乳腺癌中ERα、PR的表达与预后关系及其影响阳性率的相关因素

目的分析乳腺癌中ERα、PR的阳性率与预后的关系,探讨影响ERα、PR阳性率的相关因素。方法采用免疫组化En Vision法检测662例乳腺癌组织中ERα、PR的表达,按不同阳性率分组,Kaplan-Meier法分析预后。选择其中的80例采用两种克隆号ERα(SP1、6F11)染色并由一位高年资医师判读,以分析不同克隆号对阳性率的影响;选择其中的214例ERα(SP1)由三位不同年资医师采用Allred score、H score两种判读系统分别判读,以观察不同判读系统及医师经验对阳性率的影响。一致性采用Kappa检验。结果生存分析显示,ERα、PR低阳性组无病生存率(disease-free survival,DFS)、总生存率(overall survival,OS)均优于阴性组(DFS:P=0.021、0.003)、(OS:P=0.019、0.003),ERα、PR高阳性组DFS、OS均优于低阳性组(DFS:P=0.011、0.002)、(OS:P=0.012、0.005)。浸润性癌非特指型、浸润性小叶癌、导管原位癌ERα阳性率分别为59.5%、78.9%、63.6%,差异有统计学意义(P=0.002),PR阳性率分别为56.3%、68.9%、59.1%,差异无统计学意义(P=0.079)。不同组织学分级的浸润性癌非特指型ERα、PR阳性率差异有统计学意义(P均0.001)。不同核级导管原位癌ERα、PR阳性率差异有统计学意义(P均0.05)。克隆号SP1阳性细胞百分率、染色强度均优于6F11;判读系统H score重复性略优于Allred score;高年资医师间阳性细胞百分率、染色强度判读重复性好(κ=0.850,κ=0.824),而高年资和低年资医师之间重复性均较差(0.4κ0.75);阳性细胞百分率估计法与计数法重复性较差(κ=0.726)。结论 ERα、PR不同阳性细胞百分率与患者预后密切相关,影响ERα、PR阳性率的因素包括病理类型、组织学分级、核分级、抗体的选择、判读系统及判读医师间的差异等。     

Prolactin does not cause breast cancer and may prevent it or be therapeutic in some conditions

The polypeptide hormone prolactin (PRL), ubiquitous and multifunctional in vertebrates, always interested biologists, was of restricted concern to clinicians and researched little compared to insulin and growth hormone. PRL in lactation initially aroused relatively little interest, but it rose when with ovarian steroids and chemical carcinogens, it was implicated in rodent mammary carcinoma. It declined when PRL suppression did not counter breast cancer. Meanwhile, long-known, estrogen-related cancers in the ovary and breast did not deter wide estrogen use for contraception and supplementation despite risk, and estrogen blockers and inhibitors have improved treatment and are on trial for prophylaxis, despite serious short and long term side-effects. Despite the great differences between steroid and polypeptide, research on PRL and breast cancer mirroring that on estrogens is now growing. This is mainly negative, much due to recent prospective research reporting minor rises in plasma levels as a basis, together with some recent laboratory research, for a hypothesis that PRL induces post-menopausal breast cancer. That view contradicts a reproductive biology that evolved to benefit women and offspring. Elevated PRL in pregnancy and probably that in lactation, reduce risk. Many exogenous chemical and physical PRL-stimulants also do not increase risk. It has not been shown that PRL increases risk of breast cancer and some older and recent cell and tissue data suggest it may be the key, two-sided, in human breast tissue homeostasis. Excessive disturbance of this is unlikely to originate in PRL itself. The natural biology of PRL, the reproductive woman's hormone par excellence, and research in various fields, suggest a positive potential in the PRL family for direct prevention and treatment of breast cancer, possibly greater than that in the estrogens. It is time to debate and research this.     

11q13 is a susceptibility locus for hormone receptor positive breast cancer

A recent two-stage genome-wide association study (GWAS) identified five novel breast cancer susceptibility loci on chromosomes 9, 10, and 11. To provide more reliable estimates of the relative risk associated with these loci and investigate possible heterogeneity by subtype of breast cancer, we genotyped the variants rs2380205, rs1011970, rs704010, rs614367, and rs10995190 in 39 studies from the Breast Cancer Association Consortium (BCAC), involving 49,608 cases and 48,772 controls of predominantly European ancestry. Four of the variants showed clear evidence of association (P ≤ 3 × 10(-9) ) and weak evidence was observed for rs2380205 (P = 0.06). The strongest evidence was obtained for rs614367, located on 11q13 (per-allele odds ratio 1.21, P = 4 × 10(-39) ). The association for rs614367 was specific to estrogen receptor (ER)-positive disease and strongest for ER plus progesterone receptor (PR)-positive breast cancer, whereas the associations for the other three loci did not differ by tumor subtype.     

Obesity is associated with a poorer prognosis in women with hormone receptor positive breast cancer

Objective

Whether moderate to severe obesity (body mass index (BMI) ≥ 30 to <40 kg/m²) contributes to breast cancer recurrence and mortality remains uncertain.

Subjects and methods

1199 women, recruited within 12 months of their diagnosis of hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2−) invasive breast cancer completed an enrolment questionnaire and an annual follow-up questionnaire every 12 months for another 5 years. The impact of obesity on time to either local or distant recurrence or new breast cancer, or death due to breast cancer was determined by Cox regression. Women in the most extreme categories of BMI (<18.5 and ≥40) were excluded from the analysis.

Results

Of the 1155 included women, mean age, 58.4 ± 11.6 years, 53.8% had Stage 1 disease and 88.9% received oral adjuvant endocrine therapy (OAET) within 2 years of diagnosis. The likelihood of an event was significantly associated with moderate to severe obesity (HR = 1.71, 95%CI, 1.12–2.62, p = 0.014), disease beyond Stage 1 (HR = 2.87, 95% CI 1.73–4.75, p < 0.001), OAET (HR = 0.26, 95%CI 0.14–0.46, p < 0.001), mastectomy (HR = 3.28, 95%CI 1.98–5.44, p < 0.001) and radiotherapy (HR = 2.12, 95%CI 1.24–3.63, p = 0.006). For Stage 1 disease, only moderate to severe obesity (HR 3.23, 95%CI 1.48–7.03, p = 0.003) and OAET use (HR 0.41, 95%CI 0.17–0.98, p = 0.046) were significantly associated with an event.

Conclusion

Moderate to severe obesity is associated with a poorer invasive breast cancer prognosis; this is also true for women with Stage 1 disease, and is independent of age and treatment.     

Assessment of hormone receptor status in breast cancer

The aim of the present paper was to investigate the most adequate method for the assessment of hormone receptor status in breast cancer in routine clinical settings. Subjects were 486 patients with primary breast cancer who underwent surgery and postoperative tamoxifen monotherapy in 1982-1993. Using representative sections of the primary lesion in each patient, estrogen receptors (ER) were immunohistochemically stained. Patients were divided into ER-positive and ER-negative groups using various methods, and then overall and 5 year recurrence-free survival rates were compared. The results of ER status, which are diagnosed on entire cancer area and invasive cancer area, matched in 98% of cases. When assessing prognosis based on the proportion of positive cells, a significant difference in 5 year recurrence-free survival was seen between ER-positive and ER-negative patients for a cut-off of 10%, and in overall and 5 year survival for a cut-off of 33%. Based on the proportion and the intensity of positive cells (Allred score), a significant difference was seen in overall and 5 year survival for a cut-off in total scores between 4 and 5 points. When assessing hormone receptors of breast cancer in routine clinical settings, it is sufficient to determine the proportion of positive cells in the entire cancer area.     

致Graves病的人促甲状腺激素受体多肽位点筛查

目的通过检测人促甲状腺激素受体(thyroid-stimu lating hormone receptor,TSHR)多肽片段与人白细胞抗原(hum an leukocyte antigen,HLA)分子的结合力,寻找人TSHR作为自身抗原导致G raves病的多肽位点。方法应用ELISA方法检测31条人工合成的膜外区人TSHR多肽片段与8种HLA分子的结合,通过计算IC50值,确定能与G raves病易感基因HLA-DR3和HLA-DQA1*0501高亲和力结合的多肽片段,并检测它们与G raves病保护基因HLA-DR7及HLA-DQA1*0201的结合能力。结果合成的31条TSHR多肽片段与HLA-DR3及-DR7的结合能力相近,且半数以上的多肽片段能与HLA-DQA1*0501及-DQA1*0201高亲和力结合。人TSHR多肽片段与HLA-DR分子结合能力为DR2>DR5>DR18>DR3/DR7>DR1,而与HLA-DQ分子的结合则为DQA1*0201>DQA1*0501。人TSHR多肽片段183~198、195~210、248~263、301~320、343~362及357~376能同时与HLA-DR3及HLA-DQA1*0501高亲和力结合,IC50值均<1μmol/L;而它们与HLA-DR7及HLA-DQA1*0201的结合力低。结论膜外区人TSHR多肽片段183~198、195~210、248~263、301~320、343~362及357~376有可能为导致G raves病的自身抗原多肽位点。     

Information needs of post-menopausal women with hormone receptor positive early-stage breast cancer considering adjuvant endocrine therapy

Objective

To identify questions that post-menopausal women with receptor-positive early-stage breast cancer want answered before their adjuvant-endocrine-therapy decision is made.

Methods

We surveyed patients eligible for adjuvant-endocrine therapy in the previous 3–18 months. Participants rated the importance of getting each of 95 questions answered before the decision is made (options: essential/desired/not important or no opinion/avoid). For each question rated “essential”/“desired”, the participant also identified the purpose(s) for the answer: to help her understand, decide, plan, or other reason(s).

Results

The response rate was 55% (188/343). Participants rated a mean of 57 (range: 1–95) questions “essential”, 80 (range: 1–95) “essential” or “desired”, and 2 (range: 0–27) “avoid”. Every question was “essential” to ≥31% of participants, and “essential”/“desired” to ≥63%. All but eleven questions were rated as “avoid” by ≥1 participant. The most frequent purposes for “essential” questions were to: understand their situations (mean 45, range: 0–95), decide (mean 18, range: 0–94), and plan (mean 13, range: 0–95).

Conclusion

Many patients want a lot of information before this decision is made but there is wide variation within the group in both the number and in which questions they want answered.

Practice implications

Patient education in this setting needs to be tailored to the needs of the individual patient.     

Androgen receptor may be responsible for gender disparity in gastric cancer

Men are at a higher risk of developing gastric cancer than women. However, the exact mechanisms responsible for the gender differences remain unclear. Recently, a number of epidemiological and genotyping studies have attributed the gender disparity in male-predominant cancers to the disruption of androgen receptor (AR) homeostasis. Moreover, previous data indicated that AR expression is an independent unfavorable prognostic factor in gastric cancer, suggesting that AR may play an important role in gastric carcinogenesis. In addition, mounting evidence suggests that AR is involved in many signaling pathways associated with gastric carcinogenesis. On the basis of the aforementioned evidence, we postulate that AR exhibits oncogenic properties in gastric cancer via several possible mechanisms, which may partly explain the higher prevalence of gastric cancer among males.     

99mTc-thymine scintigraphy may be a promising method in the diagnosis of breast cancer

OBJECTIVE:

Mammography has been established as the gold standard for the detection of breast cancer, and imaging techniques such as ultrasonography, magnetic resonance imaging, scintigraphy and positron emission tomography may be useful to improve its sensitivity and specificity. The objective of this study with breast scintigraphy was to evaluate the uptake of 99mTc-thymine in mammary lesions.

METHODS:

A total of 45 patients were included in this study. Thirty-three patients (73%) were subjected to surgery or percutaneous biopsy, providing histopathological data. The other 12 patients who remained under surveillance received clinical examinations and biannual mammography with a normal follow-up of at least three years, the data from which were used for comparison with the scintimammography results.

RESULTS:

The majority of patients (64.4%) had clinically impalpable lesions with a mammogram diagnosis of microcalcifications, impalpable nodules, or focal asymmetry. Of the studied lesions, 87% were smaller or equal to 20 mm in diameter, and 22% had malignant histopathological findings. Scintigraphy with 99mTc-thymine had a sensitivity of 70%, a specificity of 85.7%, positive and negative predictive values of 58.3% and 90.9%, respectively, and an accuracy of 82.2%.

CONCLUSIONS:

The results of this study are consistent with those previously reported by other authors. The good specificity and high negative predictive value of this technique and the absence of uptake in the heart indicate that it may be a promising complementary method in clinical practice and that it may contribute to reducing unnecessary benign biopsies.     

Place of hormone receptor determination in the therapeutic strategy of breast cancer

Up to the discovery of hormonal receptors it was somewhat uncertain to prescribe hormonotherapy for the treatment of a breast cancer. The presence of estrogen receptors (ER) and progesterone receptors (PR) allows the estimation of the probability of hormone-dependence. The response to endocrine therapy will be expected with a rate of: 80% of the tumors PR +; 30% of the tumors ER+ but PR-; 10% of the tumors ER - and PR -. The response to chemotherapy is no accurately correlated with the concentration of receptors. The planning of therapy will be founded on the following principles. ER -: less favourable prognosis and unlikely response to endocrine therapy, therefore chemotherapy if the other prognostic factors are bad. ER +: endocrine therapy is required, especially if PR +. The role of chemotherapy ought to be discussed with respect to the other prognostic factors. All these factors are reviewed and a decision-tree of the treatment of advanced breast cancers is put forward. In short, it is obvious that the receptors assays have to be carried out as for as possible.     

Chromosomal alterations cause the high rates and wide ranges of drug resistance in cancer cells

Conventional mutation-selection theories have failed to explain (i) how cancer cells become spontaneously resistant against cytotoxic drugs at rates of up to 10(-3) per cell generation, orders higher than gene mutation, even in cancer cells; (ii) why resistance far exceeds a challenging drug-a state termed multidrug resistance; (iii) why resistance is associated with chromosomal alterations and proportional to their numbers; and (iv) why resistance is totally dependent on aneuploidy. We propose here that cancer-specific aneuploidy generates drug resistance via chromosomal alterations. According to this mechanism, aneuploidy varies the numbers and structures of chromosomes automatically, because it corrupts the many teams of proteins that segregate, synthesize, and repair chromosomes. Aneuploidy is thus a steady source of chromosomal variation from which, in classical Darwinian terms, resistance-specific aneusomies are selected in the presence of chemotherapeutic drugs. Some of the thousands of unselected genes that hitchhike with resistance-specific aneusomies can thus generate multidrug resistance. To test this hypothesis, we determined the rates of chromosomal alterations in clonal cultures of human breast and colon cancer lines by dividing the fraction of nonclonal karyotypes by the number of generations of the clone. These rates were about 10(-2) per cell generation, orders higher than mutation. Chromosome numbers and structures were determined in metaphases hybridized with color-coded chromosome-specific DNA probes. Further, we tested puromycin-resistant subclones of these lines for resistance-specific aneusomies. Resistant subclones differed from parental lines in four to seven specific aneusomies, of which different subclones shared some. The degree of resistance was roughly proportional to the number of these aneusomies. Thus, aneuploidy is the primary cause of the high rates and wide ranges of drug resistance in cancer cells.     

Usefulness of liquid-based cytology in hormone receptor analysis of breast cancer specimens

Immunohistochemical (IHC) analysis of the hormone receptor (HR) in breast cancer cytology is an important issue nowadays. Several studies have shown discrepancy in the HR status between the primary tumor and metastases. Cytology can be used for patients with metastatic disease. Although cytological assessment of HR is an excellent method, it has not been routinely used because of the difficulty in consistently preparing multiple good quality slides. Liquid-based cytology (LBC) preparation is considered as the key to resolving the aforementioned problem; however, few studies have reported the HR assessment in breast cancer using LBC. Therefore, the HR status of LBC slides from 82 breast cancers was compared with that of the corresponding surgical specimens. The HR assay in both the LBC slides and surgical specimens was conducted by IHC using an autostainer. For the IHC staining, the protocol recommended by the manufacturer for paraffin-embedded sections was used for both the cytology and histology specimens. The HR results of the cytology agreed with those of the histology in 80 of the 82 cases (accuracy rate, 98%) for estrogen receptor, and in 78 of the 82 cases (accuracy rate, 95%) for progesterone receptor. The overall accuracy of the HR status on the cytology and the histology was 99% in 81 of the 82 cases. In conclusion, in HR analysis of breast cancers, LBC followed by IHC using an autostainer was useful for the standard processing of cytological specimens and showed a good correlation with the results of analysis on the histology specimens.     

Chronic metabolic acidosis may be the cause of cachexia: body fluid pH correction may be an effective therapy

Cachexia is a pathological state characterized by weight loss and protein mobilization during various diseases. Nutritional supplementation or appetite stimulants are unable to restore the loss of lean body mass. Agents interfering with TNF-alpha have not been very successful to date. Only eicosapentaenoic acid was able to interfere with the action of proteolysis-inducing factors. An acceleration of proteolysis and branched-chain amino acid oxidation was correlated with chronic metabolic acidosis. Therefore, we suggest here that the main cause of cachexia is the increased acidity of the body fluids, which results in a higher and non-specific proteolysis of muscle proteins. Moderate hypoxia might be close related to lactic acid production within the whole body, not only in the cancer cells. Anorexia seems to be a consequence, but a cause of cachexia: the cachectic patients are in fact well fed, unfortunately they use fatty acids from their fat and glucose via muscle proteins, amino acids, alanine, and lactic acid. Our hypothesis is consistent with the most findings reported in literature and opens new ways for cachexia prevention and therapy, such as pH correction or higher oxygenation.     

The underlying cause of cervical cancer in oral contraceptive users may be related to cervical mucus changes

Oral contraceptives (OCs) remain among the most effective reversible methods of birth control available today, providing almost 100% effectiveness with an impressively high margin of safety and other important health benefits. However, concerns have been raised about the role that the hormones in OCs might play in the pathogenesis of cervical cancer. Evidence shows that long-term use of OCs (five or more years) may be associated with an increased risk of cancer of the cervix. The mechanism of increased risk of cervical cancer in OCs users has long been debated, and remains uncertain. Our hypothesis is that scanty, thick, and highly viscous cervical mucus obtained in OCs users intimately involved in the pathogenesis of cervical cancer. Possibly, this architecture of cervical mucus may modulate and prolong the effect of carcinogenic agents, which have been carried by coitus and stored in posterior vaginal fornix, on squamocolumnar junction of cervix by not permitting them to be removed because of its highly viscous pattern. The role of cervical mucus changes by means of specific mucin protein changes on the pathophysiology of cervical cancer in OCs users should be investigated.     

Bone mineral density in breast cancer patients with positive estrogen receptor tumor status

AIM: The aim was to investigate bone mineral density (BMD) in breast cancer patients with positive estrogen receptor (ER) tumor status. METHODS: The participants were 110 postmenopausal breast cancer patients with positive estrogen receptor (ER+) tumor status. Two hundred and sixty-one age-matched, healthy postmenopausal women, all of whom were selected from our pooled data, served as controls. Age, age at menopause, years since menopause (YSM), height, weight, and body mass index (BMI, wt/ht(2)) were recorded. Lumbar spine (L2-4) BMD and Z-score were assessed by dual-energy X-ray absorptiometry. RESULTS: Bone mineral density in breast cancer patients was significantly higher than that in controls (0.89+/-0.12 g/cm(2) versus 0.84+/-0.16 g/cm(2), P<0.01). The Z-score in breast cancer patients was also higher than that in controls (110+/-13.6% versus 100+/-9.8%, P<0.001). Higher BMD and Z-score in breast cancer patients remained significant after adjusting for age, YSM, and BMI (P<0.05). CONCLUSIONS: Postmenopausal breast cancer patients with positive ER tumor status have higher BMD. Positive ER tumor status may be associated with higher cumulative exposure to estrogen.     

Women's interest in genetic testing for breast cancer susceptibility may be based on unrealistic expectations

We report on results of an interview study assessing women's attitudes toward and hypothetical interest in genetic susceptibility testing for breast cancer. Data are from 246 interviews with women of varying ethnicity (African American, European American, Native American, and Ashkenazi Jewish), family history of breast cancer (negative, positive, and borderline), and educational level. Semistructured interviews included questions on general health beliefs; attitudes, experiences, and concerns about breast cancer; and hypothetical interest in genetic testing. Influence of specific test characteristics was assessed with 14 Likert scales varying negative and positive predictive value, timing of disease, possible medical interventions following a positive result. Results reported include both statistical and qualitative analysis. We found that women had a high level of interest in testing which, in general, did not vary by ethnicity, level of education, or family history. Interest in testing appeared to be shaped by an exaggerated sense of vulnerability to breast cancer, limited knowledge about genetic susceptibility testing, and generally positive views about information provided through medical screening. However, study participants were most interested in a test that didn't exist (high positive predictive value followed by effective, noninvasive, preventive therapy) and least interested in the test that does exist (less than certain positive predictive value, low negative predictive value, and limited, invasive, and objectionable therapeutic options). Our data suggest that without a careful counseling process, women could easily be motivated toward interest in a test which will not lead to the disease prevention they are seeking.