The whole-genome sequencing of prospectively collected tissue biopsies from 442 patients with metastatic breast cancer reveals that, compared to primary breast cancer, tumor mutational burden ...doubles, the relative contributions of mutational signatures shift and the mutation frequency of six known driver genes increases in metastatic breast cancer. Significant associations with pretreatment are also observed. The contribution of mutational signature 17 is significantly enriched in patients pretreated with fluorouracil, taxanes, platinum and/or eribulin, whereas the de novo mutational signature I identified in this study is significantly associated with pretreatment containing platinum-based chemotherapy. Clinically relevant subgroups of tumors are identified, exhibiting either homologous recombination deficiency (13%), high tumor mutational burden (11%) or specific alterations (24%) linked to sensitivity to FDA-approved drugs. This study provides insights into the biology of metastatic breast cancer and identifies clinically useful genomic features for the future improvement of patient management.
Abstract Background As neoadjuvant chemotherapy (NAC) is increasingly used to downstage patients with breast cancer, the timing of the sentinel node (SN) biopsy has become an important issue. This ...review was conducted to determine the accuracy of SN biopsy following NAC. Methods We searched Medline, Embase and Cochrane databases from 1993 to February 2009 for studies on patients with invasive breast cancer who underwent SN biopsy after NAC followed by an axillary lymph node dissection (ALND). Results Of 574 eligible studies, 27 were included in this review with a total study population of 2148 patients. The pooled SN identification rate was 90.9% (95% confidence interval (CI) = 88.0–93.1%) and the false-negative rate was 10.5% (95% CI = 8.1–13.6%). Negative predictive value and accuracy after NAC were 89.0% (95% CI = 85.1–92.1%) and 94.4% (95% CI = 92.6–95.8%), respectively. The reported SN success rates were heterogeneous and several variables were reported to be associated with decreased SN accuracy, i.e. initially positive clinical nodal status. Conclusions There is a potential role for SN biopsy following NAC which could be considered on an individual basis. However, there is insufficient evidence to recommend this as a standard procedure. Further research with subgroup analysis using variables reported to be associated with decreased SN accuracy is required in order to clearly define its value in the subgroups of breast cancer patients.
During the COVID-19 pandemic recommendations were made to adapt cancer care. This population-based study aimed to investigate possible differences between the treatment of patients with metastatic ...cancer before and during the pandemic by comparing the initial treatments in five COVID-19 periods (weeks 1-12 2020: pre-COVID-19, weeks 12-20 2020: 1st peak, weeks 21-41 2020: recovery, weeks 42-53 2020: 2nd peak, weeks 1-20 2021: prolonged 2nd peak) with reference data from 2017 to 2019. The proportion of patients receiving different treatment modalities (chemotherapy, hormonal therapy, immunotherapy or targeted therapy, radiotherapy primary tumor, resection primary tumor, resection metastases) within 6 weeks of diagnosis and the time between diagnosis and first treatment were compared by period. In total, 74,208 patients were included. Overall, patients were more likely to receive treatments in the COVID-19 periods than in previous years. This mainly holds for hormone therapy, immunotherapy or targeted therapy and resection of metastases. Lower odds were observed for resection of the primary tumor during the recovery period (OR 0.87; 95% CI 0.77-0.99) and for radiotherapy on the primary tumor during the prolonged 2nd peak (OR 0.84; 95% CI 0.72-0.98). The time from diagnosis to the start of first treatment was shorter, mainly during the 1st peak (average 5 days, p < .001). These findings show that during the first 1.5 years of the COVID-19 pandemic, there were only minor changes in the initial treatment of metastatic cancer. Remarkably, time from diagnosis to first treatment was shorter. Overall, the results suggest continuity of care for patients with metastatic cancer during the pandemic.
According to current treatment standards, patients with metastatic breast cancer at diagnosis receive palliative therapy. Local treatment of the breast is only recommended if the primary tumor is ...symptomatic. Recent studies suggest that surgical removal of the primary tumor has a favorable impact on the prognosis of patients with primary metastatic breast cancer. We performed a systematic review of the literature to weigh the evidence for and against breast surgery in this patient group. Ten retrospective studies were found in which the use of breast surgery in primary metastatic breast cancer and its impact on survival was examined. The hazard ratios of the studies were pooled to provide an estimate of the overall effect of surgery, and the results and conclusions of the studies were analyzed. A crude analysis, without adjustment for potential confounders, showed that surgical removal of the breast lesion in stage-IV disease was associated with a significantly higher overall survival rate in seven of the ten studies, and a trend toward a better survival in the three remaining studies. Surgery of the primary tumor appeared to be an independent factor for an improved survival in the multivariate analyses from the individual studies, with hazard ratios ranging from 0.47 to 0.71. The pooled hazard ratio for overall mortality was 0.65 (95% CI 0.59–0.72) in favor of the patients undergoing surgery. This systematic review of the literature suggests that surgery of the primary breast tumor in patients with stage-IV disease at initial presentation does have a positive impact on survival. In order to provide a definite answer on whether local tumor control in patients with primary metastatic disease improves survival, a randomized controlled trial comparing systemic therapy with and without breast surgery is needed.
Chromosomal instability in cancer consists of dynamic changes to the number and structure of chromosomes
. The resulting diversity in somatic copy number alterations (SCNAs) may provide the variation ...necessary for tumour evolution
. Here we use multi-sample phasing and SCNA analysis of 1,421 samples from 394 tumours across 22 tumour types to show that continuous chromosomal instability results in pervasive SCNA heterogeneity. Parallel evolutionary events, which cause disruption in the same genes (such as BCL9, MCL1, ARNT (also known as HIF1B), TERT and MYC) within separate subclones, were present in 37% of tumours. Most recurrent losses probably occurred before whole-genome doubling, that was found as a clonal event in 49% of tumours. However, loss of heterozygosity at the human leukocyte antigen (HLA) locus and loss of chromosome 8p to a single haploid copy recurred at substantial subclonal frequencies, even in tumours with whole-genome doubling, indicating ongoing karyotype remodelling. Focal amplifications that affected chromosomes 1q21 (which encompasses BCL9, MCL1 and ARNT), 5p15.33 (TERT), 11q13.3 (CCND1), 19q12 (CCNE1) and 8q24.1 (MYC) were frequently subclonal yet appeared to be clonal within single samples. Analysis of an independent series of 1,024 metastatic samples revealed that 13 focal SCNAs were enriched in metastatic samples, including gains in chromosome 8q24.1 (encompassing MYC) in clear cell renal cell carcinoma and chromosome 11q13.3 (encompassing CCND1) in HER2
breast cancer. Chromosomal instability may enable the continuous selection of SCNAs, which are established as ordered events that often occur in parallel, throughout tumour evolution.
Osimertinib is prescribed to patients with metastatic non-small cell lung cancer (NSCLC) and a sensitizing EGFR mutation. Limited data exists on the impact of patient characteristics or osimertinib ...exposure on effectiveness outcomes. This was a Dutch, multicenter cohort study. Eligible patients were ≥18 years, with metastatic EGFRm+ NSCLC, receiving osimertinib. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. Kaplan-Meier analyses and multivariate Cox proportional hazard models were performed. In total, 294 patients were included. Primary EGFR-mutations were mainly exon 19 deletions (54%) and p.L858R point mutations (30%). Osimertinib was given in first-line (40%), second-line (46%) or beyond (14%), with median PFS 14.4 (95% CI: 9.4-19.3), 13.9 (95% CI: 11.3-16.1) and 8.7 months (95% CI: 4.6-12.7), respectively. Patients with low BMI (<20.0 kg/m
) had significantly shorter PFS/OS compared to all other subgroups. Patients with a high plasma trough concentration in steady state (C
; >271 ng/mL) had shorter PFS compared to a low C
(<163 ng/mL; aHR 2.29; 95% CI: 1.13-4.63). A significant longer PFS was seen in females (aHR = 0.61, 95% CI: 0.45-0.82) and patients with the exon 19 deletion (aHR = 0.58, 95% CI: 0.36-0.92). A trend towards longer PFS was seen for TP53 wild-type patients, while age did not impact PFS. Patients with a primary EGFR exon 19 deletion had longer PFS, while a low BMI, male sex and a high C
were indicative for shorter PFS and/or OS. Age was not associated with effectiveness outcomes of osimertinib.
There are many reports on the frequency of non–sentinel lymph node involvement when isolated tumor cells are found in the sentinel node, but results and recommendations for the use of an axillary ...lymph node dissection differ among studies. This systematic review was conducted to give an overview of this issue and to provide recommendations for the use of an axillary lymph node dissection in these patients. We searched Medline, Embase, and Cochrane databases from January 1, 2002, through November 27, 2007, for articles on patients with invasive breast cancer who had isolated tumor cells in the sentinel lymph node (according to the sixth edition of the Cancer Staging Manual of the American Joint Committee on Cancer) and who also underwent axillary lymph node dissection. Of 411 selected articles, 29 (including 836 patients) were included in this review. These 29 studies were heterogeneous, reporting a wide range of non–sentinel lymph node involvement (defined as the presence of isolated tumor cells or micro- or macrometastases) associated with isolated tumor cells in the sentinel lymph node, with an overall pooled risk for such involvement of 12.3% (95% confidence interval = 9.5% to 15.7%). This pooled risk estimate was marginally higher than the risk of a false-negative sentinel lymph node biopsy examination (ie, 7%–8%) but marginally lower than the risk of non–sentinel lymph node metastases in patients with micrometastases (ie, approximately 20%) who are currently eligible for an axillary lymph node dissection. Because 36 (64%) of the 56 patients with isolated tumor cells in their sentinel lymph node also had non–sentinel lymph node macrometastases, those patients with isolated tumor cells in the sentinel lymph node without other indications for adjuvant systemic therapy might be candidates for axillary lymph node dissection.
Our study was performed to determine the frequency of recall for bilateral breast lesions at screening mammography and compare its outcome with respect to unilateral recall. We included 329 132 ...screening mammograms (34 889 initial screens and 294 243 subsequent screens) from a Dutch screening mammography program between January 2013 and January 2018. During a 2‐year follow‐up, we collected radiological data, pathology reports and surgical reports of all recalled women. At bilateral recall, the lesion with the highest Breast Imaging Reporting and Data System score was used as the index lesion when comparing screening mammography characteristics at bilateral vs unilateral recall. A total of 9806 women were recalled at screening (recall rate, 3.0%). Bilateral recall comprised 2.8% (271/9806) of all recalls. Biopsy was more frequently performed after bilateral recall than unilateral recall (54.6% 148/271 vs 44.1% 4201/9535, P < .001), yielding a lower positive predictive value (PPV) of biopsy after bilateral recall (42.6% vs 51.7%, P = .029). The PPV of recall was comparable for both groups (23.2% 63/271 vs 22.8% 2173/9535, P = .85). Invasive cancers after bilateral recall were larger than those diagnosed after unilateral recall (P = .02), but histological subtype, histologic grading, receptor status and proportions of lymph node positive cancers were comparable. Bilateral recall infrequently occurs at screening mammography. Biopsy is more frequently performed following bilateral recall, but the PPV of recall is similar for unilateral and bilateral recall. Invasive cancers of both groups show comparable pathological features except of a larger tumor size after bilateral recall.
What's new?
Data on bilateral breast cancer in a screened population is sparse, and information on bilateral recall is lacking. Based on more than 329,000 screening mammograms, our study shows that bilateral recall occurs infrequently at screening mammography, and that the majority of these recalls are false positives. Invasive cancer has comparable pathological features in bilateral and unilateral breast cancer patients, except larger tumour size after bilateral recall. Altogether, the results highlight the need for screening radiologists to pay vigorous attention to the contralateral breast after detecting a screening mammographic abnormality in order to facilitate a timely diagnosis of bilateral breast cancer.
Physicians are moving away from routine axillary lymph node dissection (ALND) in clinically node-negative breast cancer. We conducted a systemic review on the safety of this policy. Pubmed and ...Cochrane library were searched for. Sixty-eight studies were included: studies of clinically node-negative patients in the pre-sentinel node (SN) era; observational studies of SN-negative patients, without ALND; comparative studies of SN-negative patients, with a non-ALND and an ALND group; SN-positive studies, of patients without ALND. Primary endpoint was the pooled axillary recurrence rate (ARR) of each category; secondary endpoint was overall survival (OS) rate. In pre-SN studies, with larger tumors and less systemic therapy, ARR without ALND after 5–10 years follow-up was 12–18%, with 5% reduced OS. In the observational SN-negative studies, with median follow-up of 36 months, the pooled ARR was 0.6% (95% CI 0.6–0.8). In the comparative SN-negative studies, pooled ARR was 0.4% (95% CI 0.2–0.6) without ALND versus 0.3% (95% CI 0.1–0.6) with ALND at 31 and 47 months, respectively, and no survival disadvantage. In SN-positive studies, ARR was up to 1.7% (95% CI 1.0–2.7) at 30 months. For patients with an H&E positive SN the ARR without ALND was 5% after 23 months, which may imply rates as high as 13 and 18% after 5 and 8 years. In conclusion, this systematic review confirms the safety of omitting ALND in SN-negative patients. There is a potential role for avoiding ALND in selected SN-positive patients, but eligibility criteria and the role of systemic therapy need further to be elucidated.
The added value of capecitabine to adjuvant gemcitabine monotherapy (GEM) in pancreatic ductal adenocarcinoma (PDAC) was shown by the ESPAC‐4 trial. Real‐world data on the effectiveness of ...gemcitabine plus capecitabine (GEMCAP), in patients ineligible for mFOLFIRINOX, are lacking. Our study assessed whether adjuvant GEMCAP is superior to GEM in a nationwide cohort. Patients treated with adjuvant GEMCAP or GEM after resection of PDAC without preoperative treatment were identified from The Netherlands Cancer Registry (2015‐2019). The primary outcome was overall survival (OS), measured from start of chemotherapy. The treatment effect of GEMCAP vs GEM was adjusted for sex, age, performance status, tumor size, lymph node involvement, resection margin and tumor differentiation in a multivariable Cox regression analysis. Secondary outcome was the percentage of patients who completed the planned six adjuvant treatment cycles. Overall, 778 patients were included, of whom 21.1% received GEMCAP and 78.9% received GEM. The median OS was 31.4 months (95% CI 26.8‐40.7) for GEMCAP and 22.1 months (95% CI 20.6‐25.0) for GEM (HR: 0.71, 95% CI 0.56‐0.90; logrank P = .004). After adjustment for prognostic factors, survival remained superior for patients treated with GEMCAP (HR: 0.73, 95% CI 0.57‐0.92, logrank P = .009). Survival with GEMCAP was superior to GEM in most subgroups of prognostic factors. Adjuvant chemotherapy was completed in 69.5% of the patients treated with GEMCAP and 62.7% with GEM (P = .11). In this nationwide cohort of patients with PDAC, adjuvant GEMCAP was associated with superior survival as compared to GEM monotherapy and number of cycles was similar.
What's new?
The benefit of treating pancreatic ductal adenocarcinoma (PDAC) with a combination of gemcitabine plus capecitabine (vs gemcitabine alone) was previously shown in a carefully controlled clinical trial. But does this approach work as well in the real world? In this study, the authors found that the answer is yes—patients had significantly better overall survival (OS) with the combined therapy than with gemcitabine alone. These results may aid in the selection of adjuvant chemotherapy for patients who are not eligible for modified FOLFIRINOX (fluorouracil, leucovorin, irinotecan and oxaliplatin).
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