Background Radiotherapy for breast cancer as delivered in the 1970s has been associated with increased risk of cardiovascular disease, but recent studies of associations with modern regimens have ...been inconclusive. Few data on long-term cardiovascular disease risk according to specific radiation fields are available, and interaction with known cardiovascular risk factors has not been examined. Methods We studied treatment-specific incidence of cardiovascular disease in 4414 10-year survivors of breast cancer who were treated from 1970 through 1986. Risk of cardiovascular disease in these patients was compared with general population rates and evaluated in Cox proportional hazards regression models. All statistical tests were two-sided. Results After a median follow-up of 18 years, 942 cardiovascular events were observed (standardized incidence ratio = 1.30, 95% confidence interval CI = 1.22 to 1.38; corresponding to 62.9 excess cases per 10 000 patient-years). Breast irradiation only was not associated with increased risk of cardiovascular disease. However, radiotherapy to either the left or right side of the internal mammary chain was associated with increased cardiovascular disease risk for the treatment period 1970–1979 (for myocardial infarction, hazard ratio HR = 2.55, 95% CI = 1.55 to 4.19; P<.001; for congestive heart failure, HR = 1.72, 95% CI = 1.22 to 2.41; P = .002) compared with no radiotherapy. Among patients who received internal mammary chain radiotherapy after 1979, risk of myocardial infarction declined over time toward unity, whereas the risks of congestive heart failure (HR = 2.66, 95% CI = 1.27 to 5.61; P = .01) and valvular dysfunction (HR = 3.17, 95% CI = 1.90 to 5.29; P<.001) remained increased. Patients who underwent radiotherapy plus adjuvant chemotherapy (cyclophosphamide, methotrexate, and fluorouracil) after 1979 had a higher risk of congestive heart failure than patients who were treated with radiotherapy only (HR = 1.85, 95% CI = 1.25 to 2.73; P = .002). Smoking and radiotherapy together were associated with a more than additive effect on risk of myocardial infarction (HR = 3.04, 95% CI = 2.03 to 4.55; P for departure from additivity = .039). Conclusions Radiotherapy as administered from the 1980s onward is associated with an increased risk of cardiovascular disease. Irradiated breast cancer patients should be advised to refrain from smoking to reduce their risk for cardiovascular disease.
Purpose: Recently, a 76-gene prognostic signature able to predict distant metastases in lymph node–negative (N − ) breast cancer patients was reported. The aims of this study conducted by TRANSBIG ...were to independently validate these results
and to compare the outcome with clinical risk assessment.
Experimental Design: Gene expression profiling of frozen samples from 198 N − systemically untreated patients was done at the Bordet Institute, blinded to clinical data and independent of Veridex. Genomic
risk was defined by Veridex, blinded to clinical data. Survival analyses, done by an independent statistician, were done with
the genomic risk and adjusted for the clinical risk, defined by Adjuvant! Online.
Results: The actual 5- and 10-year time to distant metastasis were 98% (88-100%) and 94% (83-98%), respectively, for the good profile
group and 76% (68-82%) and 73% (65-79%), respectively, for the poor profile group. The actual 5- and 10-year overall survival
were 98% (88-100%) and 87% (73-94%), respectively, for the good profile group and 84% (77-89%) and 72% (63-78%), respectively,
for the poor profile group. We observed a strong time dependence of this signature, leading to an adjusted hazard ratio of
13.58 (1.85-99.63) and 8.20 (1.10-60.90) at 5 years and 5.11 (1.57-16.67) and 2.55 (1.07-6.10) at 10 years for time to distant
metastasis and overall survival, respectively.
Conclusion: This independent validation confirmed the performance of the 76-gene signature and adds to the growing evidence that gene
expression signatures are of clinical relevance, especially for identifying patients at high risk of early distant metastases.
In this study, we quantified 249 mature micro-RNA (miRNA) transcripts in estrogen receptor-positive (ER⁺) primary breast tumors of patients with lymph node-negative (LNN) disease to identify miRNAs ...associated with metastatic capability. In addition, the prognostic value of the candidate miRNAs was determined in ER⁻/LNN breast cancer. Unsupervised analysis in a prescreening set of 38 patients identified three subgroups predominantly driven by three miRNA signatures: an ER-driven luminal B-associated miRNA signature, a stromal miRNA signature, and an overexpressed miRNA cluster located on chromosome 19q23, but these intrinsic miRNA signatures were not associated with tumor aggressiveness. Supervised analysis in the initial subset and subsequent analysis in additional tumors significantly linked four miRNAs (miR-7, miR-128a, miR-210, and miR-516-3p) to ER⁺/LNN breast cancer aggressiveness (n = 147) and one miRNA (miR-210) to metastatic capability in ER⁻/LNN breast cancer (n = 114) and in the clinically important triple-negative subgroup (n = 69) (all P < 0.05). Bioinformatic analysis coupled miR-210 to hypoxia/VEGF signaling, miR-7 and miR-516-3p to cell cycle progression and chromosomal instability, and miR-128a to cytokine signaling. In conclusion, our work connects four miRNAs to breast cancer progression and to several distinct biological processes involved therein.
A number of microarray studies have reported distinct molecular profiles of breast cancers (BC), such as basal-like, ErbB2-like, and two to three luminal-like subtypes. These were associated with ...different clinical outcomes. However, although the basal and the ErbB2 subtypes are repeatedly recognized, identification of estrogen receptor (ER) -positive subtypes has been inconsistent. Therefore, refinement of their molecular definition is needed.
We have previously reported a gene expression grade index (GGI), which defines histologic grade based on gene expression profiles. Using this algorithm, we assigned ER-positive BC to either high-or low-genomic grade subgroups and compared these with previously reported ER-positive molecular classifications. As further validation, we classified 666 ER-positive samples into subtypes and assessed their clinical outcome.
Two ER-positive molecular subgroups (high and low genomic grade) could be defined using the GGI. Despite tracking a single biologic pathway, these were highly comparable to the previously described luminal A and B classification and significantly correlated to the risk groups produced using the 21-gene recurrence score. The two subtypes were associated with statistically distinct clinical outcome in both systemically untreated and tamoxifen-treated populations.
The use of genomic grade can identify two clinically distinct ER-positive molecular subtypes in a simple and highly reproducible manner across multiple data sets. This study emphasizes the important role of proliferation-related genes in predicting prognosis in ER-positive BC.
We explored whether the five previously reported molecular subtypes in breast cancer show a preference for organ-specific relapse and searched for molecular pathways involved. The "intrinsic" gene ...list describing the subtypes was used to classify 344 primary breast tumors of lymph node-negative patients. Fisher exact tests were used to determine the association between a tumor subtype and a particular site of distant relapse in these patients who only received local treatment. Modulated genes and pathways were identified in the various groups using Significance Analysis of Microarrays and Global Testing. Bone relapse patients were most abundant in the luminal subtypes but were found less than expected in the basal subtype. The reverse was true for lung and brain relapse patients with the remark that absence of lung relapse was luminal A specific. Finally, a pleura relapse, although rare, was found almost exclusively in both luminal subtypes. Many differentially expressed genes were identified, of which several were in common in a subtype and the site to which the subtype preferentially relapsed. WNT signaling was up-regulated in the basal subtype and in brain-specific relapse, and down-modulated in the luminal B subtype and in bone-specific relapse. Focal adhesion was found up-regulated in the luminal A subtype but down-regulated in lung relapse. The five major molecular subtypes in breast cancer are evidently different with regard to their ability to metastasize to distant organ(s), and share biological features and pathways with their preferred distant metastatic site.
In a comparison of mammography with magnetic resonance imaging (MRI) for screening women at high risk for breast cancer, MRI was more sensitive but less specific than mammography.
A comparison of ...mammography with magnetic resonance imaging in more than 1000 women with a genetic or familial predisposition to breast cancer.
The cumulative lifetime risk of breast cancer among Dutch women is approximately 11 percent.
1
A family history of breast cancer or the presence of a germ-line mutation of the
BRCA1
or
BRCA2
gene increases this risk considerably and is often associated with a diagnosis at a young age.
2
,
3
Among high-risk women, the risk of breast cancer can be reduced by prophylactic mastectomy,
4
,
5
prophylactic oophorectomy,
6
,
7
or chemoprevention.
8
Early diagnosis as a result of intensive surveillance may also decrease the rate of death from breast cancer.
Randomized trials have shown that mammographic screening of all women who are between . . .
To understand the biology of low-risk breast cancer alleles, and to investigate whether these loci also contribute to disease progression that was once established, we examined the association of ...SNPs tagging the low-risk breast cancer loci in or near
FGFR2
,
LSP1
,
MAP3K1,
H19
,
TOX3
,
POU5F1P1
,
MYC
, and 2q35, with clinical, pathological characteristics, prognosis, and mRNA expression of the nearest genes. Tumor DNA samples of 2,480 breast cancer patients were available. Out of this cohort, 1,290 patients with lymph-node negative disease who did not receive adjuvant systemic therapy, the SNP status was associated with metastasis-free survival (MFS). In 1,401 patients, the mRNA expression levels of
FGFR2
,
LSP1
,
MAP3K1,
H19
,
TOX3
,
POU5F1P1,
and
MYC
were determined and correlated with SNP genotypes. The SNP rs2981582 in
FGFR2
was significantly associated with positive ER and PgR status (
P
< 0.001 and
P
= 0.003, respectively). No other significant associations with patient or tumor characteristics were observed. Only rs2107425 near
H19
was significantly associated with shorter MFS in uni- and multi-variate analysis (HR: 1.53, CI: 1.12–2.08,
P
= 0.006 and HR: 1.59, CI: 1.16–2.20,
P
= 0.004, respectively), with the more aggressive minor allele displaying a recessive trait. The minor allele of SNP rs3803662 located near the
TOX3
gene was associated with lower mRNA expression of this gene. In conclusion, except for the association of rs13283662 with
TOX3
gene expression indicating a tumor suppressor role of
TOX3
, our findings suggest that breast cancer low-risk loci generally do not affect expression of the nearest gene in breast tumor tissue. Also the prognosis of patients is largely not affected by low-risk breast cancer loci except for the SNP near
H19.
How, this SNP affects prognosis warrants further study as it does not operate through altering
H19
mRNA expression.
Epithelial to mesenchymal transition (EMT) is typically defined by the acquisition of a spindle cell morphology in combination with loss of E-cadherin and upregulation of mesenchymal markers. ...However, by studying E-cadherin inactivation in 38 human breast cancer cell lines, we noted that not all cell lines that had undergone EMT had concomitantly lost E-cadherin expression. We further investigated this discrepancy functionally and in clinical breast cancer specimens. Interestingly, reconstitution of wild-type
E
-
cadherin
cDNA in a E-cadherin negative cell line that had undergone EMT (MDA-MB-231) did not revert the spindle morphology back to an epithelial morphology. Neither were changes observed in the expression of several markers known to be involved in the EMT process. Similarly, upregulation of E-cadherin via global DNA demethylation in eleven cell lines that had undergone EMT did not induce a change in cell morphology, nor did it alter the expression of EMT markers in these cells. Next, we extracted genes differentially expressed between cell lines that had undergone EMT versus cell lines that had not undergone EMT. Caveolin-1 was identified to be an excellent marker for EMT, irrespective of E-cadherin status (specificity and sensitivity of 100 %). Consistent with our observations in the breast cancer cell lines, expression of Caveolin-1 identified a subset of basal breast cancers, particularly of metaplastic pathology, and only 50 % of these lacked E-cadherin expression. The discrepancy between E-cadherin loss and EMT was thus reproduced in clinical samples. Together, these results indicate that in human breast cancer loss of E-cadherin is not causal for EMT and even not a necessity.
The biology of tumors relapsing to bone is poorly understood. In this study, we initiated a search for genes that are implicated in tumors relapsing to bone in breast cancer.
We analyzed 107 primary ...breast tumors in patients who were all lymph node negative at the time of diagnosis and all had experienced relapse. Total RNA isolated from frozen tumor samples was used to gather gene expression data using oligo microarrays.
A panel of 69 genes was found significantly differentially expressed between patients who experienced relapse to bone versus those who experienced relapse elsewhere in the body. The most differentially expressed gene, TFF1, was confirmed by quantitative reverse transcriptase polymerase chain reaction in an independent cohort (n = 122; P = .0015). Our differentially expressed genes, combined with a recently reported gene set relevant to tumors relapsing to bone in an animal model system, pointed to the involvement of the fibroblast growth factor receptor signaling pathway in preference of tumor cells that relapse to bone. Given that patients who experience relapse to bone may benefit from bisphosphonate therapy, we developed a classifier of 31 genes, which in an independent validation set correctly predicts all tumors relapsing to bone with a specificity of 50%.
Our study identifies a panel of genes relevant to bone metastasis in breast cancer. The subsequently developed classifier of tumors relapsing to bone could, after thorough confirmation on an extended number of independent samples, and in combination with our previously developed high-risk profile, provide a diagnostic tool for the recommendation of adjuvant bisphosphonate therapy in addition to endocrine therapy or chemotherapy.
BRCA1/2 mutation carriers and women from a hereditary breast(/ovarian) cancer family have a highly increased risk of developing breast cancer (BC). Prophylactic mastectomy (PM) results in the ...greatest BC risk reduction. Long-term data on the efficacy and sequels of PM are scarce.
From 358 high-risk women (including 236 BRCA1/2 carriers) undergoing PM between 1994 and 2004, relevant data on the occurrence of BC in relation to PM, complications in relation to breast reconstruction (BR), mutation status, age at PM and preoperative imaging examination results were extracted from the medical records, and analyzed separately for women without (unaffected, n = 177) and with a BC history (affected, n = 181).
No primary BCs occurred after PM (median follow-up 4.5 years). In one previously unaffected woman, metastatic BC was detected almost 4 years after PM (primary BC not found). Median age at PM was younger in unaffected women (P < .001), affected women more frequently were 50% risk carriers (P < .001). Unexpected (pre)malignant changes at PM were found in 3% of the patients (in 5 affected, and 5 unaffected women, respectively). In 49.6% of the women opting for BR one or more complications were registered, totaling 215 complications, leading to 153 surgical interventions (71%). Complications were mainly related to cosmetic outcome (36%) and capsular formation (24%).
The risk of developing a primary BC after PM remains low after longer follow-up. Preoperative imaging and careful histological examination is warranted because of potential unexpected (pre)malignant findings. The high complication rate after breast reconstruction mainly concerns cosmetic issues.
PDF
