Margreet Lüchtenborg

Response of Circulating Tumor Cells to Systemic Therapy in Patients With Metastatic Breast Cancer: Comparison of Quantitative Polymerase Chain Reaction and Immunocytochemical Techniques

PURPOSE We previously developed a quantitative system for the detection of cytokeratin 19 (CK-19) transcripts using reverse transcriptase polymerase chain reaction (PCR) to detect breast carcinoma cells in blood and bone marrow. The aim of this study was to determine the value of this system in monitoring patients with metastatic disease and to compare it with an established immunocytochemical method. PATIENTS AND METHODS Patients with progressive, locally advanced, and metastatic breast cancer (all stage IV) who were due to start systemic treatment were recruited. Blood samples were analyzed for CK-19 transcripts using quantitative PCR (QPCR) and immunocytochemistry (ICC) throughout their course of treatment. RESULTS One hundred forty-five blood samples were obtained from 22 patients over 13 months. Seventy-two (49.6%) of these samples were positive by QPCR, and 56 (42%) of 133 were positive by ICC. Of the 133 specimens analyzed by both techniques, 95 (71.4%) had the same results for each, and of the 71 samples that were positive, 40 (56%) were positive by both methods. The relationship between the number of cells detected and the QPCR values was statistically significant (P <.0001). Of the 25 courses of assessable treatment, 17 (68%) of 25 treatment outcomes (either response or disease progression) were reflected by QPCR measurements, and 12 (57%) of 21 were reflected by ICC. During the course of the study, five patients showed a response, and of these, ICC was in agreement in four cases (80%) and QPCR in three cases (60%). Eighteen courses of treatment resulted in progression of the disease; however, only 15 of these were assessable by ICC. ICC was in agreement in eight (53%) of 15 of these cases, and QPCR in 15 (83%) of 18 cases. CONCLUSION Circulating carcinoma cells are frequently found in patients with metastatic breast cancer. In the majority of patients, cancer cell numbers as evaluated by QPCR or ICC reflected the outcome of systemic treatment.

Hospital volume, proportion resected and mortality from oesophageal and gastric cancer: a population-based study in England, 2004–2008

Objective This study assessed the associations between hospital volume, resection rate and survival of oesophageal and gastric cancer patients in England. Design 62 811 patients diagnosed with oesophageal or gastric cancer between 2004 and 2008 were identified from a national population-based cancer registration and Hospital Episode Statistics-linked dataset. Cox regression analyses were used to assess all-cause mortality according to hospital volume and resection rate, adjusting for case-mix variables (sex, age, socioeconomic deprivation, comorbidity and type of cancer). HRs and 95% CIs, according to hospital volume, were evaluated for three predefined periods following surgery: <30, 30–365, and >365 days. Analysis of mortality in relation to resection rate was performed among all patients and among the 13 189 (21%) resected patients. Results Increasing hospital volume was associated with lower mortality (ptrend=0.0001; HR 0.87, 95% CI 0.79 to 0.95 for hospitals resecting 80+ and compared with <20 patients a year). In relative terms, the association between increasing hospital volume and lower mortality was particularly strong in the first 30 days following surgery (ptrend<0.0001; HR 0.52, (0.39 to 0.70)), but a clinically relevant association remained beyond 1 year (ptrend=0.0011; HR 0.82, (0.72 to 0.95)). Increasing resection rates were associated with lower mortality among all patients (ptrend<0.0001; HR 0.86, (0.84 to 0.89) for the highest, compared with the lowest resection quintile). Conclusions With evidence of lower short-term and longer-term mortality for patients resected in high-volume hospitals, this study supports further centralisation of oesophageal and gastric cancer surgical services in England.

High Procedure Volume Is Strongly Associated With Improved Survival After Lung Cancer Surgery

PURPOSE Studies have reported an association between hospital volume and survival for non-small-cell lung cancer (NSCLC). We explored this association in England, accounting for case mix and propensity to resect. METHODS We analyzed data on 134,293 patients with NSCLC diagnosed in England between 2004 and 2008, of whom 12,862 (9.6%) underwent surgical resection. Hospital volume was defined according to number of patients with resected lung cancer in each hospital in each year of diagnosis. We calculated hazard ratios (HRs) for death in three predefined periods according to hospital volume, sex, age, socioeconomic deprivation, comorbidity, and propensity to resect. RESULTS There was increased survival in hospitals performing > 150 surgical resections compared with those carrying out < 70 (HR, 0.78; 95% CI, 0.67 to 0.90; Ptrend < .01). The association between hospital volume and survival was present in all three periods of follow-up, but the magnitude of association was greatest in the early postoperative period. CONCLUSION High-volume hospitals have higher resection rates and perform surgery among patients who are older, have lower socioeconomic status, and have more comorbidities; despite this, they achieve better survival, most notably in the early postoperative period.

Persistence of bone marrow micrometastases in patients receiving adjuvant therapy for breast cancer: Results at 4 years

We have previously developed a quantitative PCR (QPCR) technique for the detection of cytokeratin 19 (CK19) transcripts in blood and bone marrow and compared this to immunocytochemistry (ICC). Together, both have shown promise for monitoring therapeutic efficacy in patients with metastatic breast cancer. The aim of this study was to determine the feasibility and value of these assays for minimal residual disease (MRD) in monitoring efficacy of adjuvant therapy following surgery for primary breast cancer. Bone marrow aspirates and peripheral blood samples were taken at the time of surgery from patients with primary breast cancer and no evidence of metastases on conventional scans. These were tested for the presence of CK19 mRNA transcripts and cytokeratin positive cells. Follow‐up bone marrow aspirates were taken at 3, 6, 12, 24, 36 and 48 months. Prior to surgery, 51% of patients displayed evidence of disseminated cancer cells in the bone marrow by either or both QPCR and ICC. Of 91 patients who had repeat samples assayed, 87% and 65% had positive results at some time using QPCR and ICC, respectively. All patients received adjuvant systemic therapy and in 44 cases where there was a positive result in either the pretreatment or 3‐month aspirate, 32/44 (73%) showed a fall in CK19:ABL ratio (QPCR) and 15/24 (63%) showed a reduction in the number of cytokeratin‐positive cells (ICC) during follow‐up. These results indicate that MRD persists despite adjuvant therapy in a majority of patients with primary breast cancer up to 4 years following surgery.

Variation in surgical resection for lung cancer in relation to survival: population-based study in England 2004-2006.

BACKGROUND Compared with some European countries, England has low lung cancer survival and low use of surgical resection for lung cancer. The use of surgical resection varies within England. We assessed the relationship between surgical resection rate and the survival of lung cancer patients in England. METHODS We extracted data on 77,349 non-small cell lung cancer (NSCLC) patients diagnosed between 2004 and 2006 from the English National Cancer Repository Dataset. We calculated the frequency of surgical resection by age, socio-economic deprivation and geographical area. We used Cox regression to compute mortality hazard ratios according to quintiles of frequency of surgical resection amongst all 77,349 lung cancer patients, and separately for the 6900 patients who underwent surgical resection. RESULTS We found large geographical variation in the surgical resection rate for NSCLC in PCT areas (3-18%). A high frequency of resection was strongly inversely associated with overall mortality (HR 0.88, 95% CI 0.86-0.91 for the highest compared to the lowest resection quintile) and only moderately associated with mortality amongst the resected patients (HR 1.15, 95% CI 0.98-1.36). Compared to the highest resection quintile, 5420 deaths could be delayed in the overall NSCLC group, whereas about 146 more deaths could be expected amongst the resected patients. CONCLUSION The differences in the magnitudes of both the hazard ratios and the absolute excess deaths within resected patients and all NSCLC patients suggests that lung cancer survival in England could plausibly increase if a larger proportion of patients underwent surgical resection. Carefully designed research into the possible benefit of increasing resection rates is indicated.

The effect of comorbidity on stage-specific survival in resected non-small cell lung cancer patients

AIM To quantify the effect of comorbidity on stage-specific survival in resected non-small cell lung cancer (NSCLC) patients. METHODS From the Danish Lung Cancer Registry, 20,461 patients diagnosed with lung cancer between 1st January 2005 and 31st December 2010 were identified. Among 3152 NSCLC patients who underwent surgical resection, mortality hazard ratios were calculated during three consecutive time periods following surgery (0-1 month, 1 month-1 year and >1 year) according to Charlson comorbidity score (CCS 0, 1, 2, 3+), Eastern Cooperative Oncology Group (ECOG) performance status, lung function, age, sex, pathological T (pT) and N (pN) stage using Cox proportional hazard modelling. The Kaplan Meier method was used to describe stage-specific survival according to the CCS. RESULTS Severe comorbidity (CCS 3+) was independently associated with significantly higher death rates throughout the three periods of follow-up [Hazard ratio (HR) 2.06 (1.13-3.75) for CCS 3+ in 0-1 month, 1.57 (1.17-2.12) 3+ during1 month-1 year and 1.84 (1.42-2.37) after 1 year]. Stage-specific 5-year survival in patients with severe comorbidity was significantly lower than in patients without comorbid disease [e.g. 38% (95% confidence interval (CI) 23-53%) for pT1 and CCS 3+ versus 69% (62-75%) for pT1 and CCS 0]. CONCLUSION Severe comorbidity affects survival of NSCLC patients who undergo surgical resection by as much as a single stage increment and this effect persists throughout follow-up. Further research may be necessary to help identify which patients are most likely to benefit from surgery.

Smoking and Colorectal Cancer: Different Effects by Type of Cigarettes?

Although smoking is suggested to be a risk factor for colorectal cancer, the evidence to date is conflicting and may be confounded. Moreover, the effect of tobacco smoke may vary by time since initiation, type of tobacco product, anatomic subsites, and among ethnic groups. Data were derived from two consecutive population-based case-control studies conducted among Caucasians, Japanese, Native Hawaiians, Filipinos, and Chinese in Hawaii, including 1,959 ethnicity-, sex-, and age-matched case-control pairs. A lifetime history of smoking for different tobacco products and information on other risk factors were obtained by in-person interviews. Odds ratios (OR) and corresponding 95% confidence intervals (95% CI) were estimated using conditional logistic regression models with adjustment for potential confounders. Subjects who ever smoked were at an increased risk of colorectal cancer compared with never smokers (OR, 1.23; 95% CI, 0.99-1.52 for men and OR, 1.27; 95% CI, 1.01-1.59 for women). Increasing quartiles of pack-years over all tobacco products showed a clear dose-dependent association in men [for the highest quartile, Q4 (>40 pack-years) versus never smokers: OR, 1.48; 95% CI, 1.12-1.96; Ptrend = 0.002]. The dose-response trend was also present in women [for the highest quartile, Q4 (>30 pack-years) versus never smokers: OR, 1.38; 95% CI, 0.91-1.95; Ptrend = 0.04] and each ethnic group. There was a suggestion of a difference in risk with type of tobacco product. Non-filtered cigarettes increased risk of both colon and rectal cancer [for Q4 versus never smokers: OR, 1.59; 95% CI, 1.15-2.21; Ptrend = 0.001 and OR, 1.84; 95% CI, 1.18-2.86; Ptrend = 0.02, respectively], whereas filtered cigarettes seemed to increase risk of rectal but not colon cancer (OR, 1.37; 95% CI, 0.88-2.13; Ptrend = 0.06 and OR, 1.05; 95% CI, 0.79-1.39; Ptrend = 0.98, respectively). The effect of smoking was not limited to the distant past, and accumulated pack-years of smoking seemed to be more important than the time in which smoking occurred. The data from this large study corroborate previous reports of a positive association between smoking and colorectal cancer and suggest that the association may vary by type of cigarette. (Cancer Epidemiol Biomarkers Prev 2007;16(7):1341–7)

Completeness of case ascertainment and survival time error in English cancer registries : impact on 1-year survival estimates

Background:It has been suggested that cancer registries in England are too dependent on processing of information from death certificates, and consequently that cancer survival statistics reported for England are systematically biased and too low.Methods:We have linked routine cancer registration records for colorectal, lung, and breast cancer patients with information from the Hospital Episode Statistics (HES) database for the period 2001–2007. Based on record linkage with the HES database, records missing in the cancer register were identified, and dates of diagnosis were revised. The effects of those revisions on the estimated survival time and proportion of patients surviving for 1 year or more were studied. Cases that were absent in the cancer register and present in the HES data with a relevant diagnosis code and a relevant surgery code were used to estimate (a) the completeness of the cancer register. Differences in survival times calculated from the two data sources were used to estimate (b) the possible extent of error in the recorded survival time in the cancer register. Finally, we combined (a) and (b) to estimate (c) the resulting differences in 1-year cumulative survival estimates.Results:Completeness of case ascertainment in English cancer registries is high, around 98–99%. Using HES data added 1.9%, 0.4% and 2.0% to the number of colorectal, lung, and breast cancer registrations, respectively. Around 5–6% of rapidly fatal cancer registrations had survival time extended by more than a month, and almost 3% of rapidly fatal breast cancer records were extended by more than a year. The resulting impact on estimates of 1-year survival was small, amounting to 1.0, 0.8, and 0.4 percentage points for colorectal, lung, and breast cancer, respectively.Interpretation:English cancer registration data cannot be dismissed as unfit for the purpose of cancer survival analysis. However, investigators should retain a critical attitude to data quality and sources of error in international cancer survival studies.

Recent trends in resection rates among non-small cell lung cancer patients in England

Background Lung cancer resection rates are low in England, but reports have indicated an increase in recent years. We analysed the recent trends in surgical resection by age, sex, socioeconomic deprivation and surgical procedure in England. Methods Data on 286 217 patients with non-small cell lung cancer diagnosed between 1998 and 2008 were extracted from the English Cancer Repository Dataset and information on surgical resection for these patients was retrieved from linked Hospital Episode Statistics records. We calculated the OR of undergoing surgery per 1-year increment by age, sex, socioeconomic deprivation and surgical procedure. A multinomial logistic regression model was used to assess the association between age and type of surgery. Results The proportion of patients with non-small cell lung cancer undergoing surgery increased from 8.8% in 1998 to 10.6% in 2008. The increase was similar between levels of socioeconomic deprivation, slightly more pronounced among women (OR=1.023 per 1-year calendar increment, 95% CI 1.016 to 1.029) than men (OR=1.010, 95% CI 1.005 to 1.015) and most prominent with increasing age (75–79 age group: OR 1.051, 95% CI 1.041 to 1.062; 80–84 age group: OR 1.102, 95% CI 1.080 to 1.124; and 85+ age group: OR 1.130, 95% CI 1.069 to 1.193). Increasing age was associated with a decreased likelihood of undergoing pneumonectomy (OR 0.88, 95% CI 0.87 to 0.89 per 5-year age increment) or sleeve resection (OR 0.75, 95% CI 0.71 to 0.79) compared with lobectomy, and a slightly increased likelihood of undergoing a wedge resection (OR 1.08, 95% CI 1.06 to 1.10). Conclusion Resection rates have increased in England in recent years and most markedly so in the older age groups.

Tumor Stage Affects Risk and Prognosis of Contralateral Breast Cancer: Results From a Large Swedish-Population–Based Study

PURPOSE The number of breast cancer survivors at risk of developing contralateral breast cancer (CBC) is increasing. However, ambiguity remains regarding risk factors and prognosis for women with CBC. PATIENTS AND METHODS In a cohort of 42,670 women with breast cancer in the Uppsala/Örebro and Stockholm regions in Sweden in 1992 to 2008, we assessed risk factors for and prognosis of metachronous CBC by using survival analysis. Breast cancer-specific survival for women with CBC was evaluated and compared with results for women with unilateral breast cancer (UBC) by using time-dependent Cox-regression modeling. RESULTS An increased risk for CBC was observed among women who had primary breast cancer with ≥ 10 involved lymph nodes compared with node-negative women (adjusted hazard ratio [HR], 1.8; 95% CI, 1.2 to 2.7). The prognosis was poorer in women with CBC than with UBC. The hazard of dying from breast cancer was especially high for women with a short interval time to CBC (adjusted HR, 2.3; 95% CI, 1.8 to 2.8 for CBC diagnosed ≤ 5 years v UBC) and gradually decreased with longer follow-up time but remained higher than the hazard originating from the primary tumor for ≥ 10 years. CONCLUSION Women with advanced-stage primary breast cancer had an increased risk of developing CBC. CBC is associated with an increased risk of dying from breast cancer throughout a long period of follow-up after the primary tumor. Our findings suggest that the event of CBC marks a new clinical situation in terms of investigations for metastases, treatment considerations, and follow-up strategy.