Long-term adverse health conditions, including secondary malignant neoplasms, are common in childhood cancer survivors. Although mortality attributable to secondary malignancies declined over the past decades, the risk for developing a solid secondary malignant neoplasm did not. Endocrine-related malignancies are among the most common secondary malignant neoplasms observed in childhood cancer survivors. In this systematic review, we describe risk factors for secondary malignant neoplasms of the breast and thyroid, since these are the most common secondary endocrine-related malignancies in childhood cancer survivors. Radiotherapy is the most important risk factor for secondary breast and thyroid cancer in childhood cancer survivors. Breast cancer risk is especially increased in survivors of Hodgkin lymphoma who received moderate- to high-dosed mantle field irradiation. Recent studies also demonstrated an increased risk after lower-dose irradiation in other radiation fields for other childhood cancer subtypes. Premature ovarian insufficiency may protect against radiation-induced breast cancer. Although evidence is weak, estrogen–progestin replacement therapy does not seem to be associated with an increased breast cancer risk in premature ovarian-insufficient childhood cancer survivors. Radiotherapy involving the thyroid gland increases the risk for secondary differentiated thyroid carcinoma, as well as benign thyroid nodules. Currently available studies on secondary malignant neoplasms in childhood cancer survivors are limited by short follow-up durations and assessed before treatment regimens. In addition, studies on risk-modifying effects of environmental and lifestyle factors are lacking. Risk-modifying effects of premature ovarian insufficiency and estrogen–progestin replacement therapy on radiation-induced breast cancer require further study.
M Wijnen, M M van den Heuvel-Eibrink, M Medici, R P Peeters, A J van der Lely, and S J C M M Neggers
R M O'Regan and F R Khuri
The ras family of proto-oncogenes are upstream mediators of several essential cellular signal transduction pathways involved in cell proliferation and survival. Point mutations of ras oncogenes result in constitutively active Ras and have been shown to be oncogenic. However, ras activation can occur in the absence of ras mutations secondary to upstream receptor activation. The first important step in Ras activation is farnesylation by farnesyl transferase, and inhibitors of this enzyme have been demonstrated to inhibit Ras signaling, and have anti-tumor effects. However, it is now clear that farnesyl transferase inhibitors (FTIs) have activity independent of Ras, most likely due to effects on prenylated proteins downstream of Ras, which explains their activity in several malignancies, including breast cancer, where ras mutations are rare. Several FTIs are in clinical development for the treatment of solid tumors. Preclinical evidence suggests that FTIs can inhibit breast cancers in vitro and in vivo, and a phase II trial of the FTI, R115777, in patients with advanced breast cancer produced encouraging results. Based on prior successful outcomes with agents targeting the estrogen and epidermal growth factor receptor pathways in breast cancer, the FTIs, used alone or more likely with other agents, may be the next exciting targeted therapy in breast cancer.
Erin E Swinstead, Ville Paakinaho, and Gordon L Hager
Reprogramming of the chromatin landscape is a critical component to the transcriptional response in breast cancer. Effects of sex hormones such as estrogens and progesterone have been well described to have a critical impact on breast cancer proliferation. However, the complex network of the chromatin landscape, enhancer regions and mode of function of steroid receptors (SRs) and other transcription factors (TFs), is an intricate web of signaling and functional processes that is still largely misunderstood at the mechanistic level. In this review, we describe what is currently known about the dynamic interplay between TFs with chromatin and the reprogramming of enhancer elements. Emphasis has been placed on characterizing the different modes of action of TFs in regulating enhancer activity, specifically, how different SRs target enhancer regions to reprogram chromatin in breast cancer cells. In addition, we discuss current techniques employed to study enhancer function at a genome-wide level. Further, we have noted recent advances in live cell imaging technology. These single-cell approaches enable the coupling of population-based assays with real-time studies to address many unsolved questions about SRs and chromatin dynamics in breast cancer.
Christian F Singer, Anneliese Fink-Retter, Daphne Gschwantler-Kaulich, Theresia Thalhammer, Gernot Hudelist, Ruth Mueller, Klaus Czerwenka, and Ernst Kubista
The suppression of local estrogens levels is of key importance in the treatment of ER-positive breast cancer. Essentially all endocrine strategies act by either suppressing estrogen formation or competitively inhibiting receptor-binding in tumor cells. Nevertheless, little is still known about the local expression of aromatase and sulfotransferase which are the key modulators of intra-tumoral estrogen levels. We have performed immunohistochemostry to investigate the expression of aromatase and sulfotransferase in 42 samples obtained directly from malignant breast tumors, and compared it to biopsies obtained from uninvolved tissue in the vicinity of the invasion front, and to distant breast tissue. We found that aromatase was equally detectable in both tumor epithelial and stroma, but was mostly epithelial in non-malignant tissues (P = 0.00008, Fisher’s exact test). Also, aromatase protein expression was significantly more common in tumoral stroma when compared with peritumoral and distant breast stroma (P = 0.00005, and P < 0.00001 respectively). With the notable exception of cystosarcoma phylloides, sulfotransferase protein was detectable only in epithelial tissues, regardless of the location within the diseased breast. However, epithelial sulfotransferase was correlated with epithelial aromatase (r = 0.35461, P = 0.0009, Spearman’s ρ test) and with the epithelial ER status (r = 0.29313, P = 0.005). We have demonstrated a differential aromatase and sulfotransferase protein expression pattern that is dependent on the spatial relation to a malignant breast tumor. Our results indicate a net increase in intratumoral active estrogen levels through increased stromal aromatization, while physiological local inactivation by sulfotransferase activity remains essentially unchanged.
C Knabbe and G Zugmaier
H Schmidberger, R M Hermann, C F Hess, and G Emons
Adjuvant radiotherapy and adjuvant endocrine therapy are commonly given to patients with invasive breast cancer or with ductal carcinoma in situ (DCIS). Although both therapies have been well established through a number of randomized studies, little is known about a possible interaction of both treatment modalities if they are given simultaneously. A number of in vitro studies have indicated that tamoxifen treatment might reduce the intrinsic radiosensitivity of MCF-7 breast cancer cells. Conversely, estradiol treatment increases the intrinsic radiosensitivity of MCF-7 cells. In one available animal study, an antagonistic effect of tamoxifen and ionizing radiation (XRT) could not be observed. Retrospective analyses of randomized clinical studies have not indicated an antagonistic effect of tamoxifen on the effectiveness of XRT, since local control has been consistently higher when XRT was combined with tamoxifen, compared with treatment with XRT alone, regardless of whether tamoxifen was started simultaneously with radiotherapy or after completion of radiotherapy. Currently there are no clinical data available that would suggest an adverse effect of adjuvant tamoxifen treatment started prior to or simultaneously with radiotherapy in breast cancer or DCIS. However, since an antagonistic effect of tamoxifen and simultaneous chemotherapy has been reported recently, the issue of simultaneous versus sequential radiation and tamoxifen treatment in breast cancer should be addressed in further studies.
C Orlando, C Casini Raggi, S Bianchi, V Distante, L Simi, V Vezzosi, S Gelmini, P Pinzani, M Cameron Smith, A Buonamano, E Lazzeri, M Pazzagli, L Cataliotti, M Maggi, and M Serio
Somatostatin analogs are effective in inhibiting growth of human breast cancer cell lines. These antiproliferative effects are mediated by specific receptors located on cell membranes. The somatostatin receptor subtype 2 (sst2) is the principal mediator of somatostatin effects in normal and cancer cells, and its presence has already been demonstrated in breast cancer. The purpose of our study was to evaluate the clinical relevance of the expression of sst2 by quantifying its mRNA in a large group of infiltrating breast cancers and their corresponding normal tissues. The expression of sst2 mRNA was measured with quantitative real time RT-PCR in 169 breast cancers and in their corresponding unaffected tissues. We evaluated the association of sst2 expression with the commonest clinical-pathologic features of breast cancer. The correlation with a marker of cell proliferation (Ki-67) and with receptor concentration was also evaluated. In cancer tissues, we found that the absolute concentrations of sst2 mRNA were significantly higher in estrogen receptor (ER)-positive samples (P=0.002) as well as in lymph-node-negative cancers (P=0.04) (Student's t-test or one-way ANOVA). In addition, sst2 mRNA was significantly higher in breast cancers than in corresponding unaffected tissues (P=0.0002). However, when the clinical-pathologic parameters were considered, this gradient maintained its statistical significance only in tumors expressing positive prognostic markers, such as the presence of ER (P=0.0005) and progesterone receptors (PgR) (P=0005), and the lack of lymph-node involvement (P=0.0003). The same difference was also significant in postmenopausal women (P=0.001) and in T1 patients (P=0.001). In addition, sst2 mRNA expression was significantly higher (P=0.008) in low-proliferating breast cancers. Finally, we found that the quantitative expression of sst2 mRNA was directly related to the PgR concentration in breast cancer tissues (P<0.001). Our data seem to indicate that an upregulation of sst2 gene expression is a common feature of breast cancers which, on the basis of conventional predictive parameters, are expected to have a better prognosis. Featuring a possible role of somatostatin analogs in combined endocrine therapies for breast cancer, our results seem to confirm that the sst2 status of the tumor should be previously investigated.
I Számel, B Budai, K Daubner, J Kralovánszky, Sz Ottó, J Tóth, and I Besznyák
Gross cystic disease (GCD) of the breast may be associated with a higher risk for the development of breast cancer. High levels of sex steroids, steroid hormone precursors, prolactin and cations have been found in breast cyst fluid (BCF) by several investigators. Accordingly, endocrine parameters and the cationic composition of BCF may be considered as useful characteristics to follow patients bearing macrocysts. In this study we have investigated the concentrations of estradiol (E2), progesterone, testosterone, dehydroepiandrosterone (DHA) and DHA-3-sulfate (DHA-S), prolactin, potassium (K+) and sodium (Na+) in BCF aspirated from 99 women. The mean age of the patients was 49.8 years (range 32-58). The hormone levels were measured by RIA methods; K+ and Na+ were determined by flame photometry. Estradiol, progesterone, testosterone, DHA, DHA-S, prolactin and K+ showed significant accumulation in the BCF compared with their respective serum values. The K+/Na+ ratio proved to be useful in dividing cysts into type I (≥1), type II (<1 but ≥0.1) and type III (<0.1) subgroups. For type I BCF, higher DHA, DHA-S and prolactin concentrations were detected. Linear regression analysis established a highly significant (P<0.001) correlation between the concentrations of E2 and DHA-S (r=0.686), and also between testosterone and DHA-S (r=0.711). These findings indicate that type I BCF might be a marker for 'active' GCD of the breast, and suggest that it may be associated with an increased breast cancer risk, since this group of patients is supposed to have cysts with apocrine metaplasia. It is suggested therefore that when BCF is aspirated, sex steroids, steroid precursors and cations should be routinely measured, and women with type I cysts should be regularly examined.
R J Santen and H A Harvey
Aromatase, a cytochrome P-450 enzyme that catalyzes the conversion of androgens to estrogens, is the major mechanism of estrogen synthesis in the post-menopausal woman. We review some of the recent scientific advances which shed light on the biologic significance, physiology, expression and regulation of aromatase in breast tissue. Inhibition of aromatase, the terminal step in estrogen biosynthesis, provides a way of treating hormone-dependent breast cancer in older patients. Aminoglutethimide was the first widely used aromatase inhibitor but had several clinical drawbacks. Newer agents are considerably more selective, more potent, less toxic and easier to use in the clinical setting. This article reviews the clinical data supporting the use of the potent, oral competitive aromatase inhibitors anastrozole, letrozole and vorozole and the irreversible inhibitors 4-OH androstenedione and exemestane. The more potent compounds inhibit both peripheral and intra-tumoral aromatase. We discuss the evidence supporting the notion that aromatase inhibitors lack cross-resistance with antiestrogens and suggest that the newer, more potent compounds may have a particular application in breast cancer treatment in a setting of adaptive hypersensitivity to estrogens. Currently available aromatase inhibitors are safe and effective in the management of hormone-dependent breast cancer in post-menopausal women failing antiestrogen therapy and should now be used before progestational agents. There is abundant evidence to support testing these compounds as first-line hormonal therapy for metastatic breast cancer as well as part of adjuvant regimens in older patients and quite possibly in chemoprevention trials of breast cancer.
Ton van Agthoven, Anieta M Sieuwerts, Danielle Meijer, Marion E Meijer-van Gelder, Thecla L A van Agthoven, Roya Sarwari, Stefan Sleijfer, John A Foekens, and Lambert C J Dorssers
Although endocrine treatment of breast cancer is effective and common practice, in advanced disease the development of resistance is nearly inevitable. To get more insight into individual genes that account for resistance against hormonal agents, we have executed functional genetic screens and subsequently evaluated the clinical relevance of several identified genes with respect to tumor aggressiveness and tamoxifen resistance in estrogen receptor-positive patients. Estrogen-dependent human breast cancer cells were transduced with different retroviral cDNA expression libraries and subjected to selective cultures with various anti-estrogens. From a total of 264 resistant cell clones, 132 different genes were recovered by PCR. By applying stringent selection criteria, we identified 15 breast cancer anti-estrogen resistance (BCAR) genes individually yielding resistance. BCAR genes were recovered with differential frequencies for the diverse culture conditions and anti-estrogen drugs. Analysis of the relation of BCAR genes (EIF1, FBXL10, HRAS, NRG1, PDGFRA, PDGFRB, RAD21, and RAF1) with tamoxifen treatment in patients with advanced disease showed significant association with clinical benefit and progression-free survival for EIF1 and PDGFRA mRNA levels. Furthermore, PDGFRA and HRAS mRNA levels were significantly associated with tumor aggressiveness in lymph node-negative patients who had not received adjuvant systemic therapy. In conclusion, our functional genetic screens showed that BCAR genes differ in their ability to confer resistance towards distinct anti-estrogens. Based on the clinical relevance of several BCAR genes, further studies are warranted to characterize the underlying mechanisms, which may ultimately lead to the development of novel treatments and more individualized management of breast cancer patients.