patients (HR = 0.66; 95% CI: 0.47–0.91). This was confirmed in the meta-analysis: β-blocker use was associated with progression/recurrence-free (HR = 0.58; 95% CI: 0.38–0.89) and BC-specific survival (HR = 0.74; 95% CI: 0.55–1.00) in TNBC patients only.Conclusion In our cohort of BC patients and in the meta-analysis, β-blocker use was associated with prolonged BC-specific survival only in TNBC patients.Subject terms: Cancer epidemiology, Breast cancer     

Exploring racial disparities in treatment patterns and outcomes for patients with multiple myeloma using real world data

This retrospective observational study evaluated racial disparities among Black and White patients with multiple myeloma (MM). We included patients from a longitudinal de-identified EHR-derived database who had ≥2 visits recorded on or after 1/1/2011, documented treatment, and race listed as White or Black. Black patients (n = 1172) were more likely female (54.8%/42.9%) and younger (<65 years, 40.8%/30.8%) than White patients (n = 4637). Unadjusted median real-world overall survival (rwOS) indexed to first-line of therapy (LOT) was 64.6 months (95% CI: 57.8–74.0) for Blacks and 54.5 months (95% CI: 50.9–56.2) for Whites. Adjusted rwOS estimates (for sex, age at index date, and practice type) to either first- (aHR = 0.94; 95% CI: 0.84–1.06) or second-LOT (aHR = 0.90; 95% CI: 0.77–1.05) were similar. Unadjusted derived response rate (dRR) during first-LOT was 84.8% (95% CI: 80.7–88.1) for Blacks and 86.9% (95% CI: 85.0–88.5) for Whites (odds ratio [OR] = 0.78 [95% CI: 0.57–1.10]); in second-LOT, 67.2% (95% CI: 58.4–75.0) for Blacks and 72.4% (95% CI: 68.1–76.3) for Whites (OR = 0.72 [95% CI: 0.46–1.13]). High representation of Black patients enabled this robust analysis, albeit with limitations inherent to the observational data source, the retrospective design, and the analytic use of newly derived endpoints requiring further validation.Subject terms: Epidemiology, Myeloma     

Sugar-sweetened beverage,artificially sweetened beverage and sugar intake and colorectal cancer survival

Background The influence of a high sugar diet on colorectal cancer (CRC) survival is unclear.Methods Among 1463 stage I–III CRC patients from the Nurses’ Health Study and Health Professionals Follow-up Study, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for CRC-specific and all-cause mortality in relation to intake of post-diagnosis sugar-sweetened beverages (SSB), artificially sweetened beverages (ASB), fruit juice, fructose and other sugars.Results Over a median 8.0 years, 781 cases died (173 CRC-specific deaths). Multivariable-adjusted HRs for post-diagnosis intake and CRC-specific mortality were 1.21 (95% CI: 0.87–1.68) per 1 serving SSBs per day (serving/day) and 1.24 (95% CI: 0.95–1.63) per 20 grams fructose per day. Significant positive associations for CRC-specific mortality were primarily observed ≤5 years from diagnosis (HR per 1 serving/day of SSBs = 1.59, 95% CI: 1.06–2.38). Significant inverse associations were observed between ASBs and CRC-specific and all-cause mortality (HR for ≥5 versus <1 serving/week = 0.44, 95% CI: 0.26–0.75 and 0.70, 95% CI: 0.55–0.89, respectively).Conclusions Higher post-diagnosis intake of SSBs and sugars may be associated with higher CRC-specific mortality, but only up to 5 years from diagnosis, when more deaths were due to CRC. The inverse association between ASBs and CRC-specific mortality warrants further examination.Subject terms: Epidemiology, Cancer epidemiology, Colorectal cancer, Nutrition     

Early radiologic signal of responsiveness to immune checkpoint blockade in microsatellite-stable/mismatch repair-proficient metastatic colorectal cancer

Background Immune checkpoint blockade (ICB) results in radiologic tumour response dynamics that differ from chemotherapy efficacy measures and require an early signal of clinical utility.Methods Previously untreated, unresectable microsatellite-stable (MSS)/mismatch repair-proficient (pMMR) colorectal cancer (CRC) patients were randomly assigned to the oxaliplatin-based Nordic FLOX regimen (control arm) or repeat sequential two FLOX cycles and two ICB cycles (experimental arm). The radiologic response was assessed every 8 weeks. In this post hoc analysis, we explored early target lesion (TL) dynamics as indicator of ICB responsiveness. Progression-free survival (PFS) was the primary endpoint.Results Using a landmark analysis approach, we categorised experimental-arm patients into ≥10% (N = 19) or <10% (N = 16) TL reduction at the first post-baseline response assessment. Median PFS for the groups was 16.0 (95% confidence interval (CI), 12.3–19.7) and 3.9 months (95% CI, 2.3–5.5), respectively, superior and inferior (both P < 0.01) to the median PFS of 9.8 months (95% CI, 4.9–14.7) for control arm patients (N = 31).Conclusions Radiologic TL reduction of ≥10% at the first post-baseline response assessment identified patients with ICB-responsive metastatic MSS/pMMR-CRC. This pragmatic measure may be used to monitor patients in investigational ICB schedules, enabling early treatment adaptation for unresponsive cases.Trial registration ClinicalTrials.gov number, {"type":"clinical-trial","attrs":{"text":"NCT03388190","term_id":"NCT03388190"}}NCT03388190 (02/01/2018).Subject terms: Colorectal cancer, Prognostic markers, Cancer imaging, Prognostic markers     

Long-term risk of subsequent cancer incidence among hereditary and nonhereditary retinoblastoma survivors

Background Increased sarcoma and melanoma risks after hereditary retinoblastoma are well established, whereas less is known about epithelial subsequent malignant neoplasms (SMNs) and risks for multiple (≥2) SMNs.Methods Leveraging long-term follow-up and detailed histologic information, we quantified incident SMN risk among 1128 hereditary and 924 nonhereditary retinoblastoma survivors (diagnosed 1914–2006; follow-up through 2016). Standardised incidence ratios (SIRs) compared cancer risk after retinoblastoma relative to the general population. We estimated cumulative incidence accounting for competing risk of death.Results Hereditary survivors had statistically significantly increased SMN risk (N = 239; SIR = 11.9; 95% confidence interval [CI] 10.4–13.5), with SIRs >80-fold for sarcomas, nasal cavity tumours and pineoblastoma. Significantly increased risks were also observed for melanoma and central nervous system, oral cavity and breast SMNs (SIRs = 3.1–17), but not the uterus, kidney, lung, bladder, pancreas or other types. Cumulative incidence 50 years following hereditary retinoblastoma was 33.1% (95% CI 29.0–37.2) for a first SMN and 6.0% (95% CI 3.8–8.2) for a second SMN. SMN risk was not increased after nonhereditary retinoblastoma (N = 25; SIR = 0.8; 95% CI 0.5–1.2).Conclusion Beyond the established sarcoma and melanoma risks after hereditary retinoblastoma, we demonstrate increased risk for a more limited number of epithelial malignancies than previously suggested. Cumulative incidence estimates emphasise long-term SMN burden after hereditary retinoblastoma.Subject terms: Cancer epidemiology, Eye cancer, Paediatric cancer     

Prognostic and predictive significance of nuclear HIF1α expression in locally advanced HNSCC patients treated with chemoradiation with or without nimotuzumab

Background Anti-EGFR-based therapies have limited success in HNSCC patients. Predictive biomarkers are greatly needed to identify the patients likely to be benefited from these targeted therapies. Here, we present the prognostic and predictive association of biomarkers in HPV-negative locally advanced (LA) HNSCC patients.Methods Treatment-naive tumour tissue samples of 404 patients, a subset of randomised Phase 3 trial comparing cisplatin radiation (CRT) versus nimotuzumab plus cisplatin radiation (NCRT) were analysed to evaluate the expression of HIF1α, EGFR and pEGFR by immunohistochemistry and EGFR gene copy change by FISH. Progression-free survival (PFS), locoregional control (LRC) and overall survival (OS) were estimated by Kaplan–Meier method. Hazard ratios were estimated by Cox proportional hazard models.Results Baseline characteristics of the patients were balanced between two treatment groups (CRT vs NCRT) and were representative of the trial cohort. The median follow-up was of 39.13 months. Low HIF1α was associated with better PFS [HR (95% CI) = 0.62 (0.42–0.93)], LRC [HR (95% CI) = 0.56 (0.37–0.86)] and OS [HR (95% CI) = 0.63 (0.43–0.93)] in the CRT group. Multivariable analysis revealed HIF1α as an independent negative prognostic biomarker. For patients with high HIF1α, NCRT significantly improved the outcomes [PFS:HR (95% CI) = 0.55 (0.37–0.82), LRC:HR (95% CI) = 0.55 (0.36–0.85) and OS:HR (95% CI) = 0.54 (0.36–0.81)] compared to CRT. While in patients with low HIF1α, no difference in the clinical outcomes was observed between treatments. Interaction test suggested a predictive value of HIF1α for OS (P = 0.008).Conclusions High HIF1α expression is a predictor of poor clinical response to CRT in HPV-negative LA-HNSCC patients. These patients with high HIF1α significantly benefited with the addition of nimotuzumab to CRT.Clinical trial registration Registered with the Clinical Trial Registry of India (Trial registration identifier—CTRI/2014/09/004980).Subject terms: Tumour biomarkers, Head and neck cancer, Tumour biomarkers, Head and neck cancer, Predictive markers     

Oral antibiotic use and early-onset colorectal cancer: findings from a case-control study using a national clinical database

Background Antibiotic-induced gut dysbiosis has been associated with colorectal cancer (CRC) in older adults. This study will investigate whether an association exists between antibiotic usage and early-onset colorectal cancer (CRC), and also evaluate this in later-onset CRC for comparison.Methods A case-control study was conducted using primary care data from 1999–2011. Analysis were conducted separately in early-onset CRC cases (diagnosed < 50 years) and later-onset cases (diagnosed ≥ 50 years). Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals (CI) for the associations between antibiotic exposure and CRC by tumour location, adjusting for comorbidities.Results Seven thousands nine hundred and three CRC cases (445 aged <50 years) and 30,418 controls were identified. Antibiotic consumption was associated with colon cancer in both age-groups, particularly in the early-onset CRC cohort (<50 years: adjusted Odds Ratio (OR_adj) 1.49 (95% CI 1.07, 2.07), p = 0·018; ≥50 years (OR_adj (95% CI) 1.09 (1.01, 1.18), p = 0·029). Antibiotics were not associated with rectal cancer (<50 years: OR_adj (95% CI) 1.17 (0.75, 1.84), p = 0.493; ≥50 years: OR_adj (95% CI) 1.07 (0.96, 1.19), p = 0.238).Conclusion Our findings suggest antibiotics may have a role in colon tumour formation across all age-groups.Subject terms: Cancer epidemiology, Colon cancer, Colon cancer, Cancer epidemiology     

Impact of age on sorafenib outcomes in hepatocellular carcinoma: an international cohort study

Background There is no consensus on the effect of sorafenib dosing on efficacy and toxicity in elderly patients with hepatocellular carcinoma (HCC). Older patients are often empirically started on low-dose therapy with the aim to avoid toxicities while maximising clinical efficacy. We aimed to verify whether age impacts on overall survival (OS) and whether a reduced starting dose impacts on OS or toxicity experienced by the elderly.Methods In an international, multicentre cohort study, outcomes for those aged <75 or ≥75 years were determined while accounting for common prognostic factors and demographic characteristics in univariable and multivariable models.Results Five thousand five hundred and ninety-eight patients were recruited; 792 (14.1%) were aged ≥75 years. The elderly were more likely to have larger tumours (>7 cm) (39 vs 33%, p < 0.01) with preserved liver function (67 vs 57.7%) (p < 0.01). No difference in the median OS of those aged ≥75 years and <75 was noted (7.3 months vs 7.2 months; HR 1.00 (95% CI 0.93–1.08), p = 0.97). There was no relationship between starting dose of sorafenib 800 mg vs 400 mg/200 mg and OS between those <75 and ≥75 years. The elderly experienced a similar overall incidence of grade 2–4 sorafenib-related toxicity compared to <75 years (63.5 vs 56.7%, p = 0.11). However, the elderly were more likely to discontinue sorafenib due to toxicity (27.0 vs 21.6%, p < 0.01). This did not vary between different starting doses of sorafenib.Conclusions Clinical outcomes in the elderly is equivalent to patients aged <75 years, independent of dose of sorafenib prescribed.Subject terms: Targeted therapies, Hepatocellular carcinoma     

Association between post-treatment circulating biomarkers of inflammation and survival among stage II–III colorectal cancer patients

Background Biomarker studies on colorectal cancer (CRC) prognosis are limited to pre-diagnostic or pre-operative measures. Post-treatment biomarkers are not well understood for their associations with CRC survival.Methods We included 306 eligible incident stage II–III CRC cases from the population-based Seattle Colon Cancer Family Registry. Concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), adiponectin, and leptin were measured using post-treatment plasma samples. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and CRC-specific mortality were calculated using Cox proportional hazard models.Results Elevated levels of CRP, IL-6, MCP-1, and adiponectin were significantly associated with a higher risk of all-cause mortality within 10 years post blood draw with HRs (95% CI) of 1.32 (1.10–2.59), 2.72 (2.07–3.56), 1.97 (1.18–3.28) and 1.71 (1.14–2.58), respectively. IL-6 and adiponectin had a dose–response effect (P_trend < 0.0001). For CRC-specific mortality, we observed positive associations for CRP (HR = 1.75, 95% CI: 1.2–2.56), IL-6 (HR = 5.02, 95% CI: 2.92–8.59), MCP-1 (HR = 3.78, 95% CI: 1.41–10.08), and adiponectin (HR = 3.16, 95% CI: 1.27–7.86), and inverse association for leptin (HR = 0.44, 95% CI: 0.29–0.68) within the first year of blood draw, whereas the association for IL-6 remained statistically significant over 10 years.Conclusion Our results support the role of chronic inflammation in CRC progression and suggested several post-treatment inflammatory biomarkers, particularly IL-6, are promising prognostic markers for stage II–III CRC patients.Subject terms: Prognostic markers, Colorectal cancer, Epidemiology     

Phase II Study of Panitumumab Monotherapy in Chemotherapy‐Naïve Frail or Elderly Patients with Unresectable RAS Wild‐Type Colorectal Cancer: OGSG 1602

Lessons Learned

• Panitumumab monotherapy showed favorable efficacy and feasibility in the treatment of frail or elderly patients with RAS wild‐type unresectable colorectal cancer.
• It is especially effective for left‐sided tumors; therefore, panitumumab as first‐line treatment could be an additional therapeutic option for frail elderly patients, particularly in those who are unsuitable for upfront oxaliplatin‐based or irinotecan‐based combination regimens.

BackgroundFirst‐line panitumumab monotherapy is expected to be well tolerated and improve survival in patients ineligible for intensive chemotherapy. However, its safety and efficacy in chemotherapy‐naïve frail or elderly patients with unresectable RAS wild‐type (WT) colorectal cancer (CRC) have not been studied. The aim of this phase II trial was to evaluate the efficacy and safety of panitumumab as first‐line treatment.MethodsWe conducted a multicenter phase II study on patients aged ≥76 years or ≥65 years considered unsuitable for intensive chemotherapy. Panitumumab 6 mg/kg of intravenous infusion was administered every 2 weeks. The primary endpoint was disease control rate (DCR). Secondary endpoints included progression‐free survival (PFS), overall survival (OS), response rate (RR), time to treatment failure (TTF), and incidence of grade 3 or 4 toxicities.ResultsThirty‐six patients (median age: 81 [range, 67–88] years) were enrolled between February 2017 and August 2018. Two patients were excluded from the analysis of efficacy: one from lack of image examination at baseline and the other from lack of a measurable lesion. Thirty‐three (91.6%) patients had a performance status (PS) of 0 or 1, whereas two (5.6%) patients and one (2.8%) patient had a PS of 2 and 3, respectively. Twenty‐eight patients (77.8%) had left‐sided CRC, whereas eight (22.2%) had right‐sided CRC. The RR was 50.0% (95% confidence interval [CI], 32.4–67.6), including three patients (8.8%) who had complete responses. A total of 26.5% had stable diseases, resulting in a DCR of 76.5% (90% CI, 61.5–87.7). The RR of patients with left‐ and right‐sided tumors was 65.4% (95% CI, 44.3–82.8) and 0.0% (95% CI, 0.0–36.9), respectively. Major grade 3 or 4 nonhematologic toxicities were rash (n = 6, 16.7%), hypomagnesemia (n = 4, 11.1%), fatigue (n = 3, 8.3%), paronychia (n = 2, 5.6%), and hyponatremia (n = 2, 5.6%). The only grade 3 hematologic toxicity was neutropenia (n = 1, 2.8%).ConclusionPanitumumab monotherapy showed favorable efficacy and feasibility in frail or elderly patients with RAS WT unresectable CRC. Survival analysis including OS, PFS, and TTF is currently in progress.     

Metformin plus lrinotecan in patients with refractory colorectal cancer: a phase 2 clinical trial

Background Patients with refractory colorectal (CRC) cancer have few treatment options. This trial tests the combination of metformin and irinotecan in this setting.Methods A phase 2 single-arm trial was conducted, patients received metformin 2500 mg orally a day plus irinotecan 125 mg/m² intravenously weekly D1 and D8 every 21 days. The primary endpoint was the disease control rate according to the Response Evaluation Criteria in Solid Tumors version 1.1 at 12 weeks.Results Between December 2015 and January 2018, 41 patients were enrolled. Seventeen patients (41%) met the primary endpoint of disease control in 12 weeks; hence, the study was deemed positive. The median progression-free survival was 3.3 months (CI 95%, 2.0–4.5 months), and the median overall survival was 8.4 months (CI 95%, 5.9–10.8 months). Both mutation RAS status and disease control at 12 weeks impacted overall survival in the multivariate model (HR 2.28, CI 95%, 1.12–4.7, p = 0.02; and HR 0.21, CI 95%, 0.08–0.5, p = 0.001, respectively). The most common adverse event was diarrhoea (29.2% grade 3).Conclusions In this trial, metformin plus irinotecan demonstrated disease control in patients with refractory CRC. Further trials with optimised diarrhoea control are needed to confirm these results.Subject terms: Drug development, Chemotherapy     

The Effect of Duration of Lenalidomide Maintenance and Outcomes of Different Salvage Regimens in Patients with Multiple Myeloma (MM)

The optimal duration of lenalidomide maintenance post-autologous stem cell transplant (ASCT) in Multiple Myeloma (MM), and choice of therapy at relapse post-maintenance, need further evaluation. This retrospective study assessed outcomes of patients with MM (n = 213) seen at Mayo Clinic, Rochester between 1/1/2005–12/31/2016 who received lenalidomide maintenance post-ASCT. The median PFS was 4 (95% CI: 3.4, 4.5) years from diagnosis of MM; median OS was not reached (5-year OS: 77%). Excluding patients who stopped lenalidomide maintenance within 3 years due to progression on maintenance, ≥3 years of maintenance had a superior 5-year OS of 100% vs. 85% in <3 years (p = 0.011). Median PFS was 7.2 (95% CI: 6, 8.5) years in ≥3 years vs. 4.4 (95% CI: 4.3, 4.5) years in <3 years (p < 0.0001). Lenalidomide refractoriness at first relapse was associated with inferior PFS2 [8.1 (95% CI: 6.4, 9.9) months vs. 19.9 (95% CI: 9.7, 30.2; p = 0.002) months in nonrefractory patients]. At first relapse post-maintenance, median PFS2 was superior with daratumumab-based regimens [18.4 (95% CI: 10.9, 25.9) months] versus regimens without daratumumab [8.9 (95% CI: 5.5, 12.3) months; p = 0.006]. Daratumumab + immunomodulatory drugs had superior median PFS2 compared to daratumumab + bortezomib [NR vs 1 yr (95% CI: 0.5, 1.5); p = 0.004].Subject terms: Myeloma, Myeloma     

The impact of anthracyclines in intermediate and high-risk HER2-negative early breast cancer—a pooled analysis of the randomised clinical trials PlanB and SUCCESS C

Background Anthracycline/cyclophosphamide-taxane-containing chemotherapy (AC-T) is the standard of care in the adjuvant treatment of HER2-negative early breast cancer (EBC), but recent studies suggest omission of anthracyclines for reduced toxicity without compromising efficacy.Methods Based on individual patient data (n = 5924) pooled from the randomised Phase III trials PlanB and SUCCESS C, we compared disease-free survival (DFS) and overall survival (OS) between intermediate to high-risk HER2-negative EBC-patients treated with either six cycles of docetaxel/cyclophosphamide (TC6) or an AC-T regime using univariable and adjusted multivariable Cox regression models.Results AC-T conferred no significant DFS or OS advantage in univariable (DFS: hazard ratio (HR) for TC vs. AT 1.05, 95% confidence interval (CI): 0.89–1.24, P = 0.57; OS: HR 1.00, 95% CI: 0.80–1.26, P = 1.00) and adjusted multivariable analysis (DFS: HR 1.01, 95% CI: 0.86–1.19, P = 0.91; OS: HR 0.97, 95% CI: 0.77–1.22, P = 0.79). Patients receiving TC6 had significantly fewer grade 3–4 adverse events. Exploratory subgroup analysis showed that AC-T was associated with significantly better DFS and OS in pN2/3 patients, specifically in those with lobular histology.Conclusion For most patients with HER2-negative EBC, AC-T is not associated with a survival benefit compared to TC6. However, patients with lobular pN2/pN3 tumours seem to benefit from anthracycline-containing chemotherapy.Subject terms: Randomized controlled trials, Breast cancer     

Molecular subtype-specific efficacy of anti-EGFR therapy in colorectal cancer is dependent on the chemotherapy backbone

Background Patient selection for addition of anti-EGFR therapy to chemotherapy for patients with RAS and BRAF wildtype metastatic colorectal cancer can still be optimised. Here we investigate the effect of anti-EGFR therapy on survival in different consensus molecular subtypes (CMSs) and stratified by primary tumour location.Methods Retrospective analyses, using the immunohistochemistry-based CMS classifier, were performed in the COIN (first-line oxaliplatin backbone with or without cetuximab) and PICCOLO trial (second-line irinotecan with or without panitumumab). Tumour tissue was available for 323 patients (20%) and 349 (41%), respectively.Results When using an irinotecan backbone, anti-EGFR therapy is effective in both CMS2/3 and CMS4 in left-sided primary tumours (progression-free survival (PFS): HR 0.44, 95% CI 0.26–0.75, P = 0.003 and HR 0.12, 95% CI 0.04–0.36, P < 0.001, respectively) and in CMS4 right-sided tumours (PFS HR 0.17, 95% CI 0.04–0.71, P = 0.02). Efficacy using an oxaliplatin backbone was restricted to left-sided CMS2/3 tumours (HR 0.57, 95% CI 0.36–0.96, P = 0.034).Conclusions The subtype-specific efficacy of anti-EGFR therapy is dependent on the chemotherapy backbone. This may provide the possibility of subtype-specific treatment strategies for a more optimal use of anti-EGFR therapy.Subject terms: Colorectal cancer, Chemotherapy, Metastasis