Tamoxifen in early breast cancer

CORRESPONDENCE

Rodrigo Arriagada Instituto de Radiomedicina, Casilla 124, Santiago 34, Chile 1

2

Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998; 351: 1451–67. Early Breast Cancer Trialists’ Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomised trials involving 31 000 recurrences and 24 000 deaths among 75 000 women. Lancet 1992; 339: 1–15; 71–85.

Sir—The Early Breast Cancer Trialists’ Collaborative Group1 present an updated overview of many randomised trials of adjuvant tamoxifen. However, because there is no non-invasive biological marker to assess the therapeutic effects of tamoxifen in vivo, it has been impossible to individualise the therapeutic dose of this drug. We have examined enhanced CD36 expression on peripheral blood monocytes during tamoxifen treatment as a candidate marker for individualising the therapeutic dose. We measured CD36 expression on monocytes quantitatively by flow cytometry with FITC-conjugated antiCD36 (OKM5, Ortho) in 46 patients with breast cancer on tamoxifen for 1–5 years (figure). CD36 expression in 46 patients (arithmetic mean channel fluorescence: mean [SD] 1270·4 [602·2] fluorescence intensity units) was significantly higher than that in 33 healthy volunteers (634·4 [323·5] fluorescence intensity units. Student’s t test p<0·001). The biological response to sex hormones may vary considerably between individuals, and CD36 expression in 15 of 46 cases (32·6%) was below 957·9 fluorescence intensity

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3 Ogawa Y, Murata Y, Nishioka A, Inomata T, Yoshida S. Tamoxifen-induced fatty liver in breast cancer patients. Lancet 1998; 351: 725. 4 Pinto HC, Baptista A, Camilo ME, de Costa EB, Valente A, de Moura MC. Tamoxifenassociated steatohepatitis—report of three cases. J Hepatol 1995; 23: 95–97. 5 Diehl AM, Goodman Z, Ishak KG. Alcohol-like liver disease in nonalcoholics. Gastroenterology 1988; 95: 1056–62.

3000 CD36 (fluorescent intensity units)

the discussion of the 1998 paper, it is said that ER-negative women aged 50 or more benefit from treatment in terms of recurrence (16% [SD 5%] and mortality (12% [5]) reduction. It would be interesting to know the number of patients randomised in this subset. By contrast, ER-positive patients aged less than 50 do not seem to benefit greatly, if they are on adjuvant chemotherapy, in terms of mortality reduction (39% [22]), and there is only a borderline effect in terms of recurrence reduction (40% [19]). Again, it would be pertinent to know on how many patients the evidence of a tamoxifen effect in the presence of chemotherapy is based. The main question for clinicians is to know if indeed there are independent predictive factors (age, ER) for the tamoxifen effect in patients with early breast cancer.

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CD36 expression on monocytes and liver/spleen ratio* *Ratio of computed-tomography values in Housfield units.

units (mean +1 SD of healthy volunteers), suggesting the presence of low responders to tamoxifen. Therefore, tailoring the therapeutic dose of tamoxifen to the individual might contribute to improvement of outlook for these patients. Up to now, CD36 messenger RNA in breast tissues was the only biological marker with which to monitor the effects of tamoxifen in vivo.2 We suggest that enhanced CD36 expression may non-invasively measure similar biological effects of tamoxifen in vivo. Ogawa et al3 have shown that fatty liver is a common adverse effect of tamoxifen treatment. Indeed, ten of 14 of our patients with fatty liver (liver/spleen ratio <0·9) showed enhanced CD36 expression (above 1281—ie, mean +2 SD of healthy volunteers) and ten of 21 patients with enhanced CD36 expression showed fatty liver. Regular ultrasonography or computed tomographic examination in addition to laboratory tests may be needed to rule out liver metastasis during tamoxifen treatment and to monitor fatty changes of the liver, since steatohepatitis is related to liver cirrhosis in some cases although fatty changes usually spontaneously regress after cessation of tamoxifen treatment.4,5 Toshiji Saibara, Yasuhiro Ogawa, *Saburo Onishi Departments of *Medicine, Radiology, Kochi Medical School, Nankoku 783-8505, Japan 1

2

Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998; 351: 1451–67. Silva IDC, Salicioni AM, Russo IH, Higgy NA, Gebrim LH, Russo J. Tamoxifen down-regulates CD36 messenger RNA levels in normal and neoplastic human breast tissues. Cancer Res 1997; 378: 378–81.

Sir—The dominant message to emerge from the EBCTCG’s 19981 analysis of trials of adjuvant tamoxifen therapy is that the relative efficacy of this agent is principally dependent on ER status of the primary tumour. This message contrasts with conclusions from earlier analyses that clinical benefits of tamoxifen were partly independent of ER protein values, and that ER-poor patients could have improvements in local recurrence rates and overall survival.2,3 With longer duration of follow-up, together with data for tamoxifen therapy of about 5 years, these measures of clinical effect have proved modest in tumours with a low ER. Methods of ER measurement have hindered interpretation of earlier data, some of which are included in the most recent analysis. The non-ER-mediated actions of tamoxifen in the adjuvant setting should not be dismissed outright; these earlier clinical trial results spurned novel hypotheses and prompted research into alternate modes of action of tamoxifen and related Mechanisms triphenylethylenes.4 involving stromal induction of negative growth factors such as TGF␤ were invoked in relation to development and carcinogenesis, but the relative contribution of these alternate modes of action to the antitumour effects of tamoxifen are likely to be highly dependent on the state of tumour development at which treatment is given. There are many data indicating that both positive and negative growth factors determine hormonal effects, and growth factor loops may even be targets for some conventional agents.5 Tamoxifen seems to have a direct modulatory effect on growth factors for which the presence of ER protein may not be essential. In the precancerous and early stages of carcinogenesis, the balance of these growth factors may be a critical determinant of both initiation (eg, sensitivity to carcinogens) and evolution of malignant cell clones. Tamoxifen could modulate levels of growth factors via both ER dependent and independent mechanisms in these early phases. As disease progresses, the latter may become exhausted, leading to dominance of ER-dependent effects.

THE LANCET • Vol 352 • August 1, 1998

CORRESPONDENCE

J R Benson Chelsea and Westminster Hospital, London SW10 9NH, UK 1

2

3

4

5

Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of randomised trials. Lancet 1998; 351: 1451–67. Nolvadex Adjuvant Trial Organisation. Controlled trial of tamoxifen as a single adjuvant agent in the management of early breast cancer. Br J Cancer 1988; 57: 608–11. Early Breast Cancer Trialists Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic or immune therapy. 133 randomised trials involving 31 000 recurrences and 24 000 deaths among 75 000 women. Lancet 1992; 339: 1–5; 71–75. Colletta AA, Benson JR, Baum M. Alternate mechanisms of action of antioestrogens. Breast Cancer Res Treat 1994; 31: 5–9. Baselga J, Mendelsohn J. The epidermal growth factor receptor as a target for therapy in breast carcinoma. Breast Cancer Res Treat 1994; 27: 127.

Exhaled nitric oxide and pulmonary response to iloprost in systemic sclerosis Sir—Giovanni Rolla and colleagues (May 16, p 1491)1 report a remarkable increase in exhaled NO in a patient with systemic sclerosis after intravenous infusion of glyceryl trinitrate (GTN) and postulate that “exhaled NO measurement after pharmacological stimuli may give important information on the responsiveness of the pulmonary circulation”. Although this conclusion could turn out to be correct, further

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This time dependency of tamoxifen action could be relevant to recent trial results showing much greater efficacy of about 5 years’ tamoxifen in ER-positive tumours. When prescribed for 1–2 years only, there may be functionally significant expression of ERindependent mechanisms of action, whereas over 5 years, such mechanisms may not be substainable because, for example, of limited production of TGF␤ or fibroblast insensitivity to tamoxifen. Therefore ER-independent mechanisms would become less important and ER-mediated ones would dominate, leading to the differential efficacy of tamoxifen based on ER status. Tamoxifen may serve to reduce the incidence of breast cancer, irrespective of ER status, and could also influence the drift from ER positivity to hormonal independence in cells during tumour growth, thereby modifying response to hormonal therapies: this may be a potientially important aspect of tamoxifen action because half the tumours in premenopausal women (the target population for prevention) are classified as ER poor.

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Effects of glyceryl trinitrate infusion on gaseous NO and CO2 in a patient undergoing open heart surgery Excretion of NO was 146·9, 147, 115·9, and 147·3 ppb per min, respectively for baseline, 2, 5, and 10 min after initiation of GTN infusion at a rate of 10 mg/h.

analysis of their data leaves one in doubt on methodological and mechanistic grounds. Following findings in animals,2 we have shown3 in patients undergoing open heart surgery increased exhaled NO values after intravenous administration of GTN intraoperatively.3 A common aspect of these studies is that a large bolus of GTN causes a rapid and transient rise in exhaled NO when monitored during endotracheal intubation in exclusion of NO from the upper airways and from ambient air. Rolla and colleagues recorded a substantial rise in exhaled NO during infusion of GTN at a rate of 33 ␮g/min for 20 minutes, but do not provide the exact timing, duration, and conditions of the measurements. These could be important variables and could be of use in the mechanistic interpretation. GTN-induced increase in exhaled NO is believed to result from enzymatic conversion of GTN and release of NO to the gas phase. Excretion of the number of NO molecules from GTN can be calculated from the infused dose, the volume of ventilation, and the fractional molar excretion of GTN (FeGTN). FeGTN of 0·002 has been reported in lambs2 and we calculate the value of 0·015 for human beings from our data with bolus injection of GTN.3 On the assumption of a minimum minute ventilation of 6 L, it follows that an infusion of 33 ␮g/min GTN per minute would increase gaseous NO values by 12·3 parts per billion (ppb) over a minute. This increase should be considered together with endogenous excretion of NO. We have monitored

endogenous NO values in ten patients during open heart surgery and calculated an average minute excretion of 259 (SD 44) ppb. This represents a large signal-to-noise ratio and suggests that the dose of GTN used by Rolla et al is unlikely to contribute much to exhaled NO values. It is therefore not very surprising that we and others4 could not show an increase in exhaled NO during and after 10-min infusions of even higher concentrations of GTN (10 mg/h, n=3, figure), despite systemic effects such as drop in arterial pressure. There might be methodological reasons to account for the effects of GTN in patients with sclerosis. Great variability with exhaled NO could be obtained, dependent on measurement conditions (eg, tidal measurements or single breath measurements done with special flows against predetermined resistance).5 Therefore, technical details and improvements in exhaled NO detection would be worth discussing even in short communications. Beyond technical considerations, biological mechanisms could also explain Rolla and colleagues’ findings. These could include GTN-induced changes in pulmonary capillary blood flow and haemoglobin content or modulation of shunt fraction with potential effects on exhaled NO. In this scenario, however, the effects of the reported doses of GTN on exhaled NO values could be limited to patients with systemic sclerosis for they are not seen in healthy volunteers or in patients requiring open heart surgery. Measurement of endogenous exhaled NO and particularly changes in NO production on pharmacological

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