26th Annual San Antonio Breast Cancer Symposium, San Antonio, Texas, USA, 3-6 December 2003: update on clinical research

The San Antonio Breast Cancer Symposium is an international meeting dedicated to the translation of advances in cellular and molecular biology of breast disease into clinical improvements in prevention, diagnosis and treatment. This report summarizes the clinical highlights of the 26th annual meeting held in San Antonio, Texas on 3–6 December 2003. Breast care for women will be improved by reports concerning optimal adjuvant hormonal therapy, advances in chemotherapy and a shift in the clinical philosophy of breast cancer care from maximum tolerable treatment to minimum effective therapy.     

Vinorelbine and the topoisomerase 1 inhibitors: Current and potential roles in breast cancer chemotherapy

Summary Vinorelbine is a semi-synthetic vinca alkaloid which was initially developed in France in the 1980's. Due to its unique structure it is considerably less neurotoxic than vincristine. Several phase II studies have shown that vinorelbine is active in metastatic breast cancer therapy with response rates of 20–30% in pretreated and 40–50% in nonpretreated patients respectively. Higher response rates have been noted when vinorelbine is used in combination regimens. The main dose-limiting toxicity seen with this agent has been neutropenia; neurotoxicity manifest as symptomatic paresthesia can be seen in 10% of treated patients. Oral and implantable forms of the drug have also been investigated.The topoisomerase 1 inhibitors topotecan and camptothecin 11 (CPT-11) have been less extensively evaluated in breast cancer therapy. Preclinical studies have indicated that both of these agents are active against breast cancer and some responses have been seen in phase 1 trials of topotecan. An 8% response rate was noted in a phase II trial of CPT-11 in patients with pretreated metastatic breast cancer. Further phase II trials are ongoing at present with both agents.Presented by R.C. Donehower at the 16th Annual San Antonio Breast Cancer Symposium, San Antonio TX, November 4, 1993; Mini-symposium on New Agents in Breast Cancer (supported by an educational grant from Rhône-Poulenc Rorer).     

26th Annual San Antonio Breast Cancer Symposium,San Antonio,Texas, USA, 3–6 December 2003: update on clinical research

The San Antonio Breast Cancer Symposium is an international meeting dedicated to the translation of advances in cellular and molecular biology of breast disease into clinical improvements in prevention, diagnosis and treatment. This report summarizes the clinical highlights of the 26th annual meeting held in San Antonio, Texas on 3–6 December 2003. Breast care for women will be improved by reports concerning optimal adjuvant hormonal therapy, advances in chemotherapy and a shift in the clinical philosophy of breast cancer care from maximum tolerable treatment to minimum effective therapy.     

Chromosome 11q13 markers and D-type cyclins in breast cancer

Summary One in six primary human breast cancers has DNA amplification centered on the cyclin D1 gene (CCND1) on chromosome 11q13. This genetic abnormality is preferentially associated with estrogen-receptor positive tumors and may define a sub-class of patients with an adverse prognosis. AlthoughCCND1 has the credentials of a cellular oncogene, being a target for chromosomal translocation and retroviral integration, the 11q13 amplicon encompasses several other markers andCCND1 is not the only candidate for the key gene on the amplified DNA. To assess their relative importance, we have constructed a physical map of the amplified DNA and compared the extent and frequency of amplification across the region. Since it is likely that the gene providing the selective force for amplification will be expressed at elevated levels, we have also examined expression of both RNA and protein. By these criteria, cyclin D1 remains the strongest candidate for the key oncogene on the amplicon and we are currently investigating the functional consequences of its over-expression.Presented by Gordon Peters at the 16th Annual San Antonio Breast Cancer Symposium, San Antonio TX, USA, November 4, 1993; Minisymposium on Molecular Genetics in Breast Cancer.     

The role of amphiregulin in breast cancer

Summary Amphiregulin (AR) is an epidermal growth factor (EGF)-related peptide that operates exclusively through the EGF receptor and that can bind to heparin. AR also possesses nuclear localization sequences in the extended NH₂-terminal region suggesting an additional intracellular site of action. AR mRNA and protein expression have been detected in primary human mammary epithelial cell strains, nontransformed human mammary epithelial cell lines, several human breast cancer cell lines, and primary human breast carcinomas. The frequency and levels of AR protein expression are generally higher in invasive breast carcinomas than in ductal carcinomasin situ or in normal, noninvolved mammary epithelium. In addition, AR can function as an autocrine and/or juxtacrine growth factor in human mammary epithelial cells that have been transformed by an activated c-Ha-ras proto-oncogene or by overexpression of c-erb B-2. AR expression is also enhanced by mammotrophic hormones such as estrogens and other growth factors such as EGF.Presented by David S. Salomon at the 16th Annual San Antonio Breast Cancer Symposium, San Antonio TX, USA, November 4, 1993; Minisymposium on Molecular Genetics in Breast Cancer.     

Current status of paclitaxel in the treatment of breast cancer

Summary Paclitaxel is a highly active single agent as therapy for previously untreated as well as doxorubicin-refractory metastatic breast cancer, with associated response rates of 62% and 20–48%, respectively. Complete responses with paclitaxel occur chiefly in breast cancer patients whose metastatic disease has not been previously treated with chemotherapy. Early data suggest a possible dose-response relationship for paclitaxel in metastatic breast cancer, but the optimal dose has not yet been defined. The optimal duration of infusional paclitaxel treatment is also not yet known. A study of 96-hour infusional paclitaxel in the treatment of doxorubicin- or mitoxantrone- refractory metastatic breast cancer patients has demonstrated a 48% response rate suggesting that prolonged exposures to paclitaxel may offer a therapeutic advantage. Randomized trials of 3- vs 96-hour paclitaxel are ongoing or planned. The relative efficacy of paclitaxel versus standard chemotherapy as front-line or salvage therapy for metastatic breast cancer is currently under study. In addition, two randomized trials are under way in node positive breast cancer patients to study whether treatment with paclitaxel following standard or high dose doxorubicin and cyclophosphamide adjuvant therapy results in improved patient benefit.Combining paclitaxel with other active agents in the treatment of metastatic breast cancer is an area of active investigation. Combined paclitaxel and doxorubicin, administered concurrently or sequentially, is associated with modest complete response rates in metastatic breast cancer patients. Sequential paclitaxeldoxorubicin administration is associated with more mucositis than is doxorubicinpaclitaxel when paclitaxel is administered over 24 hours. High doses of cyclophosphamide can be combined with 24- or 72-hour infusional paclitaxel, and phase II studies of this combination are warranted. Early data suggest that administering biweekly paclitaxel and cisplatin to previously untreated metastatic breast cancer patients is associated with high response rates, and confirmatory studies of this combination and schedule are planned. Preclinical data suggest that cell cycle considerations may be important in combining doxorubicin and possibly other agents with paclitaxel.Paclitaxel is an excellent substrate for P-glycoprotein, the protein product of the multidrug resistance-1 (mdr-1) gene, and phase I trials are under way combining paclitaxel with several known blockers of Pgp function. Finally, pilot studies are under way to determine whether the radiation sensitizing effects of paclitaxel can be exploited as part of radiation therapy for patients with locally advanced breast cancer.Presented by J.A. O'Shaughnessy at the 16th Annual San Antonio Breast Cancer Symposium, San Antonio TX, November 4, 1993; Mini-symposium on New Agents in Breast Cancer (supported by an educational grant from Rhône-Poulenc Rorer).     

Phytoestrogens and breast cancer risk. Review of the epidemiological evidence

Phytoestrogens are natural plant substances. The three main classes are isoflavones, coumestans, and lignans. Phytoestrogens have anticarcinogenic potential, but they have also significant estrogenic properties. For an evaluation of the effect of phytoestrogens on breast cancer risk we reviewed the analytical epidemiological data. A total of 18 studies were included [1–18]. Up to now, there are 13 studies that have assessed the direct relation between the individual dietary intake of soy products and the risk of breast cancer [1–13]. Overall, results do not show protective effects, with the exception maybe for women who consume phytoestrogens at adolescence or at very high doses [5, 7, 8]. Only four of these 13 studies are prospective, and none of them found statistically significant breast cancer reductions. Four studies assessed urinary isoflavones excretion in relation to breast cancer [14–17]. Three of these are case control studies [14–16], where excretion was measured after breast cancer occurrence and thus seriously limiting causal interpretation of the results. The only prospective study with urinary measurements before breast cancer occurrence was done in a Dutch postmenopausal population and showed a non-significant breast cancer risk reduction for high excretion [17]. Three studies measured enterolactone (lignan): two case control studies reported a preventive effect on breast cancer risk [14, 18], but the only prospective study did not [17]. In conclusion, few prospective studies (n = 5) were done to assess the effects of phytoestrogens on breast cancer risk. None of them found protective effects. However, these prospective studies did not focus on age at consumption, which seems to be important based on results from dietary case control studies done so far.     

Abstracts

11th Annual San Antonio Breast Cancer Symposium November 29–30, 1988

Abstracts     

Program

12th Annual San Antonio Breast Cancer Symposium December 7–9, 1988

Program     

Abstracts

12th Annual San Antonio Breast Cancer Symposium December 7–9, 1988

Abstracts     

26th Annual San Antonio Breast Cancer Symposium,San Antonio,Texas, USA, 3–6 December 2003: update on preclinical and translational research

The San Antonio Breast Cancer Symposium is the largest annual meeting devoted solely to breast cancer research. The late William L McGuire's vision for this meeting was to stimulate 'translational research', many years before this term became popular. In this way, the San Antonio Breast Cancer Symposium represents a forum in which basic and clinical researchers present their research side by side. Each year sees the continued evolution of our understanding of the basic mechanisms of breast cancer initiation and progression, and the clinical application of this knowledge. Major topics of discussion at the symposium this year were the cell cycle, new evolving concepts of estrogen receptor action, breast cancer stem cells, new predictive and prognostic markers (including microarray studies), and continued exploration of the mechanisms of drug resistance. This report will summarize preclinical and translational highlights from the meeting.     

26th Annual San Antonio Breast Cancer Symposium, San Antonio, Texas, USA, 3-6 December 2003: update on preclinical and translational research

The San Antonio Breast Cancer Symposium is the largest annual meeting devoted solely to breast cancer research. The late William L McGuire's vision for this meeting was to stimulate 'translational research', many years before this term became popular. In this way, the San Antonio Breast Cancer Symposium represents a forum in which basic and clinical researchers present their research side by side. Each year sees the continued evolution of our understanding of the basic mechanisms of breast cancer initiation and progression, and the clinical application of this knowledge. Major topics of discussion at the symposium this year were the cell cycle, new evolving concepts of estrogen receptor action, breast cancer stem cells, new predictive and prognostic markers (including microarray studies), and continued exploration of the mechanisms of drug resistance. This report will summarize preclinical and translational highlights from the meeting.     

26th Annual San Antonio Breast Cancer Symposium, San Antonio, Texas, USA, 3–6 December 2003: update on preclinical and translational research

The San Antonio Breast Cancer Symposium is the largest annual meeting devoted solely to breast cancer research. The late William L McGuire's vision for this meeting was to stimulate 'translational research', many years before this term became popular. In this way, the San Antonio Breast Cancer Symposium represents a forum in which basic and clinical researchers present their research side by side. Each year sees the continued evolution of our understanding of the basic mechanisms of breast cancer initiation and progression, and the clinical application of this knowledge. Major topics of discussion at the symposium this year were the cell cycle, new evolving concepts of estrogen receptor action, breast cancer stem cells, new predictive and prognostic markers (including microarray studies), and continued exploration of the mechanisms of drug resistance. This report will summarize preclinical and translational highlights from the meeting.     

Reproductive factors in relation to breast cancer characterized by p53 protein expression (United States)

Objective: To evaluate the potential etiologic heterogeneity of breast cancer by examining whether associations with reproductive and other personal characteristics differed by p53 protein expression status. Methods: Data from the Carolina Breast Cancer Study, a population-based, case–control study of 861 cases and 790 controls, were utilized. Immunohistochemical staining for the p53 protein was performed on 638 archived tumor specimens; 46% of cases were classified as p53+. Two separate unconditional logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (CI) for p53+ and p53– breast cancer relative to controls for reproductive and other personal characteristics. Analyses were performed separately for younger (45 years) and older (>45 years) women. Results: Risk factor profiles largely overlapped for p53+ and p53– breast cancer, with the exception of oral contraceptive (OC) use among younger women and a family history of breast cancer. Prolonged OC use was more strongly associated with p53+ breast cancer [OR 3.1 (95% CI: 1.2–8.1) than p53– breast cancer (OR 1.3 (95% CI: 0.6–3.2)] among younger women only. A first-degree family history of breast cancer was associated with p53+ breast cancer among younger women [OR 1.5 (95% CI: 1.0–2.2)] and older women [OR 1.4 (95% CI: 0.9–2.3)], but not p53– breast cancer in either age-group. Conclusions: These results provide little evidence of breast cancer heterogeneity as classified by p53 expression status. However, although not statistically significant, OC use among younger women and family history of breast cancer may operate through a pathway involving p53 alterations to increase risk of breast cancer.     

Complete remission after ovariectomy for advanced breast cancer correlated with estrogen receptor status and urinary androgen excretion

Summary Our previous work showed urinary androgen excretion (A) as well as estrogen receptor (ER) to predict clinical response and survival after ovariectomy for advanced breast cancer. We here compare the complete responders with the partial responders to ovariectomy. The likelihood of CR (55% of responders) rather than PR was not strongly dependent on the location of metastases or on the ER/A status (though as noted previously there were no responses at all in the ER-/A- group), but CR did appear to increase survival.Presented as an abstract at the 10th Annual Breast Cancer Symposium, San Antonio, Texas, December 11–12, 1987     

Aromatase inhibitor development for treatment of breast cancer

Summary Inhibition of estrogen production provides effective therapy for patients with hormone-dependent breast cancer. The source of estrogens in premenopausal women is predominantly the ovary, but after the menopause, estradiol is synthesized in peripheral tissues through the aromatization of androgens to estrogens. Uptake from plasma is the primary mechanism for maintenance of estradiol concentrations in breast cancer tissue in premenopausal women, whereas several steps may be operant in postmenopausal women. These include enzymatic synthesis of estradiol via sulfatase, aromatase, and 17-hydroxysteroid dehydrogenase in the tumor itself. Aromatization of androgens secreted by the adrenal to estrogens in peripheral tissues and transport to the tumor via circulation in the plasma provides another means of maintaining breast tumor estradiol levels in postmenopausal women. These various sources contribute to the high tissue estrogen levels measured in breast tumor tissue.To effectively suppress tissue concentrations of estrogens and circulating estradiol in postmenopausal patients, various aromatase inhibitors have been developed recently. These include steroidal inhibitors such as 4-hydroxy-androstenedione as well as non-steroidal compounds with imidazole and triazole structures. The most potent of these, CGS 20267, is reported to suppress levels of active estrogens (i.e., estrone, estrone sulfatase, and estradiol) by more than 95%. This compound can suppress both serum and 24-hrurine estrogens to a greater extent than produced by the second generation inhibitor, CGS 16949A. CGS 20267 is highly specific since it does not affect cortisol and aldosterone serum levels during ACTH stimulation tests nor sodium and potassium balance in 24-hr urine samples. These data suggest that CGS 20267 can be expected to bring improved response rates in the treatment of metastatic hormone-dependent breast cancer without substantial side effects.Presented by R.J. Santen at the 16th Annual San Antonio Breast Cancer Symposium, San Antonio TX, November 4, 1993; Mini-symposium on New Agents in Breast Cancer (supported by an educational grant from Rhône-Poulenc Rorer).     

Abstract Issue, 24th Annual San Antonio, Breast Cancer Symposium. December 10-13, 2001 San Antonio Marriott Rivercenter, Texas, USA.

Abstract List

Abstract Issue, 24th Annual San Antonio, Breast Cancer Symposium. December 10-13, 2001 San Antonio Marriott Rivercenter, Texas, USA.     

Migratory gene expression signature predicts poor patient outcome: Are cancer stem cells to blame?

Breast cancer metastasis accounts for the majority of deaths from this disease. In the previous issue of Breast Cancer Research, Patsialou and colleagues used a novel in vivo invasion assay to capture migrating breast cancer cells and demonstrate that the gene expression signature of these cells predicts breast cancer metastasis in a large cohort of patients. Furthermore, specific genes identified play a functional role in the invasion of MDA-MB-231 breast cancer cells and in patient-derived breast tumors. These genes regulate pathways known to be induced in invasion and metastases and play an important role in the regulation of cancer stem cells.The majority of cancer deaths result from systemic metastases, the development of which requires the coordinate regulation of complex genetic programs. Patsialou and colleagues [1] recently reported that the expression of genes related to these programs predicted the development of metastases in patients with breast cancer. Tumor metastasis is dependent upon, and orchestrated by, the genetic and epigenetic state of cancer cells and the interaction of these cells with the tumor and host microenvironments [2]. To elucidate the regulatory pathways involved in tumor invasion and metastasis, Patsialou and colleagues [3] previously developed an in vivo model in which microneedles containing a chemoattractant such as epidermal growth factor were placed in tumors in live tumor-bearing mice. In the previous issue of Breast Cancer Research, the same group used this system to isolate migratory cell populations in highly metastatic MDA-MB-231 breast cancer xenografts [1]. They used gene expression analysis of these migrated cells to define a ''human invasion signature'' (HIS). Interestingly, they demonstrated that HIS was predictive of risk of breast cancer metastasis in large cohorts of patients. This association was seen across all molecular subtypes of breast cancer and was independent of known prognostic factors. In addition to the clinical correlates of HIS, this signature identifies genes known to be involved in key processes of metastasis, including embryonic tissue development, cellular movement, and DNA replication and repair.There is now substantial evidence that breast cancers are hierarchically organized and driven by a fraction of cells that display stem cell properties. These breast cancer stem cells (BCSCs), by virtue of their relative resistance to chemotherapy and radiation therapy, may contribute to treatment resistance [4]. Furthermore, a number of groups, including our own [5], have demonstrated that BCSCs mediate invasion and metastasis both in vitro and in mouse models. Other studies have demonstrated a correlation between expression of BCSC markers such as CD44⁺/CD24^- or aldehyde dehydrogenase or gene expression profiles of enriched BCSCs with the development of metastasis and poor clinical outcome in patients with breast cancer [6]. Although these studies suggest an important relationship between CSCs and the metastatic phenotype, the gene programs in BCSCs responsible for mediating these behaviors are poorly defined.To identify genes important in the invasive process, Patsialou and colleagues examined the functional role of a number of genes identified in the HIS. They used both small interfering RNAs (siRNAs) and inhibitory antibodies to demonstrate a role for specific HIS genes in the tumor invasive phenotype. Using these techniques, they demonstrated a role for transforming growth factor-beta (TGFβ), interleukin-8 (IL-8), PTPN11, and NP1 in mediating invasion of MDA-MB-231 cells. Interestingly, all of these genes have been reported to be important regulators of CSCs. TGFβ has been shown to regulate the self-renewal of CSCs in several tumor types, and, most recently, this cytokine was shown to specifically regulate BCSCs in claudin^lo breast cancers [7], the subtype that is represented by MDA-MB-231 cells. Our group reported that the cytokine IL-8 mediates BCSC self-renewal and that the IL-8 receptor CXCR1 is preferentially expressed in BCSCs [5]. Inhibition of this receptor reduces the BCSC population in mouse xenografts, inhibiting tumor growth and metastasis [8]. PTPN11 encodes the tyrosine phosphatase SHP2, which was recently shown to promote breast cancer progression through expansion of the BCSC population [9]. This occurs via activation of the zinc finger E-box-binding homeodomain ZEB1 protein, which in turn represses Let 7 microRNA, an important BCSC regulator [10]. Finally, NPM1 (nucleophosmin) was reported to upregulate the gene profile involved in hematopoietic stem cell regulation [11].What is the relationship of genes included in HIS and the CSC phenotype? Interestingly, Patsialou and colleagues [1] reported a significant correlation of HIS with gene signatures associated with epithelial-mesenchymal transition (EMT). EMT has been implicated in tissue invasion and metastasis, and, more recently, similarities between EMT and CSCs were described [12]. However, Patsialou and colleagues found a negative correlation between HIS and previously published tumor-initiating cell (TIC) signatures. Genes that were upregulated in TIC were downregulated in HIS, while genes downregulated in TIC were enriched in HIS [1]. This apparent discrepancy may be explained by the existence of alternative CSC states [13]. We have previously proposed that CSCs may exist in either an EMT mesenchymal-like state characterized by tissue invasion and motility or an MET epithelial-like state associated with self-renewal. EMT-like CSCs are preferentially located at the tumor invasive front, where they invade blood vessels and travel to distant metastatic sites forming micrometastases. This model is consistent with reports that circulating tumor cells and micrometastases are enriched for the EMT BCSC markers CD44⁺/CD24^- but that these cells are largely quiescent as evidenced by a lack of Ki 67 expression [14]. The tumor microenvironment at metastatic sites may induce a transition of these EMT CSCs to a more epithelial mesenchymal-epithelial transition (MET) state characterized by aldehyde dehydrogenase expression, in which they self-renew and differentiate, generating the bulk tumor populations that constitute clinically relevant metastases. This model predicts that gene expression profiles of EMT and MET CSCs may be highly divergent and in fact negatively correlated with regard to genes involved in EMT/MET state transitions. This model provides a potential explanation for the negative correlations of HIS and TIC gene signatures reported by Patsialou and colleagues [1].The studies by Patsialou and colleagues represent an important advance in understanding elements of the metastatic cascade. However, these studies have several limitations. Since they rely primarily on a single claudin low cell line model, it is unclear how widely the HIS applies to other molecular subtypes of breast cancer. Although the HIS was an independent prognostic predictor across the different molecular subtypes of breast cancer, it remains unclear whether similar metastatic programs are involved in mediating metastasis in these other subtypes. Different breast cancer subtypes have different tropisms for sites of metastasis (for example, estrogen receptor-positive tumors frequently metastasize to bone, HER2-positive breast cancer to brain and TN breast cancer to liver and lung). Furthermore, recurrence occurs with markedly different latencies for these subtypes, so, clearly, additional studies are needed to understand the mechanisms which account for these critical differences. Furthermore, additional studies will be required to delineate the relationship between HIS and CSC regulatory genes. These studies have important implications for understanding the molecular basis of tumor invasion and metastasis and have significant clinical implications. Targets identified in these and similar studies may provide new opportunities to develop therapies for metastatic breast cancer.     

‘Patchwork’ fields in thermoradiotherapy for extensive chest wall recurrences of breast carcinoma

Summary Chest wall lesions of advanced breast carcinoma in 23 patients were treated with thermoradiotherapy with clinical intent between January 1987 and March 1992. Treatment consisted of external 915 MHz microwave hyperthermia with commercially available applicators and radiation therapy to doses between 32–58 Gy. Twenty-three large, diffuse lesions were treated with multiple field patchwork hyperthermia. All lesions were diffuse with or without multiple nodules 3 cm depth. All lesions had failed previous therapy. The mean number of hyperthermia fields per patient was 3.2 ± 0.4 (range of 2–7). The complete response rate was 91% in this group of extensive, diffuse lesions treated by the patchwork technique. Mean total radiation dose administered concurrently with multiple field patchwork hyperthermia was 42 ± 1 Gy. The recurrence rate was 5%. The mean survival in patients who had a complete response was 9.0 ± 1.3 months. The reduced survival among patchwork treated patients was due to the extensive tumor burden existing outside of the treated fields in these patients. The skin reactions were minor, causing minimal discomfort. There was no evidence of increased thermal damage to skin, or of tumor recurrence at junctions of hyperthermia field overlap. It is concluded that extensive, diffuse lesions of chest wall recurrence of advanced carcinoma of the breast can be treated effectively with multiple field patchwork thermotherapy.Presented in part at the 15. San Antonio Breast Cancer Symposium (December 1992).