Lymph node ratio and pN staging in patients with node-positive breast cancer: a report from the Korean breast cancer society

Patients with node-positive breast cancer are currently classified according to pN stage. Lymph node ratio (LNR), the ratio of positive to total removed lymph nodes, maybe a more useful prognostic factor in these patients. We therefore compared LNR and pN staging as prognostic factors in patients with node-positive breast cancer. Using two large prospective databases of the Korean Breast Cancer Registry (KBCR) and the Asan Medical Center (AMC) Breast Cancer Center of patients with LN-positive breast cancer from 1988 to 2005, we compared the ability of LNR and pN stage to predict patient survival by Cox regression analysis in the overall patient cohort and in subgroups categorized by age and intrinsic subtype. Patients were categorized into low- (≤0.20), intermediate- (>0.20 and ≤0.65), and high-risk (>0.65) LNR groups. The difference in mortality risk was greater among LNR groups than among patients staged pN1, pN2, and pN3, as assessed by disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) rates. In contrast to LNR risk categories, the survival curves for pN1 and pN2 stage patients overlapped in those aged <35 years and those with her2/neu-enriched or triple-negative tumors. These findings were validated by analyzing a nationwide registry of 15,488 node-positive patients, which showed that patients with pN1 and intermediate LNR risk had poorer DFS (HR 1.7, 95% CI 1.4–2.2) and CSS (HR 1.6, 95% CI 1.1–2.2) than patients with pN2 and low LNR risk. LNR is a better predictor of prognosis than pN stage in women with breast cancer, especially in high-risk patients, including younger women and women with her2/neu-enriched or triple-negative tumors. Treatment decisions should be based on LNR rather than on pN stage.     

Breast cancer-specific survival in patients with lymph node-positive hormone receptor-positive invasive breast cancer and Oncotype DX Recurrence Score results in the SEER database

Purpose

The Oncotype DX^® Breast Recurrence Score? (RS) assay is validated to predict breast cancer (BC) recurrence and adjuvant chemotherapy benefit in select patients with lymph node-positive (LN+), hormone receptor-positive (HR+), HER2-negative BC. We assessed 5-year BC-specific survival (BCSS) in LN+ patients with RS results in SEER databases.

Methods

In this population-based study, BC cases in SEER registries (diagnosed 2004–2013) were linked to RS results from assays performed by Genomic Health (2004–2014). The primary analysis included only patients (diagnosed 2004–2012) with LN+ (including micrometastases), HR+ (per SEER), and HER2-negative (per RT-PCR) primary invasive BC (N = 6768). BCSS, assessed by RS category and number of positive lymph nodes, was calculated using the actuarial method.

Results

The proportion of patients with RS results and LN+ disease (N = 8782) increased over time between 2004 and 2013, and decreased with increasing lymph node involvement from micrometastases to ≥4 lymph nodes. Five-year BCSS outcomes for those with RS < 18 ranged from 98.9% (95% CI 97.4–99.6) for those with micrometastases to 92.8% (95% CI 73.4–98.2) for those with ≥4 lymph nodes. Similar patterns were found for patients with RS 18–30 and RS ≥ 31. RS group was strongly predictive of BCSS among patients with micrometastases or up to three positive lymph nodes (p < 0.001).

Conclusions

Overall, 5-year BCSS is excellent for patients with RS < 18 and micrometastases, one or two positive lymph nodes, and worsens with additionally involved lymph nodes. Further analyses should account for treatment variables, and longitudinal updates will be important to better characterize utilization of Oncotype DX testing and long-term survival outcomes.

     

Associations between frailty and cancer-specific mortality among older women with breast cancer

Purpose

To analyze whether monitoring serum estradiol (E2) levels using a highly sensitive and specific liquid chromatography tandem mass spectrometry (LC–MS/MS) method may identify patients with AI failure with E2 levels below the lower limit of quantification (LLOQ) after schwitching from tamoxifen to letrozole.

Methods

In a prospective study of breast cancer patients switching to letrozole treatment after previous tamoxifen, plasma estrogen levels were measured at baseline and after 3- and 12-months using LC–MS/MS.

Results

Forty-six patients were classified postmenopausal and entered into the final analysis. Thirty-nine (85%) patients had three- and 12-month E2 concentrations below the LLOQ (5 pmol/L). In the seven patients classified as AI-failures during letrozole treatment, serum E2-MS level rose above 5 pmol/L at 3 months with a mean E2-MS 77.5 pmol/L or 12 months with a mean E2-MS 21 pmol/L. None of the baseline variables i.e., age at diagnosis, age at study entry, age at menarche, BMI, endometrial thickness, total ovarian volume, baseline FSH, E2-IA, or E2-MS were significantly associated with the risk of AI failure in logistic regression. E2 levels at baseline measured by E2-IA did not significantly correlate to the levels measured by E2-MS.

Conclusions

There is a relatively high risk of inadequate estrogen suppression in patients who switch from tamoxifen treatment to AIs. The use of sensitive and specific assays, such as LC–MS/MS methods, to monitor estrogen levels during AI treatment is essential to minimize the risk of a proceeding inefficient endocrine therapy.

     

Breast cancer screening case–control study design: impact on breast cancer mortality

BackgroundRecent case–control studies on the effectiveness of population-based breast cancer screening show differences in the magnitude of breast cancer mortality reduction. We investigated the role played by aspects of the case–control study design on these differences, e.g. the definition of cases and exposure to screening.Material and methodsWe investigated six case–control studies conducted in East Anglia (UK), Wales, Iceland, central and northern Italy, South Australia and The Netherlands.ResultsThe breast cancer mortality reduction in the different case–control studies ranged from 38% to 70% in the screened versus the nonscreened women. We identified differences in design, e.g. the inclusion or exclusion of the first years of screening, and the correction factor for self-selection bias.ConclusionsOverall, the design of the case–control studies was similar. The differences in the magnitude of breast cancer mortality reductions are therefore unlikely to be caused by variations in the design of the case–control studies. These differences must be due to other factors, like the organisation of the service screening programme and the attendance rate. The reduction in breast cancer mortality estimated in these case–control studies indicates that the impact of current mammographic screening is at least consistent with the effect reported by the former randomised screening trials.     

First-onset mental disorders after cancer diagnosis and cancer-specific mortality: a nationwide cohort study

BackgroundThe diagnosis of cancer is strongly associated with the risk of mental disorders even in patients with no previous history of mental disorders. Accumulating data suggest that mental distress may accelerate tumor progression. We hypothesized therefore that mental disorders after a cancer diagnosis may increase the risk of cancer-specific mortality.Patients and methodsWe conducted a nationwide cohort study including 244 261 cancer patients diagnosed in Sweden during 2004–2009 and followed them through 2010. Through the Swedish Patient Register, we obtained clinical diagnoses of all mental disorders and focused on mood-, anxiety-, and substance abuse disorders (ICD10: F10–F16, F18–F19, F32–F33, F40–F41, and F43–45) that are commonly diagnosed among patients with cancer. We further classified the studied mental disorders into first-onset or recurrent mental disorders. We used Cox regression to estimate multivariable hazard ratios (HRs) with 95% confidence intervals (CIs) as a measure of the association between mental disorders after cancer diagnosis and cancer-specific mortality, adjusting for age, sex, calendar period, educational level, cancer stage, and cancer type at diagnosis.ResultsAfter cancer diagnosis, 11 457 patients were diagnosed with mood-, anxiety-, and substance abuse disorders; of which 7236 were first-onset mental disorders. Patients with a first-onset mental disorder were at increased risk of cancer-specific mortality (HR: 1.82, 95% CI: 1.71–1.92) while patients with a recurrent mental disorder had much lower risk elevation (HR: 1.14, 95% CI: 1.05–1.24). The increased cancer-specific mortality by first-onset mental disorders was observed for almost all cancer sites/groups and the association was stronger for localized cancers (HR: 2.00, 95% CI: 1.73–2.31) than for advanced cancers (HR: 1.49, 95% CI: 1.32–1.69).ConclusionsPatients with a first-onset common mood-, anxiety-, or substance abuse disorder after cancer diagnosis may be at increased risk of cancer-specific death.     

Impact of time to distant recurrence on breast cancer-specific mortality in hormone receptor-positive breast cancer

Cancer Causes & Control - Women with hormone receptor (HR)-positive early-stage breast cancer (BC) have five-year survival rates of &gt; 90% but remain at serious risk for...     

Postmastectomy radiation and mortality in women with T1-2 node-positive breast cancer.

PURPOSE: To determine the relationship between postmastectomy radiotherapy (PMRT) and mortality in a population-based cohort of women with T1-2 node-positive breast cancer. PATIENTS AND METHODS: Using data from the Surveillance, Epidemiology, and End Results program, we identified 18,038 women with T1-2 node-positive invasive breast cancer who were treated with mastectomy between 1988 and 1995. The relationship between PMRT and mortality was determined using proportional hazards multivariate modeling and propensity score matched case-control analysis. RESULTS: Median follow-up was 8.1 years. Only 2,648 women (15%) received PMRT. After adjusting for covariates, PMRT use was not associated with mortality (hazard ratio [HR] = 0.96; 95% CI, 0.90 to 1.03). However, the interaction term for PMRT use and number of involved regional lymph nodes was significant (P = .002), suggesting that, above a certain threshold of involved nodes, a mortality benefit from PMRT may exist. Adjusted analysis stratified by number of involved nodes revealed that patients with seven or more involved nodes treated with PMRT experienced a significant reduction in all-cause (HR = 0.84; 95% CI, 0.76 to 0.93) and cause-specific mortality (HR = 0.86; 95% CI, 0.77 to 0.96). Propensity score matched case-control analysis confirmed that PMRT was associated with reduced mortality only in the subset of patients with seven or more involved nodes (HR = 0.81; 95% CI, 0.73 to 0.91 for all-cause mortality; and HR = 0.82; 95% CI, 0.72 to 0.93 for cause-specific mortality). CONCLUSION: For women with T1-2 breast cancer, PMRT is associated with a 15% to 20% relative reduction in mortality for patients with seven or more involved regional lymph nodes.     

Colorectal cancer risk in adenoma patients: a nation-wide study

Colorectal cancer incidence after adenoma removal has been studied in selected populations of adenoma patients. Our study estimates the trend in colorectal cancer incidence after adenoma removal in actual clinical practice. From PALGA, a nationwide network and registry of histo- and cytopathology in the Netherlands, we extracted data of all patients diagnosed with colorectal adenomas between 1 January 1988 and 1 October 1998. The data were used to calculate population-based colorectal cancer incidence rates after adenoma removal. A total of 78,473 adenoma patients were followed for a mean of 4.5 years after the first adenoma removal. The colorectal cancer incidence ratio compared with the general population matched by age and gender was 38.4 (37.3-39.5) in the first year after adenoma removal and 1.5 (95% confidence interval (CI): 1.4-1.6) after Year 1. The incidence ratio decreased from 2.8 (2.5-3.1) in Year 2 to 0.9 (0.6-1.2) in Years 9-11. This time trend is the opposite of the upward time trend that was expected after adenoma removal. Adenoma patients in the Netherlands are at increased risk for colorectal cancer compared to the general population. The high cancer incidence in Years 1-5 after polypectomy can be explained by a colonoscopic sensitivity for cancer of approximately 90%.     

Prognostic value of ABO blood types in young patients with breast cancer; a nationwide study in Korean Breast Cancer Society

The purpose of this study was to investigate the relationship between ABO blood types and breast cancer survival in young Korean patients. This was a retrospective study of 115,474 patients who were surgically treated for primary breast cancer between 1987 and 2011 in Korea. All data were collected by the Korean Breast Cancer Society (KBCS) online breast cancer registry. Each hospital serologically examined the ABO blood types of patients before surgery. There was no significant difference in overall survival (OS) or breast cancer-specific survival (BCSS) among ABO blood types. Type of surgery; T stage; N stage; histologic grade; status of estrogen receptor, progesterone receptor, and HER2; and chemotherapy were significant prognostic factors of OS and BCSS in univariate analysis and multivariate analyses. Compared to women with blood type O, there was a difference in OS and BCSS for blood type A, blood type B, or blood type AB. Compared to blood group non-O, patients with blood group O were more likely to have favorable prognosis when younger than 40 years. Further follow-up studies are necessary to clarify the role of the impact of ABO blood types on prognosis of breast cancer.     

A study of tumor heterogeneity in a case with breast cancer

Tumor heterogeneity has been suggested based on clinical and pathological findings. Several clinical findings can be explained by tumor evolution during progression and metastasis. We herein report a case of metastatic breast cancer indicated tumor heterogeneity by clinical findings and a genomic analysis. A 64-year-old woman with advanced breast cancer was treated with primary chemotherapy, to which primary tumor responded. After a 6 month treatment pause, lung, liver, and skin metastases developed and her serum tumor markers were elevated. None of those serum markers had been elevated before the treatment, despite the large tumor burden. Notably, there was discordance in the expression of human epidermal growth factor receptor 2 (HER2) between the primary tumor and metastatic skin lesions, with the former being negative and the latter positive. A genomic analysis was performed by in-house Breast Cancer Panel, which consisted of 53 pre-selected genes. Twenty-three somatic mutations were found in primary breast tumor and 7 in the skin metastasis. None of these 30 genes matched. However, the cell-free (cf) DNA in the plasma taken at the time of skin metastasis contained 10 mutations, 7 from the primary lesion and 3 from the metastasis. These data indicate that the clonal changes or tumor heterogeneity was shown in two solid tumors by clinical and the result of a genomic analysis. Of particular interest was that cell-free DNA could be a powerful tool to look into these dynamic changes.     

Coexisting ductal carcinoma in situ independently predicts lower tumor aggressiveness in node-positive luminal breast cancer

Primary breast invasive ductal carcinoma coexisting with ductal carcinoma in situ (IDC-DCIS) is characterized by lower proliferation rate and metastatic propensity than size-matched pure IDC. IDC-DCIS is also more often ER-positive, PR-positive and/or HER2-positive. This analysis aims to clarify whether the presence of coexisting DCIS in IDC affects tumor aggressiveness in various biological subtypes of breast cancer, respectively. Tumor data obtained from 1,355 consecutive female patients undergoing upfront surgery for primary breast cancer were analyzed retrospectively; 196 patients with pure DCIS were excluded. Based on evidence that immunohistochemistry (IHC) provides a reasonable approximation of molecular phenotypes, the tumor samples were divided into 4 groups: (1) luminal A (ER and/or PR-positive, HER2-negative, Ki67 ≤ 12), (2) luminal B (ER and/or PR-positive, HER2-negative, Ki67 > 12), (3) HER2 (HER2-positive) and (4) basal-like (triple-negative) disease. Ki67 expression and nodal involvement of IDC with or without DCIS in these groups were compared. The number of patients with luminal A, luminal B, HER2 and basal-like breast cancer were 396, 265, 258 and 117, respectively. Ki-67 was lower in IDC-DCIS than in size-adjusted pure IDC of both luminal A and luminal B subtypes (P = 0.15 and <0.005, respectively). In HER2 or basal-like tumors, there were no significant difference between pure IDC and IDC-DCIS. The presence of coexisting DCIS in IDC predicts lower biological aggressiveness in luminal cancers but not in the conventionally more aggressive HER2-positive and triple-negative subtypes.     

Long-term tamoxifen adjuvant therapy in node-positive breast cancer: A metabolic and pilot clinical study

Summary One hundred twenty-four disease-free postoperative women with ipsilateral-node-positive breast carcinoma were evaluated to assess the metabolic handling and clinical side effects of adjuvant tamoxifen for periods in excess of five years. The patients received postoperative combination chemotherapy for a median of 14 months. Thirty-eight patients received no tamoxifen. Tamoxifen 10 mgs bid was administered to 86 patients during the chemotherapy duration and has been continued in 43 of these patients for up to five years after termination of chemotherapy. Serum samples obtained in 7 patients at 3 to 4-month intervals during the first 5 years revealed that levels of tamoxifen, N-desmethyltamoxifen, and metabolite Y were generally constant throughout the period of drug administration. There was no difference in side effects observed after stopping chemotherapy between the group continuing tamoxifen and the groups stopping tamoxifen or never receiving the drug. Relapse-free survival was superior with increasing duration of exposure to tamoxifen, but this observation can only be considered preliminary due to the small number of patients involved and the study design. The clinical effects observed and the failure to demonstrate the development of a host-metabolic tolerance to tamoxifen provides a rational basis for developing a clinical trial to continue adjuvant tamoxifen therapy for periods in excess of four years after chemotherapy.