Human epidermal growth factor receptor-2 and estrogen receptor expression, a demonstration project using the residual tissue repository of the Surveillance, Epidemiology, and End Results (SEER) program.

BACKGROUND: In 2001, the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program established Residual Tissue Repositories (RTR) in the Hawaii, Iowa, and Los Angeles Tumor Registries to collect discarded tissue blocks from pathologic laboratories within their catchment areas. To validate the utility of the RTR for supplementing SEER's central database, we assessed human epidermal growth factor receptor-2 (HER2) and estrogen receptor expression (ER) in a demonstration project. MATERIALS: Using a prepared set of tissue microarrays (TMAs) residing in the Hawaii Tumor Registry (HTR), we performed standard immunohistochemistry. Breast cancers in the TMA were diagnosed in 1995, followed through 2006, and linked to SEER's main database. RESULTS: The TMA included 354 cases, representing 51% of 687 breast cancers in the HTR (1995). The HTR and TMA cases were similar with respect to patient demographics and tumor characteristics. Seventy-six percent (76%, 268 of 354) of TMA cases were HER2+ and/or ER+, i.e., 28 HER2+ER-, 12 HER2+ER+, and 228 HER2-ER+. There were 67 HER2-ER- cases and 19 were unclassified. Age distributions at diagnosis were bimodal with dominant early-onset modes for HER2+ER- tumors and dominant late-onset modes for HER2-ER+ breast cancers. Epidemiologic patterns for concordant HER2+ER+ (double-positive) and HER2-ER- (double-negative) were intermediate to discordant HER2+ER- and HER2-ER+. CONCLUSION: Results showed contrasting incidence patterns for HER2+ (HER2+ER-) and ER+ (HER2-ER+) breast cancers, diagnosed in 1995. Though sample sizes were small, this demonstration project validates the potential utility of the RTR for supplementing the SEER program.

Systematic review of the impact of breast-conserving surgery on cancer outcomes of multiple ipsilateral breast cancers.

BACKGROUND: The clinical effectiveness of treating ipsilateral multifocal (MF) and multicentric (MC) breast cancers using breast-conserving surgery (BCS) compared with the standard of mastectomy is uncertain. Inconsistencies relate to definitions, incidence, staging and intertumoral heterogeneity. The primary aim of this systematic review was to compare clinical outcomes after BCS versus mastectomy for MF and MC cancers, collectively defined as multiple ipsilateral breast cancers (MIBC). METHODS: Comprehensive electronic searches were undertaken to identify complete papers published in English between May 1988 and July 2015, primarily comparing clinical outcomes of BCS and mastectomy for MIBC. All study designs were included, and studies were appraised critically using the Newcastle-Ottawa Scale. The characteristics and results of identified studies were summarized. RESULTS: Twenty-four retrospective studies were included in the review: 17 comparative studies and seven case series. They included 3537 women with MIBC undergoing BCS; breast cancers were defined as MF in 2677 women, MC in 292, and reported as MIBC in 568. Six studies evaluated MIBC treated by BCS or mastectomy, with locoregional recurrence (LRR) rates of 2-23 per cent after BCS at median follow-up of 59·5 (i.q.r. 56-81) months. BCS and mastectomy showed apparently equivalent rates of LRR (risk ratio 0·94, 95 per cent c.i. 0·65 to 1·36). Thirteen studies compared BCS in women with MIBC versus those with unifocal cancers, reporting LRR rates of 2-40 per cent after BCS at a median follow-up of 64 (i.q.r. 57-73) months. One high-quality study reported 10-year actuarial LRR rates of 5·5 per cent for BCS in 300 women versus 6·5 per cent for mastectomy among 887 women. CONCLUSION: The available studies were mainly of moderate quality, historical and underpowered, with limited follow-up and biased case selection favouring BCS rather than mastectomy for low-risk patients. The evidence was inconclusive, weakening support for the St Gallen consensus and supporting a future randomized trial.

Spatiotemporal control of estrogen-responsive transcription in ERα-positive breast cancer cells.

Recruitment of transcription machinery to target promoters for aberrant gene expression has been well studied, but underlying control directed by distant-acting enhancers remains unclear in cancer development. Our previous study demonstrated that distant estrogen response elements (DEREs) located on chromosome 20q13 are frequently amplified and translocated to other chromosomes in ERα-positive breast cancer cells. In this study, we used three-dimensional interphase fluorescence in situ hybridization to decipher spatiotemporal gathering of multiple DEREs in the nucleus. Upon estrogen stimulation, scattered 20q13 DEREs were mobilized to form regulatory depots for synchronized gene expression of target loci. A chromosome conformation capture assay coupled with chromatin immunoprecipitation further uncovered that ERα-bound regulatory depots are tethered to heterochromatin protein 1 (HP1) for coordinated chromatin movement and histone modifications of target loci, resulting in transcription repression. Neutralizing HP1 function dysregulated the formation of DERE-involved regulatory depots and transcription inactivation of candidate tumor-suppressor genes. Deletion of amplified DEREs using the CRISPR/Cas9 genomic-editing system profoundly altered transcriptional profiles of proliferation-associated signaling networks, resulting in reduction of cancer cell growth. These findings reveal a formerly uncharacterized feature wherein multiple copies of the amplicon congregate as transcriptional units in the nucleus for synchronous regulation of function-related loci in tumorigenesis. Disruption of their assembly can be a new strategy for treating breast cancers and other malignancies.

Significance of axillary lymph node metastasis in primary breast cancer.

PURPOSE: Axillary lymph node status is the single most important prognostic variable in the management of patients with primary breast cancer. Yet, it is not known whether metastasis to the axillary nodes is simply a time-dependent variable or also a marker for a more aggressive tumor phenotype. The purpose of this study was to determine whether nodal status at initial diagnosis predicts outcome after relapse and therefore also serves as a marker of breast cancer phenotype. PATIENTS AND METHODS: Survival experience after first relapse in 1,696 primary breast cancer cases was analyzed using Cox proportional hazards regression. The following explanatory variables and their first-order interactions were considered: number of axillary lymph nodes involved (zero v one to three v four or more), hormone receptor status (any estrogen receptor [ER] negativity v ER negativity/progesterone receptor positivity v other ER positivity), primary tumor size (< 2 cm v 2 to 5 cm v > 5 cm), site of relapse (locoregional v distant), disease-free interval (< 1.5 years v 1.5 to 3 years v > 3 years), adjuvant endocrine therapy (none v any), adjuvant chemotherapy (none v any), and menopausal status (pre-, peri-, or postmenopausal). RESULTS: Axillary lymph node status, site of relapse, and hormone receptor status were all highly significant as main effects in the model. After adjustment for other variables, disease-free interval alone was only modestly significant but interacted with nodal status. After disease-free interval, hormone receptor status, and site of relapse were accounted for, survival after relapse was poorer in node-positive cases, when compared with node-negative cases. The hazard ratios for patients with one to three and four or more involved nodes were 1.2 (95% confidence interval [CI], 0.8 to 1.9) and 2.5 (95% CI, 1.8 to 3.4), respectively. CONCLUSION: Patients with four or more involved nodes at initial diagnosis have a significantly worse outcome after relapse than node-negative cases, regardless of the duration of the disease-free interval. We conclude that nodal metastasis is not only a marker of diagnosis at a later point in the natural history of breast cancer but also a marker of an aggressive phenotype.

Neoadjuvant progesterone therapy for primary breast cancer: rationale for a clinical trial.

The hormonal milieu at the time of surgery may influence mortality and disease-free survival in patients with primary breast cancer. Indeed, there is evidence that circulating unopposed estrogen is detrimental and that the presence of circulating progesterone results in an improved disease-free and overall survival rate. Thus patients who receive neoadjuvant progesterone therapy may have a better outcome. A randomized controlled trial in which women with primary breast cancer receive either progesterone or placebo before surgery is urgently needed to confirm this hypothesis.

Surgical treatment of early-stage breast cancer in the Department of Defense Healthcare System.

BACKGROUND: The choice between breast-conserving surgery and modified radical mastectomy in the treatment of women with early stage breast cancer in the Department of Defense Healthcare System may be influenced by demographic factors. STUDY DESIGN: The Department of Defense Automated Central Tumor Registry (ACTUR) was queried for women diagnosed with American Joint Committee on Cancer Stage I or II invasive breast carcinoma from January 1, 1986, to December 31, 1996. Univariate analysis and multivariate analysis were applied to the study variables. Year of diagnosis, age at diagnosis, tumor size, type of hospital, geographic region, and local availability of radiation therapy were evaluated with respect to the type of surgical treatment performed. Surgical treatment was either breast conservation therapy (BCT) or modified radical mastectomy. RESULTS: After excluding women for whom the data were incomplete (n = 308), 7,815 women were identified who met study criteria. There was a progressive increase in the use of BCT to treat tumors of all sizes from 16% to 47% over the 11 years of the study (p < 0.0001). BCT was more frequently used for smaller tumors (< 2cm), with an odds ratio of 2.46 (2.20-2.76, 95% CI). In 1996, 54% of women with T1 (< 2 cm) tumors were treated with BCT. Women treated with BCT were nearly the same age as those undergoing modified radical mastectomy (55.5 years versus 56.8 years, p < 0.0001). BCT was used at a slightly greater rate in medical centers than in community hospitals (31% versus 28%, p < 0.0001). Use of BCT varied among geographic regions from a low of 24% in the southwestern USA to a peak of 36% in the Northeast and 40% in hospitals outside of the continental United States (p < 0.0001). Local availability of radiation therapy did not influence choice of treatment. CONCLUSIONS: The use of BCT to treat early stage invasive breast carcinoma in the Department of Defense Healthcare System is increasing. But BCT is used less often to treat larger tumors. Regional differences in the use of BCT persist, even after controlling for other factors. Patient age and type of hospital (community versus academic center) appear to exert little influence on the choice of treatment. Local availability of radiation therapy did not seem to influence the choice of treatment. Our data suggest that efforts to promote the use of BCT should target the central and southwestern USA. Use of BCT should also be emphasized for women with larger tumors (> 2 cm).

Breast cancer screening.

PURPOSE AND DESIGN: Three breast cancer screening methods are commonly employed: mammography, breast self examination (BSE), and physical examination by trained personnel (PE). Case-control, retrospective, and prospective studies have examined the efficacy of these screening modalities in reducing breast cancer mortality. However, there are three biases pertinent to many of these studies: lead-time, length, and selection biases. The best way to exclude these biases is to compare screened and unscreened women in a randomized controlled trial with breast cancer mortality as the end point. Eight trials have examined the effect of mammographic screening on breast cancer mortality and two have examined the impact of screening with BSE. In addition, a large trial will soon be initiated in India to assess the impact of screening by PE on breast cancer mortality. This article reviews these trials and discusses the implications of the studies. RESULTS: The overall results of the randomized controlled trials indicate that mammographic screening in women over age 50 can reduce breast cancer mortality by about 25%. However, its efficacy in women between the ages of 40 and 49 is disputed, and another large trial has been initiated in the United Kingdom to resolve this controversy. Preliminary results of two trials indicate that BSE has no impact on breast cancer mortality. However, longer follow-up of these trials is necessary before drawing any conclusions regarding BSE. CONCLUSIONS: Mammographic screening in postmenopausal women is an effective means of reducing breast cancer mortality. However, the impact of mammographic screening on breast cancer mortality in premenopausal women is disputed. At least four potentially harmful consequences of mammographic screening merit consideration: lead time effect, radiation exposure, false-positives, and overdiagnosis. Thus, women between the ages of 40 and 49, in particular, should be informed of the potential for benefit and harm prior to mammographic screening.

The natural history of breast cancer.

The natural history of breast cancer has not been fully elucidated, but physicians are making progress in the treatment of patients with this disease. Randomized, controlled trials indicate that screening, adjuvant systemic therapy, and adjuvant radiotherapy can reduce the risk for death caused by breast cancer. More importantly, national statistics show that breast cancer death rates are now decreasing (after remaining stagnant for nearly 40 years), but additional investigation into the natural history of breast cancer is clearly warranted. The randomized controlled trials on screening and local therapy, in particular, provide important insights into the natural history of the disease. Thus, the results of these trials should serve as a basis for additional investigation. Ultimately, a better understanding of the natural history of breast cancer may translate into improved treatments and better outcomes.

Management of the axilla in primary breast cancer.

Treatment of the axilla with either radiotherapy or surgery remains an integral part of the management of patients with invasive breast cancer. In general, the standard treatment of the axilla involves a partial ALND (surgical clearance of axillary nodes from levels I and II). There is as yet no evidence that axillary treatment improves survival, but the issue remains controversial. Axillary lymph node dissection is an effective staging procedure and is essential for local control of disease in the axilla, although, with increased emphasis on mammographic screening and early detection, the incidence of node-positive breast cancers is decreasing. Today, only about 30% to 40% of all invasive breast cancers are node-positive. Thus, in most cases, the potential morbidity of ALND could be avoided if the status of the axillary nodes were ascertained with a less invasive procedure. The SLNB may eventually prove to be a preferred alternative to routine ALND. It must first be demonstrated, however, that SLNB (without completion ALND) does not adversely affect outcome. Randomized controlled trials must address these concerns, and surgeons must await completion of these studies before accepting SLNB as the standard of care.

Breast cancer: a systemic or local disease?

Since ancient times, controversy has centered on whether breast cancer is a systemic or local disease at inception. In recent years, support for the systemic hypothesis has come from randomized clinical trials showing that variations in locoregional therapy have no impact on breast cancer mortality. Yet at first glance, the results of the breast cancer screening trials seem to refute this hypothesis. These trials indicate that screening reduces breast cancer mortality by 30% in postmenopausal women. This could be interpreted to mean that 30% of postmenopausal breast cancers metastasize relatively late in their natural history and are therefore amenable to cure with early diagnosis and timely extirpation. Closer scrutiny of the results of the screening trials, however, shows that screening changes the slope of the breast cancer survival curves (so that survival is prolonged) but does not cause the curves to plateau. Thus, screening may simply increase the time to recurrence and death, rather than eliminate the risk of death for a fraction of postmenopausal women with breast cancer. One may speculate that the timely extirpation of the primary tumor reduces the burden of micrometastatic disease, allowing the host's own defense to exert an effect. Alternatively, the benefit of screening is perhaps the result of early administration of systemic therapy, when the burden of micrometastatic disease is low. Regardless, the results of the screening trials are not necessarily inconsistent with the systemic hypothesis. Longer follow-up of women enrolled in the screening trials may prove useful in better understanding the natural history of breast cancer.

American and European recommendations for screening mammography in younger women: a cultural divide?

The American Cancer Society advocates mammography screening for all women from age 40, whereas in Europe it is not recommended for women below the age of 50. Randomised prospective studies have failed to show a significant benefit from screening women aged under 50 and five potentially harmful effects of screening should be considered: lead time, overdiagnosis, radiation exposure, false positive results, and cost. Younger women must be properly informed about the potential for harm as well as for benefit before screening.

Timing of surgery for primary breast cancer with regard to the menstrual phase and prognosis.

The hormonal milieu of the patient at the time of surgery may influence the prognosis of patients with primary breast cancer. Circulating unopposed estrogen is perhaps detrimental, while circulating progesterone may confer a survival advantage. This hypothesis has particular relevance to the timing of surgery in relation to the menstrual cycle. After all, the first 14 days of the menstrual cycle (follicular phase) are characterized by high levels of circulating unopposed estrogen, while circulating progesterone is present during the second 14 days of the cycle (luteal phase). Several retrospective studies have shown that surgery during the follicular phase of the menstrual cycle results in a worse disease-free and overall survival. Randomized controlled trials addressing the effect of timing of surgery or neoadjuvant hormonal therapy on breast cancer mortality are urgently needed to confirm or refute the unopposed estrogen hypothesis. Such trials may provide important insights into the natural history of breast cancer, and a basis for significantly reducing breast cancer mortality.

Immune response in experimentally induced uremia. VII. Uremic thymocytes amplify the response of control lymph node cells to alloantigens.

The effect of experimentally induced uremia in the rat on the synergistic response between thymus cells (TC) and lymph node cells (LNC) was examined. It was found that: (1) Uremic TC and LNC interact in a synergistic fashion which is greater than that observed for control cells; (2) The response of uremic LNC to alloantigens is suppressed when compared to the response of control LNC; (3) Uremic TC provide more help to control LNC in their response to alloantigens than do control TC; and (4) Treatment of uremic rats with cortisone acetate (CA) enhances their TC ability to amplify control LNC response to alloantigens. Thus, it appears that, while the response of uremic LNC to alloantigens is markedly suppressed, there are potent amplifier cells present in the thymus of uremic rats which have the ability to act in synergism with control LNC in response to alloantigens. This effect is significantly greater than the synergistic activity of control thymocytes.

Neonatal macrosomia in maternal diabetes.

In order to determine the effect of maternal diabetes on the somatic growth of the rat fetus and to elucidate mechanisms underlying the control of fetal growth, concentrations of DNA and proteins and DNA polymerase-alpha activities in neonates were examined. The maternal status was classified as normal (no urinary glucose excretion), mildly diabetic (0.01-0.99 g/day urinary glucose), and severely diabetic (1.00 g/day or more urinary glucose). The total DNA contents in mg/neonate were 26.8 +/- 2.2 (mean +/- SEM), 31.3 +/- 2.5, and 29.4 +/- 2.7 for neonates from normal, mildly diabetic and severely diabetic mothers, respectively. The DNA polymerase activities in (cpm/g neonate) X 10(-3) for the same groups of neonates were 432 +/- 58, 1,008 +/- 74, and 888 +/- 118, respectively. These results indicate that the neonatal macrosomia disappears as the severity of maternal diabetes increases. Furthermore, DNA polymerase is one of possible biochemical sites through which macrosomia is manifested in diabetic pregnancies.