Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bisphosphonates are commonly used in patients with breast cancer to reduce skeletal-related events in metastatic disease and to mitigate bone loss associated with cancer therapy in early stage disease. In addition, adjuvant breast cancer trials evaluating the oral bisphosphonate clodronate suggested a reduction in cancer recurrence, but the findings were mixed, with 2 positive and 1 negative report. In the Austrian Breast and Colorectal Cancer Study Group (ABCSG) 12 study, adding the intravenous bisphosphonate zoledronic acid to endocrine therapy in premenopausal breast cancer patients significantly prolonged disease-free survival versus endocrine therapy alone (hazard ratio = 0.68; p = 0.008) at 62 months, and reduced local, regional, and distant recurrences. Clinical trial findings from other adjuvant trials (Z-FAST, ZO-FAST), neoadjuvant studies, and studies involving disseminated tumor cells (DTCs) are generally supportive of the ABCSG-12 conclusion, and recent data from AZURE suggest the importance of menopausal status. Preclinical studies provide data on the mechanisms of action that could mediate bisphosphonate direct and indirect anti-cancer effects. Recently, several observational studies (2 cohort studies and 2 case-control analyses) have associated oral bisphosphonate use with a lower breast cancer incidence. Such reports require cautious interpretation because confounding by indication is an issue: bisphosphonates are prescribed for women with low bone mineral density, and women with low bone density are at decreased breast cancer risk.
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PMID:Bisphosphonates and breast cancer prevention. 2186 27

Bisphosphonates are commonly used in patients with breast cancer to reduce skeletal-related events in metastatic disease and to mitigate bone loss associated with adjuvant therapy. Preclinical studies have shown that bisphosphonates may directly inhibit breast cancer cell proliferation and metastasis. Clinical trials evaluating the oral bisphosphonate clodronate as a component of adjuvant therapy identified a potential reduction in cancer recurrence. Subsequently, trials of zoledronic acid have demonstrated prolonged disease-free survival in postmenopausal or otherwise estrogen-depleted women with early breast cancer. In the ABCSG-12 trial, the addition of twice-yearly zoledronic acid (4 mg IV) to adjuvant endocrine therapy improved disease-free survival in premenopausal women undergoing ovarian suppression. Similar results were observed in postmenopausal women receiving aromatase inhibitors in the ZO-FAST trial, and in women who were at least 5 years past menopause in the AZURE trial. Four recent observational studies (2 cohort studies and 2 case-control analyses) generally support an association between oral bisphosphonate use and lower breast cancer incidence. Ongoing breast cancer adjuvant clinical trials are further evaluating bisphosphonates and, by their influence on contralateral cancers, may provide more evidence regarding the potential of bisphosphonates for breast cancer prevention.
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PMID:Bisphosphonates and breast cancer incidence and recurrence. 2214 60

Bone is the most common site of relapse in breast cancer. Unlike many other malignancies, breast cancer is often associated with late-onset metastases, most commonly seen in bone and soft tissue. Pre-clinical and clinical evidence suggest that micrometastases occur at a very early stage of cancer development but do not become overt metastases until a later time when the microenvironment is more suitable. Bisphosphonates (BPs), especially zoledronic acid (ZOL), decrease bone resorption by suppressing the activity of osteoclasts and are used to prevent further bone loss in patients with osteoporosis. In addition, pre-clinical and clinical evidence suggest that potent BPs have direct and/or indirect anti-tumor effects, through induction of apoptosis, inhibition of invasion and metastases as well as angiogenesis, and through alteration of the immune system. ZOL is approved for the treatment of metastatic cancer to bone, and has been shown to prevent skeletal related events and reduce associated pain, without a clear impact on survival. Several large clinical trials (ABSCG 12, ZO-FAST and AZURE) have studied the direct anti-tumor effect of BPs in early stage breast cancer. The results are controversial, suggesting that ZOL may have benefits in specific settings. Targeting patients at particularly high risk for relapse, and identifying surrogate markers of BP effect is clearly a critical component necessary to understand the anti-tumor effect of these agents. Disseminated tumor cells (DTCs) are surrogate markers that have been correlated with an increased risk of recurrence in patients with early stage breast cancer. Several studies have either used the presence of DTCs to assess risk and determine eligibility for BP treatment, or have used DTCs as a surrogate marker of BP anti-tumor effect. This review summarizes the pre-clinical data supporting anti-tumor effects of BPs as well as their impact on DTCs in clinical studies. New candidates for bone-targeted therapy are briefly discussed.
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PMID:Bisphosphonates and their impact on disseminated tumor cells in early stage breast cancer. 2214 61

Among women worldwide, breast cancer is the most common malignancy and a leading cause of death, accounting for approximately 6% of all cancer deaths globally. The predilection of breast cancer to metastasize to bone provides a strong rationale that antiresorptive agents such as bisphosphonates may have the potential to prevent disease recurrence. Bisphosphonates are established therapies for bone loss and for preventing skeletal-related events (SREs) from bone metastases. Moreover, intravenous nitrogen-containing bisphosphonates, such as zoledronic acid, have been shown to block multiple steps in tumor metastasis (e.g., angiogenesis, invasion, and adhesion). Recent clinical data from ABCSG-12, ZO-FAST, and AZURE demonstrate that zoledronic acid can significantly improve disease-free survival (DFS) in the adjuvant breast cancer setting in women who are naturally postmenopausal or have endocrine therapy-induced menopause. Furthermore, the ABCSG-12 trial showed durable disease-free survival benefits 2 years after completion of adjuvant therapy. These data suggest a potential role for zoledronic acid beyond bone health in breast cancer. Although it is too early to determine which patients are most likely to benefit from the anticancer potential of bisphosphonates, future research will help further guide therapy in this setting.
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PMID:Intravenous bisphosphonates for breast cancer: impact on patient outcomes and scientific concepts. 2214 63

In healthy tissue, the tight junction protein Claudin 18.2 (CLDN18.2) is present only in the gastric mucosa. Upon malignant transformation of gastric epithelial tissue, perturbations in cell polarity lead to cell surface exposure of CLDN18.2 epitopes. Moreover, CLDN18.2 is aberrantly expressed in malignancies of several other organs, such as pancreatic cancer (PC). A monoclonal antibody, zolbetuximab (formerly known as IMAB362), has been generated against CLDN18.2. In a phase 2 clinical trial (FAST: NCT01630083), zolbetuximab in conjunction with chemotherapy prolonged overall and progression-free survival over chemotherapy alone and improved quality of life. In this study, the mechanism of action and antitumor activity of zolbetuximab were investigated using nonclinical PC models. Zolbetuximab bound specifically and with strong affinity to human PC cells that expressed CLDN18.2 on the cell surface. In ex vivo systems using immune effector cells and serum from healthy donors, zolbetuximab induced antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), resulting in the lysis of cultured human PC cells. The amplitude of ADCC and CDC directly correlated with cell surface CLDN18.2 levels. The chemotherapeutic agent gemcitabine upregulated CLDN18.2 expression in cultured human PC cells and enhanced zolbetuximab-induced ADCC. In mouse xenograft tumors derived from human PC cell lines, including gemcitabine-refractory ones, zolbetuximab slowed tumor growth, benefited survival, and attenuated metastases development. The results presented here validate CLDN18.2 as a targetable biomarker in PC and support extension of the clinical development of zolbetuximab to patients with CLDN18.2-expressing PC.
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PMID:Characterization of zolbetuximab in pancreatic cancer models. 3054 62