Estimating adjuvant treatment effects in Stage II colon cancer: Comparing the synthesis of randomized clinical trial data to real-world data

There is an ongoing discussion regarding the impact of adjuvant chemotherapy in Stage II colon cancer. We therefore estimated adjuvant treatment effect in Stage II colon cancer using pooled disease-free survival (DFS) data from randomized clinical trials (RCT approach) and compared this to real-world data (RWD approach) estimates. First, we estimated the treatment effect in RCTs by (i) searching relevant trials reporting DFS data, (ii) generating patient-level data from reported DFS data and (iii) estimating treatment effect in the patient-level data. Second, the treatment effect was estimated in an observational cohort of 1,947 patients provided by the Netherlands Cancer Registry using three propensity score methods; matching, weighting and stratification. In the RCT approach, patient-level data of 4,489 patients (events: 853) were generated from seven trials which compared two of the following treatment arms: control, 5FU/LV or FOLFOX. A Cox model was used to estimate a hazard ratio (HR) of 0.77 (0.43;1.10) for 5FU/LV vs. control and 0.93 (0.72;1.15) for FOLFOX vs. 5FU/LV. In the RWD approach, HRs for any adjuvant treatment vs. control were 0.95 (0.50;1.80), 0.88 (0.24;3.21) and 1.05 (0.04;2.06) using matching, weighting and stratification, respectively. There was no significant difference with the estimates from the RCT approach (interaction test, p > 0.10). The RCT data suggest a clinically relevant benefit of adjuvant chemotherapy in terms of DFS, but the estimate did not reach statistical significance. Stratified analyses are required to evaluate whether treatment effect differs in specific subgroups.     

Germline variant burden in multidrug resistance transporters is a therapy-specific predictor of survival in breast cancer patients

Multidrug resistance due to facilitated drug efflux mediated by ATP-binding cassette (ABC) transporters is a main cause for failure of cancer therapy. Genetic polymorphisms in ABC genes affect the disposition of chemotherapeutics and constitute important biomarkers for therapeutic response and toxicity. Here we correlated germline variability in ABC transporters with disease-specific survival (DSS) in 960 breast cancer (BRCA), 314 clear cell renal cell carcinoma and 325 hepatocellular carcinoma patients. We find that variant burden in ABCC1 is a strong predictor of DSS in BRCA patients, whereas candidate polymorphisms are not associated with DSS. This association is highly drug-specific for subgroups treated with the MRP1 substrates cyclophosphamide (log-rank p = 0.0011) and doxorubicin (log-rank p = 0.0088) independent of age and tumor stage, whereas no association was found in individuals treated with tamoxifen (log-rank p = 0.13). Structural mapping of significant variants revealed multiple variants at residues involved in protein stability, cofactor stabilization or substrate binding. Our results demonstrate that BRCA patients with high variant burden in ABCC1 are less prone to respond appropriately to pharmacological therapy with MRP1 substrates, thus incentivizing the consideration of genomic germline data for precision cancer medicine.     

Effects of preoperative radiotherapy or chemoradiotherapy on postoperative pathological outcome of cervical cancer——from the large database of 46,313 cases of cervical cancer in China

ObjectiveTo investigate the effect of preoperative radiotherapy or chemoradiotherapy combined with radical surgery on pathological outcomes in cervical cancer patients.MethodsBased on a large Chinese cervical cancer database of clinical diagnosis and treatment (C4 Project), the postoperative pathological outcomes of patients who received preoperative radiotherapy or chemoradiotherapy followed by open surgery (PR group) or surgery alone (SD group) were compared.ResultsAmong the strictly selected patients, the incidence of lymph node metastasis in the PR group (n = 574) was higher than that in the SD group (231 VS 9; P < 0.001), while the incidence of vascular space invasion was lower than that in the SD group (72 VS 2041; P < 0.001). The logistic regression analysis showed that preoperative radiotherapy was a protective factor for parametrial involvement, positive surgical margins, deep cervical stromal invasion, and vascular space invasion (P < 0.05). The median number of resected lymph nodes in both groups was 18. After 1:1 case matching, the incidence of deep cervical stromal invasion and vascular space invasion was reduced by preoperative radiotherapy (292 vs 376, P < 0.001; 60 vs 106, P < 0.001). Logistic regression analysis indicated that preoperative radiotherapy was a protective factor for deep cervical stromal invasion and vascular space invasion (P < 0.05). The median numbers of resected lymph nodes in the two groups were 18 and 19, separately.ConclusionPreoperative radiotherapy can reduce both the incidence of deep cervical stromal invasion and vascular space invasion, but it cannot reduce lymph node positivity, parametrial involvement and positive surgical margins.     

Early assessment with magnetic resonance imaging for prediction of pathologic response to neoadjuvant chemotherapy in triple-negative breast cancer: Results from the phase III BrighTNess trial

IntroductionThe ability of breast magnetic resonance imaging (MRI) to predict pathologic complete response (pCR) to neoadjuvant systemic therapy (NST) varies across biological subtypes. We sought to determine how well breast MRI findings following initial treatment on the phase III BrighTNess trial correlated with pCR in patients with triple negative breast cancer (TNBC).MethodsBaseline and mid-treatment imaging and pathologic response data were available in 519 patients with stage II-III TNBC who underwent NST as per protocol. MRI complete response (mCR) was defined as disappearance of all target lesion(s) and MRI partial response (mPR) as a ≥50% reduction in the largest tumor diameter.ResultsOverall, mCR was demonstrated in 116 patients (22%), whereas 166 (32%) had mPR and 237 (46%) had stable/progressive disease (SD/PD). The positive predictive value (PPV), negative predictive value, and overall accuracy of the mid-treatment MRI for pCR were 78%, 56%, and 61%, respectively; accuracy did not differ significantly between gBRCA mutation carriers and non-carriers (52% vs. 63%, p = 0.10). When compared to patients with SD/PD, those with mPR or mCR were 3.35-fold (95% CI 2.07–5.41) more likely to have pCR at surgery. MRI response during NST was significantly associated with eligibility for breast-conserving surgery following completion of treatment (93.1% for mCR vs. 81.6% for SD/PD, p < 0.001).ConclusionsComplete response on mid-treatment MRI in the BrighTNess trial had a PPV of 78% for demonstration of pCR after completion of NST in TNBC. However, a substantial proportion of patients with mPR or SD/PD also achieved a pCR.Clinical trial registrationNCT02032277.     

Wire guided localisation for targeted axillary node dissection is accurate in axillary staging in node positive breast cancer following neoadjuvant chemotherapy

AimThis study investigated whether wire localisation of the histologically proven positive, clipped axillary lymph node (ALN) with subsequent targeted axillary dissection (TAD) following neoadjuvant chemotherapy (NACT) improves axillary staging in breast cancer.Materials and methodsWe performed a retrospective review of patients with primary breast cancer and core biopsy proven metastatic ALNs, that had an excellent nodal radiological response following NACT, treated at our centre between January 2016 and December 2018. The initial cohort of patients (Group 1) underwent sentinel lymph node biopsy (SLNB), with a minimum of three nodes were sampled. The subsequent cohort (Group 2) had a marker clip inserted in the metastatic ALN prior to NACT. This cohort underwent wire guided excision of the clipped node in addition to SLNB, with a minimum of three nodes sampled.ResultsA total of 47 patients were identified. Group 1 comprised 22 patients with a sentinel lymph node (SLN) identification rate (IR) of 95%. 25 patients (Group 2) underwent wire guided clip location and the SLN IR was 100% with a 92% clipped node IR. Evidence of pathological complete response (pCR) in the clipped node was associated with pCR in other nodes.ConclusionTargeted axillary dissection is a feasible technique following excellent response to NACT in selected patients with limited volume ALN metastasis, at diagnosis. The identification of the positive ALN during surgery is vital and the IR can be improved by clipping the node prior to NACT and wire guided localisation at the time of surgery.     

Adjuvant chemotherapy in patients with colorectal cancer. Is there a role in the older adult?

As global life expectancy has increased in most countries, there is a rising percentage of patients over 65 years old being diagnosed with colorectal cancer. Despite an increase in the incidence and prevalence of colorectal cancer in older adults, this cohort receives adjuvant therapy at a decreased rate due to anticipated intolerance. The presumed limitations seem to be based on chronologic age, competing life limiting diagnoses, and the paucity of data studying this population in major clinical trials. This review explores the data regarding disparities in the treatment of older patients with colorectal cancer, safety and efficacy of adjuvant therapy, and newer tools to make decisions based on the biologic age, rather than chronologic age, of the patient.     

Prevalence and clinical impact of TP53 germline mutations in Chinese women with breast cancer

The prevalence and clinical relevance of TP53 germline mutations in a large unselected breast cancer series are largely unknown. Here, we determined TP53 germline mutations in a large cohort of 10,053 unselected breast cancer patients through multigene panel-based next-generation and/or Sanger sequencing assays. We found that 0.5% of patients (50 cases) carried a pathogenic TP53 germline mutation in this large series of 10,053 unselected breast cancer patients, and the prevalence of TP53 germline mutation was 3.8% in very early onset breast cancer (age ≤30 years) in this large cohort. TP53 mutation carriers were significantly more likely to have early onset cancer (p < 0.001) and bilateral breast cancer (p = 0.03), they and were significantly more likely to respond to carboplatin-based neoadjuvant chemotherapy compared to anthracycline- or taxane-based regimen in terms of pathologic complete response (50% vs. 0%, p = 0.006). At the median follow-up of 54 months, TP53 mutation was an independent unfavorable factor for recurrence-free survival (RFS), distant recurrence-free survival (DRFS), and overall survival (OS) (RFS, adjusted hazard ratio [HR]: 2.24, 95% confidence interval [CI]: 1.15–4.33, p = 0.02; DRFS, adjusted HR: 2.73, 95% CI: 1.41–5.30, p = 0.003; OS, adjusted HR: 4.60, 95% CI: 2.26–9.41, p < 0.001) in multivariate analyses. Our study suggested that TP53 germline mutations occur more frequently in very early onset unselected breast cancer patients; and TP53 germline mutation carriers have a very poor survival and may benefit from carboplatin-based neoadjuvant chemotherapy in unselected breast cancer patients.     

Factors of the evolution of fatigue dimensions in patients with breast cancer during the 2 years after surgery

Women with breast cancer are increasingly being cured of the disease but fatigue remains the most frequently reported symptom. The aims of our study were to identify distinct trajectories in four fatigue dimensions during 2 years after breast cancer surgery and to explore the demographic, clinical and personality characteristics associated with these profiles. We included women from the prospective longitudinal multicenter FATSEIN cohort in France. They completed the Multidimensional Fatigue Inventory for nine follow-ups over 24 months after surgery. A group-based trajectory model identified distinct trajectories in each fatigue dimension. Multinomial logistic regression determined the factors associated with each profile. From the 459 women followed, 3–5 fatigue trajectories were revealed in each fatigue dimension, from its absence to its severest degree. In our multivariate analysis, the risk of severe fatigue was decreased in all dimensions by a high quality of life before surgery (measured by the European Organization for Research and Treatment of Cancer 30-item QoL questionnaire; e.g., for general and physical fatigue: OR = 0.93, 95% CI 0.91, 0.96), especially a high physical and emotional functions for general and physical fatigue, and a high cognitive function for mental fatigue. Both severe mental fatigue and severely reduced motivation worsened with low optimism before surgery (e.g., for mental fatigue: OR = 0.93, 95% CI 0.89, 0.97). Severely reduced activities increased by having chemotherapy (OR = 9.41, 95% CI 2.28, 38.79). Targeting women at risk for severe fatigue can provide early preventive and curative treatment and appropriate psychological support.