Is drug-induced toxicity a good predictor of response to neo-adjuvant chemotherapy in patients with breast cancer? -A prospective clinical study

Chintamani,; Singhal, Vinay; Singh, JP; Lyall, Ashima; Saxena, Sunita; Bansal, Anju

doi:10.1186/1471-2407-4-48

Cited by 27 publications

(34 citation statements)

References 24 publications

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“…These results suggest that CYP1B1 does not directly inactivate docetaxel, but rather might promote cell survival in MCF-7 Txt cells, providing an explanation for its association with drug resistance. British Journal of Cancer (2008) Breast cancer affects a significant number of women worldwide and is a leading cause of cancer deaths (Chintamani et al, 2004). Current therapies for breast cancer include locoregional (surgical) treatment, anti-hormone therapy, radiotherapy and chemotherapy (O'Driscoll and Clynes, 2006).…”

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CYP1B1 expression is induced by docetaxel: effect on cell viability and drug resistance

et al. 2008

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The cytochrome P450 CYP1B1 is consistently overexpressed in tumour cells as compared to their normal counterparts, but its precise role in drug resistance is yet to be defined. It has been reported that transfection of CYP1B1 results in increased resistance to docetaxel in V79 cells (McFadyen et al, 2001). In this study, we analysed changes in expression of CYP1B1 mRNA associated with pulse selection of MCF-7 cells with docetaxel. Docetaxel-selected MCF-7 cells (MCF-7 Txt), which showed increased resistance to this drug as compared to parental MCF-7 cells, showed a noteworthy increase in CYP1B1 mRNA expression, paralleled by increased ethoxyresorufin-O-deethylase (EROD) activity levels. This effect was not observed in cisplatin-or adriamycin-selected MCF-7 cells, or in docetaxel-selected colon, lung or pancreatic carcinoma cells. Short-term treatment with docetaxel induced CYP1B1 mRNA expression in MDA 453 and BT-20 breast carcinoma cells, but not in MCF-7 cells. Transfection of MCF-7 Txt cells with CYP1B1 siRNA did not significantly affect docetaxel-induced toxicity, but it decreased cell survival in the absence of drug. Preincubation of docetaxel with recombinant CYP1B1 did not affect drug toxicity in A549 cells. These results suggest that CYP1B1 does not directly inactivate docetaxel, but rather might promote cell survival in MCF-7 Txt cells, providing an explanation for its association with drug resistance. British Journal of Cancer (2008) Breast cancer affects a significant number of women worldwide and is a leading cause of cancer deaths (Chintamani et al, 2004). Current therapies for breast cancer include locoregional (surgical) treatment, anti-hormone therapy, radiotherapy and chemotherapy (O'Driscoll and Clynes, 2006). Chemotherapeutic treatment of breast cancer, although of great importance in the management of the disease, has limited benefits for many patients due to intrinsic or acquired resistance to the effects of anticancer drugs. Moreover, chemoresistance is often associated with a more aggressive phenotype with an increased tendency to invade and metastasise (Campbell et al, 2001).Cytochromes P450 are a family of enzymes implicated in the biotransformation of both xenobiotics and endogenous compounds. Their primary functions are the synthesis of steroids and bile acids and the detoxification of many foreign substances, such as drugs and environmental agents.CYP1B1 is the only member of the CYP1B subfamily; it catalyses the hydroxylation of 17-b-oestradiol at the C4 position (Jefcoate et al, 2000) and is involved in testosterone biotransformation as well (Shimada et al, 1999). It is also known to metabolise xenobiotics such as ethoxyresorufin, theophylline and caffeine (Shimada et al, 1997). CYP1B1 is constitutively expressed at the mRNA level in mammal steroidogenic tissues, such as rat granulosa cells (Dasmahapatra et al, 2002) and its expression can be induced in these and other tissues by peptide hormones, cAMP and ligands of the aryl hydrocarbon receptor (AhR). Crosstalk has been described...

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“…Breast cancer affects a significant number of women worldwide and is a leading cause of cancer deaths (Chintamani et al, 2004). Current therapies for breast cancer include locoregional (surgical) treatment, anti-hormone therapy, radiotherapy and chemotherapy (O'Driscoll and Clynes, 2006).…”

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CYP1B1 expression is induced by docetaxel: effect on cell viability and drug resistance

et al. 2008

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“…It is also recommended to stay below the superior most IBN in order not to interfere with the lymphatic drainage of the upper extremity. Keeping dissection below the superior most IBN has been observed in various studies to be associated with lower incidence of upper limb lymphedema [4][5][6]. If one decides to sacrifice the intercostobrachial nerves, it is recommended that a cold knife rather than diathermy should be used to prevent postoperative neuralgia (Fig.…”

Section: Commandment-7-intercosto-brachial Nerves (Ibn)mentioning

confidence: 99%

“…This is primarily due to the fact that majority of breast cancers in the developing countries are locally advanced at presentation. These cancers may actually require some form of neoadjuvant chemotherapy to make them resectable [2][3][4]. This operation (MRM), however, is still the workhorse, and most surgeons must be trained to perform an optimum and oncologically safe MRM.…”

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Ten Commandments of Safe and Optimum Mastectomy for Breast Cancer

Chintamani

2014

Indian J Surg

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“…Among patients with locally advanced breast cancer treated with neoadjuvant FAC regimen (5-fluorouracil, adriamycin, cyclophosphamide), Chintamani et al showed a significant positive correlation between the presence of vomiting (r = + 0.558), alopecia (r = + 0.802), and response to neoadjuvant chemotherapy. A significant negative correlation was observed between the absence of side effects and poor response to neoadjuvant chemotherapy [3]. The study of Ching-Hung et al was a retrospective study and GC use was not randomized but GCs were ordered by the physicians on an as-needed basis.…”

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Glucocorticoids in breast cancer treatment: real benefit or selection bias?

Guner

Dizdar

2018

Breast Cancer Res Treat

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We read with great interest the article by Lin et al. published in Breast Cancer Research and Treatment on the effect of glucocorticoid (GC) use on survival in patients with breast cancer [1]. The authors showed that concomitant use of glucocorticoids improved survival in patients who received adjuvant anthracycline-based chemotherapy for stage I-III breast cancer. The authors suggested that low doses of GC might have a priming effect and potentiate the cytotoxic effect of chemotherapy on tumor cells or the immunomodulatory effects of short-term use of low doses of GC might be the underlying mechanism for the improved survival. Although these potential mechanisms may explain the findings, we have an additional concern that should be addressed in the discussion.The association between toxicity of chemotherapy and clinical outcomes has long been recognized regarding cancer treatments. Abola et al abstracted treatment toxicity and clinical outcome data from a sample of 99 phase III oncology randomized clinical trials and showed that treatments with relatively greater toxicity compared with their controls had relatively higher rates of clinical efficacy in terms of progression-free survival (PFS). In particular, greater relative gastrointestinal toxicity among treatments was associated with greater relative PFS compared with controls (P = 0.007) [2]. Among patients with locally advanced breast cancer treated with neoadjuvant FAC regimen (5-fluorouracil, adriamycin, cyclophosphamide), Chintamani et al showed a significant positive correlation between the presence of vomiting (r = + 0.558), alopecia (r = + 0.802), and response to neoadjuvant chemotherapy. A significant negative correlation was observed between the absence of side effects and poor response to neoadjuvant chemotherapy [3]. The study of Ching-Hung et al. was a retrospective study and GC use was not randomized but GCs were ordered by the physicians on an as-needed basis. Thus we can assume that the patients who received more GC were those who experienced more GC-treated toxicities including nausea/vomiting, hypersensitivity reactions, etc., and needed additional or higher doses of GC for the treatment of these toxicities. Given the association between toxicity and efficacy in the abovementioned studies, one explanation for the improved efficacy in this patient population might be simply selection bias, i.e., patients with higher GC use might represent a subgroup who experienced higher toxicity and improved efficacy. Considering the toxicities of GCs, potential benefit of GCs on overall survival should be prospectively confirmed before implementing in clinical practice.

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Is drug-induced toxicity a good predictor of response to neo-adjuvant chemotherapy in patients with breast cancer? -A prospective clinical study

Cited by 27 publications

References 24 publications

CYP1B1 expression is induced by docetaxel: effect on cell viability and drug resistance

CYP1B1 expression is induced by docetaxel: effect on cell viability and drug resistance

Ten Commandments of Safe and Optimum Mastectomy for Breast Cancer

Glucocorticoids in breast cancer treatment: real benefit or selection bias?

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