Triple negative breast cancer: a brief review of its characteristics and treatment options

Triple negative breast cancer (TNBC), an aggressive variant of breast cancer, is characterized by lack of expression of the estrogen (ER) and progesterone receptors (PRs) and the human epidermal growth factor receptor (HER-2) that are commonly observed in other breast cancer subtypes. The TNBC subtype primarily occurs in younger women of African American or Hispanic descent and tumors tend to be high grade and initially responsive to chemotherapy. However, TNBC is characteristically aggressive with high recurrence, metastatic, and mortality rates. Treatment options are limited since the hormonal receptor and HER-2 antagonists typically used for other breast cancers are ineffective. As such, the mainstay of treatment of TNBC is traditional systemic cytotoxic chemotherapy. Potential future therapies for TNBC include targeted molecular strategies including poly (adenosine diphosphate ribose) polymerase (PARP) and epidermal growth factor receptor (EGFR) inhibitors and antiangiogenic agents. Further research aimed at identifying unique genetic characteristics of TNBC may allow development of other targeted molecular chemotherapy treatment options.     

Estrogen receptors as therapeutic targets in breast cancer

The estrogen receptor alpha (ERalpha) has proven to be the single most important target in breast cancer over the last 30 years. The use of the selective ER modulator (SERM) tamoxifen for the treatment and prevention of breast cancer has changed therapeutics. The SERM raloxifene, approved for the treatment of osteoporosis, lacks tamoxifen's increased risk for endometrial cancer and is being evaluated for the prevention of breast cancer. Other SERMs approved or under development for use against breast cancer or osteoporosis include toremifene, GW5638, GW7604 (the active metabolite of GW5638), idoxifene, lasofoxifene, arzoxifene, bazedoxifene, EM-800 and acolbifene (the active metabolite of EM-800). Aromatase inhibitors (AIs) have recently proven to be more efficacious than tamoxifen as first-line therapy, efficacious for second-line therapy (e.g. against tamoxifen-resistant disease), and useful for extended adjuvant therapy after tamoxifen. The AIs include the non-steroidal agents letrozole and anastrole, and the steroidal agent exemestane. The pure antiestrogen fulvestrant has proven to be just as effective as AIs. Other pure antiestrogens, ZK-703, ZK-253, RU 58668 and TAS-108 show great promise. The development of resistance to endocrine therapy remains a clinically important problem, and laboratory models based on human breast cancer cells grown as tumors in immune-compromised mice have led to important insights into this problem. Progesterone receptor-negative status of ER-positive breast cancers may reflect altered growth factor receptor signaling, and helps to explain why this subclass of tumors exhibits lower response rates to tamoxifen compared to cancers typed progesterone receptor-positive. Crosstalk among plasma membrane-localized ER, growth factor receptor signaling, and nuclear-localized ER provide further insights into antihormonal-resistant breast cancer.     

Nuclear hormone receptor signals as new therapeutic targets for urothelial carcinoma

Unlike prostate and breast cancers, urothelial carcinoma of the urinary bladder is not yet considered as an endocrine-related neoplasm, and hormonal therapy for bladder cancer remains experimental. Nonetheless, there is increasing evidence indicating that nuclear hormone receptor signals are implicated in the development and progression of bladder cancer. Androgen-mediated androgen receptor (AR) signals have been convincingly shown to induce bladder tumorigenesis. Androgens also promote the growth of AR-positive bladder cancer cells, although it is controversial whether AR plays a dominant role in bladder cancer progression. Both stimulatory and inhibitory functions of estrogen receptor signals in bladder cancer have been reported. Various studies have also demonstrated the involvement of other nuclear receptors, including progesterone receptor, glucocorticoid receptor, vitamin D receptor, and retinoid receptors, as well as some orphan receptors, in bladder cancer. This review summarizes and discusses available data suggesting the modulation of bladder carcinogenesis and cancer progression via nuclear hormone receptor signaling pathways. These pathways have the potential to be an extremely important area of bladder cancer research, leading to the development of effective chemopreventive/therapeutic approaches, using hormonal manipulation. Considerable uncertainty remains regarding the selection of patients who are likely to benefit from hormonal therapy and optimal options for the treatment.     

Prevention of breast cancer: current state of the science and future opportunities

Despite significant progress in breast cancer treatment, mammary tumours still represent the second most frequent cause of cancer-related death in women in the US, with > 211,000 new cases in 2005; however, an expanding range of options for early diagnosis and more reliable risk assessment offers new alternatives for disease control by cancer prevention. Completed large studies with the classical selective estrogen receptor modulator (SERM) tamoxifen have demonstrated that preventing breast cancer pharmacologically is now possible. Novel SERMs, aromatase inhibitors and gonadotropin-releasing hormone agonists targeting hormonal pathways are being tested in clinical trials, revealing the potential for dramatic reductions in tumour incidence with minimal side effects; however, SERMs and aromatase inhibitors are effective only against estrogen receptor-positive tumours, thus chemopreventive drugs targeting other critical signalling pathways (such as retinoids, selective COX inhibitors and tyrosine kinase inhibitors) may provide a means to prevent estrogen receptor-negative breast cancer. In the future, hormonal and estrogen receptor-independent agents may be combined to prevent the development of all mammary tumours. This article reviews the current and novel strategies for breast cancer prevention.     

抗ErbB2抗体曲妥珠单抗的耐药机制与展望

曲妥珠单抗(trastuzumab)在治疗ErbB2高表达的乳腺癌病人中存在耐药现象,对其机制进行研究发现,主要有曲妥珠单抗同ErbB2受体的有效结合受阻、EGFR家族受体和IGF-IR等共表达以及PI3K-AKT信号通路的异常活化等方面。针对这些机制研制了一些可能提高曲妥珠单抗疗效的新型药物。     

Prevention of breast cancer: current state of the science and future opportunities

Despite significant progress in breast cancer treatment, mammary tumours still represent the second most frequent cause of cancer-related death in women in the US, with > 211,000 new cases in 2005; however, an expanding range of options for early diagnosis and more reliable risk assessment offers new alternatives for disease control by cancer prevention. Completed large studies with the classical selective estrogen receptor modulator (SERM) tamoxifen have demonstrated that preventing breast cancer pharmacologically is now possible. Novel SERMs, aromatase inhibitors and gonadotropin-releasing hormone agonists targeting hormonal pathways are being tested in clinical trials, revealing the potential for dramatic reductions in tumour incidence with minimal side effects; however, SERMs and aromatase inhibitors are effective only against estrogen receptor-positive tumours, thus chemopreventive drugs targeting other critical signalling pathways (such as retinoids, selective COX inhibitors and tyrosine kinase inhibitors) may provide a means to prevent estrogen receptor-negative breast cancer. In the future, hormonal and estrogen receptor-independent agents may be combined to prevent the development of all mammary tumours. This article reviews the current and novel strategies for breast cancer prevention.     

Non-steroidal anti-estrogens in the treatment of breast cancer

The non-steroidal selective estrogen receptor modulator (SERM) tamoxifen has been used as standard first-line therapy for postmenopausal breast cancer since the 1970s, during which time over 400,000 lives have been saved. Nevertheless, much attention has been paid to the side effect profile of tamoxifen, particularly in terms of cardiovascular and endometrial abnormalities. Third generation non-steroidal aromatase inhibitors, such as anastrozole and letrozole, have been approved as an alternative, although it is still too early to judge what long-term adverse effects might be associated with prolonged restriction of the supply of estrogen. Novel SERMs have demonstrated improved characteristics over tamoxifen, reducing or eliminating certain adverse events while retaining breast tumor-reducing efficacy. Thus, these agents could provide a direct substitute for tamoxifen. In addition, other estrogen receptor (ER) subtype-selective modulators are under investigation, and the importance of ERbeta as a positive prognostic indicator may open up further therapeutic opportunities. Resistance to hormonal therapies is still a major problem and identifiying the onset of the development of resistance, together with earlier intervention with inhibitors of growth-factor driven cell survival pathways, in combination or sequentially, requires more intense study.     

Fulvestrant: a new type of estrogen receptor antagonist for the treatment of advanced breast cancer

Postmenopausal women with hormone receptor- positive tumors are candidates for endocrine treatment. Current treatment options include the selective estrogen receptor modulators (e.g., tamoxifen and toremifene), which inhibit estrogen receptor signaling, and the aromatase inhibitors (e.g., anastrozole and letrozole), which prevent the conversion of androgens into estrogen in postmenopausal women. As most patients eventually become resistant to endocrine agents, there is a need for new treatments that are effective, well tolerated and lack cross-resistance with currently available therapies. This review describes the development of fulvestrant (Faslodex), a new type of endocrine agent, which is an estrogen receptor antagonist with no agonist effects. Phase III clinical trials have found that fulvestrant is as effective and well tolerated as anastrozole for treating postmenopausal patients with advanced breast cancer who have progressed on one prior endocrine therapy. In addition, fulvestrant has first-line efficacy similar to that of tamoxifen in patients with estrogen receptor-positive and/or progesterone receptor-positive breast cancer. Moreover, in a compassionate-use program, it has become clear that fulvestrant is not cross-resistant with other therapies. Therefore, fulvestrant is a versatile new treatment option for postmenopausal women with advanced breast cancer who have progressed on prior endocrine therapy.     

Preclinical and clinical studies of novel breast cancer drugs targeting molecules involved in protein kinase C signaling, the putative metastasis-suppressor gene Cap43 and the Y-box binding protein-1

Breast cancer is a common cause of tumors in women. The development of effective adjuvant therapies using drugs such as anthracyclines, taxanes, and aromatase inhibitors has improved the survival of breast cancer patients. Molecular cancer therapeutics are also attracting attention, and targeted molecular therapies, such as trastuzumab, have already contributed to effective new treatments for breast cancer. Other candidate targeted molecular therapies for breast cancer, including erlotinib, gefitinib, lapatinib, bevacizumab, and celecoxib, are currently undergoing clinical evaluation, and promising results are expected. The current review provides an up-to-date summary of the preclinical and clinical development of these drugs for breast cancer. In particular, we focus on therapies targeting protein kinase C (PKC) signaling, the putative metastasis-suppressor gene Cap43/N-myc downstream-regulated gene 1 (NDRG1)/differentiation-related gene-1 (Drg-1), and the Y-box binding protein-1 (YB-1). The PKC signaling pathway is widely considered to be a promising target for the development of novel therapeutics. Cap43 expression is significantly modulated by estrogen and/or anti-estrogens in breast cancer cells that are positive for estrogen receptor-alpha (ER-alpha). Cap43 is therefore of particular interest as a molecular indicator of the therapeutic efficacy of anti-estrogenic agents in breast cancer. The nuclear expression of YB-1 plays an essential role in the acquisition of malignant characteristics by breast cancer cells, through epidermal growth factor receptor 2 (HER2)-Akt-dependent pathways. Basic research investigating the key selective molecular changes that sustain breast cancer growth and progression, as demonstrated for PKC, Cap43, and YB-1, is allowing the development of specific targeted molecular diagnostics and therapeutics.     

Adding to the mix: fibroblast growth factor and platelet-derived growth factor receptor pathways as targets in non-small cell lung cancer

The treatment of advanced non ? small cell lung cancer (NSCLC) increasingly involves the use of molecularly targeted therapy with activity against either the tumor directly, or indirectly, through activity against host-derived mechanisms of tumor support such as angiogenesis. The most well studied signaling pathway associated with angiogenesis is the vascular endothelial growth factor (VEGF) pathway, and the only antiangiogenic agent currently approved for the treatment of NSCLC is bevacizumab, an antibody targeted against VEGF. More recently, preclinical data supporting the role of fibroblast growth factor receptor (FGFR) and platelet-derived growth factor receptor (PDGFR) signaling in angiogenesis have been reported. The platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) pathways may also stimulate tumor growth directly through activation of downstream mitogenic signaling cascades. In addition, 1 or both of these pathways have been associated with resistance to agents targeting the epidermal growth factor receptor (EGFR) and VEGF. A number of agents that target FGF and/or PDGF signaling are now in development for the treatment of NSCLC. This review will summarize the potential molecular roles of PDGFR and FGFR in tumor growth and angiogenesis, as well as discuss the current clinical status of PDGFR and FGFR inhibitors in clinical development.     

Trilostane in advanced breast cancer

Antiestrogens, principally tamoxifen, and aromatase inhibitors have been used as the first- and second-line therapy in patients with advanced postmenopausal breast cancer for many years. However, some patients acquire resistance to these treatments and, at present, further endocrine treatment is achieved by merely substituting the current medication with a different antiestrogen or aromatase inhibitor. Trilostane offers an alternative endocrine treatment due to its unique mode of action. It is an allosteric modulator of the estrogen receptor and targets both the estrogen- and growth factor-dependent pathways through which estradiol stimulates cell proliferation. In clinical trials, trilostane has been shown to be an effective treatment for breast cancer in patients who have relapsed after receiving treatment with one or more forms of endocrine therapy. Ongoing and future clinical trials are examining the potential for the use of trilostane in premenopausal breast cancer, as well as in other malignancies such as prostate cancer.     

PET imaging of steroid receptor expression in breast and prostate cancer

The vast majority of breast and prostate cancers express specific receptors for steroid hormones, which play a pivotal role in tumor progression. Because of the efficacy of endocrine therapy combined with its relatively mild side-effects, this intervention has nowadays become the treatment of choice for patients with advanced breast and prostate cancer, provided that their tumors express hormone receptors. However, in case of breast cancer it is well known that part of the patients have hormone receptor-negative tumors at diagnosis, whereas other patients have discordant receptor expression across lesions. In addition, receptor expression can change during therapy and result in resistance to this therapy. Besides several lines of hormonal treatments, also other strategies to affect the hormone receptors are currently under investigation, namely histone deacetylases (HDAC) and heat shock protein (HSP) inhibitors. Knowledge of the actual receptor status can support optimal treatment decision-making and the evaluation of new drugs. Positron emission tomography (PET) is a non-invasive nuclear imaging technique that allows monitoring and quantification of hormone receptor expression across lesions throughout the body. Several PET tracers have been developed for imaging of the most relevant hormone receptors in breast and prostate cancer: i.e. the estrogen, progesterone and androgen receptors. Some of these PET tracers have been successfully applied in early clinical studies. This review will give an overview of the current status of PET imaging of hormone receptors in breast and prostate cancer.     

Trilostane in advanced breast cancer

Antiestrogens, principally tamoxifen, and aromatase inhibitors have been used as the first- and second-line therapy in patients with advanced postmenopausal breast cancer for many years. However, some patients acquire resistance to these treatments and, at present, further endocrine treatment is achieved by merely substituting the current medication with a different antiestrogen or aromatase inhibitor. Trilostane offers an alternative endocrine treatment due to its unique mode of action. It is an allosteric modulator of the estrogen receptor and targets both the estrogen- and growth factor-dependent pathways through which estradiol stimulates cell proliferation. In clinical trials, trilostane has been shown to be an effective treatment for breast cancer in patients who have relapsed after receiving treatment with one or more forms of endocrine therapy. Ongoing and future clinical trials are examining the potential for the use of trilostane in premenopausal breast cancer, as well as in other malignancies such as prostate cancer.     

Aromatase inhibitors: a new paradigm in breast cancer treatment

Microsomal cytochrome P450 (CYP 450) enzyme aromatase belongs to CYP 19 super family. It is involved in the conversion of androgens to estrogens. In postmenopausal women the main sites of aromatisation are skin, adipose tissue and breast. Aromatase localized in breast tumor produces sufficient estrogen for its proliferation. Hence it is an important target for the treatment of hormone dependent breast cancer in postmenopausal women. There are mainly two types of aromatase inhibitors, one is steroidal another is nonsteroidal type. The first and second generation aromatase inhibitors encounter the undesirable drug- drug interactions besides being not very specific and plagued with pharmacokinetic problems. Third generation aromatase inhibitors developed recently are more potent and specific with a greater capacity to annihilate circulating estrogen levels. These agents have satisfactory pharmacokinetic profiles and are devoid of major drug-drug interactions. Third generation aromatase inhibitors became drugs of choice for both first and second line treatment of advanced breast cancer. Aromatase inhibitors can also be used for neoadjuvant therapy of breast cancer in which they have achieved better therapeutic efficacy than tamoxifen. Early results of ATAC (Armidex Tamoxifen Alone or Combination) trial suggest that anastrozole is superior to tamoxifen in adjuvant setting for disease free survival, particularly in receptor positive patients, and in reducing the incidence of contralateral breast cancer. Therapeutic potential of aromatase inhibitors stretches beyond the postmenopausal breast cancer treatment as they also play a role in the treatment of estrogen dependent benign and malignant conditions such as gynaecomastia, prostate cancer, fibroadenomata and the induction of ovulation. By virtue of their ability to reduce estrogen levels they pose problems like demineralization of bone, hot flushes and anti-implantation effects.     

Monoclonal antibody-based targeted therapy in breast cancer

Advances in molecular biology have identified tumor markers that not only predict prognosis and therapeutic response but may also function as potential therapeutic targets. Activated growth factor receptors induce breast cancer cells to proliferate, invade, and metastasize in experimental models. Overexpression of growth factor receptors has been associated with a poor clinical outcome in breast cancer patients. Biological therapy with monoclonal antibody directed against growth factor receptor pathways became important targeted therapy in breast cancer and is being pursued on various fronts. The anti-HER2 antibody trastuzumab is approved in the metastatic setting and is now trying to find the place in the adjuvant setting. Phase II and III studies with antibodies directed against VEGF and EGFR are also ongoing.     

Promising molecular targeted therapies in breast cancer

In recent years, there has been a significant improvement in the understanding of molecular events and critical pathways involved in breast cancer. This has led to the identification of novel targets and development of anticancer therapies referred to as targeted therapy. Targeted therapy has high specificity for the molecules involved in key molecular events that are responsible for cancer phenotype such as cell growth, survival, migration, invasion, metastasis, apoptosis, cell-cycle progression, and angiogenesis. Targeted agents that have been approved for breast cancer include trastuzumab and lapatinib, directed against human epidermal growth factor receptor 2 (HER2) and bevacizumab, directed against vascular endothelial growth factor (VEGF). Several other targeted agents currently under evaluation in preclinical and clinical trials include inhibitors of epidermal growth factor receptor (EGFR), dual EGFR and HER2 inhibitors, VEGF/VEGFR inhibitors, and agents that interfere with crucial signaling pathways such as PI3K/AKT/mTOR and RAS/MEK/ERK; agents against other tyrosine kinases such as Src, insulin-like growth factor (IGF)/IGF-receptor (IGFR); agents that promote apoptosis such as Poly ADP ribose polymerase inhibitors; agents that target invasion and metastasis such as matrix metalloproteinases inhibitors and others. In this review, we highlight the most promising targeted agents and their combination with mainstream chemotherapeutic drugs in clinical trials.     

Novel strategies in cancer therapeutics: targeting enzymes involved in cell cycle regulation and cellular proliferation

Tumor development, growth, and progression depend on some combination of altered cell cycle regulation, excessive growth factor pathway activation, and decreased apoptosis. Understanding the complex molecular mechanisms that underlie these processes should therefore lead to the identification of potential targets for therapeutic intervention. The estrogen receptor and HER-2/neu were among the earliest targets investigated, ultimately leading to the widespread use of tamoxifen and trastuzumab, respectively, in the treatment of breast cancer. Major research advances have since led to other classes of targeted therapies, including cyclin-dependent kinase inhibitors, histone deactylase inhibitors, and receptor tyrosine kinase inhibitors. The following review provides a discussion of the molecular biology associated with each of these types of therapies as well as a detailed summary of the preclinical and clinical data published on selected compounds from each of these subgroups.     

Treatment of premenopausal women with early breast cancer: old challenges and new opportunities

Breast cancer occurring in women before the age of menopause continues to be a major medical and psychological challenge. Endocrine therapy has emerged as the mainstay of adjuvant treatment for women with estrogen receptor-positive tumours. Although the suppression of ovarian function (by oophorectomy, irradiation of the ovaries or gonadotropin releasing factor analogues) is effective as adjuvant therapy if used alone, its value has not been proven after chemotherapy. This is presumably because of the frequent occurrence of chemotherapy-induced amenorrhoea. Tamoxifen reduces the risk of recurrence by approximately 40%, irrespective of age and the ovarian production of estrogens. The worth of ovarian function suppression in combination with tamoxifen is unproven and is being investigated in an intergroup randomised clinical trial (SOFT [Suppression of Ovarian Function Trial]). Aromatase inhibitors are more effective than tamoxifen in postmenopausal women but are only being investigated in younger patients. The use of chemotherapies is identical in younger and older patients; however, at present the efficacy of chemotherapy in addition to ovarian function suppression plus tamoxifen is unknown in premenopausal patients with endocrine responsive disease. 'Targeted' therapies such as monoclonal antibodies to human epidermal growth factor receptor (HER)-2, HER1 and vascular endothelial growth factor, 'small molecule' inhibitors of tyrosine kinases and breast cancer vaccines are rapidly emerging. Their use depends on the function of the targeted pathways and is presently limited to clinical trials. Premenopausal patients are best treated in the framework of a clinical trial.