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How bark from the Pacific yew tree improved the treatment of breast cancer

By Jenny Bryan

In this month’s article on landmark drugs, Jenny Bryan looks at the discovery of taxanes and how they revolutionised the treatment of breast cancer

In the mid-1990s, the taxanes — paclitaxel (Taxol) and docetaxel (Taxotere) — made newspaper headlines because they were derived from yew trees, rather than for their anticancer activity and novel mode of action. But nearly 20 years later, oncologists are still learning how to use the taxanes to best advantage for breast and ovarian cancer patients.

Chris Twelves, professor of clinical pharmacology and oncology and head of Clinical Cancer Research Groups at Leeds Institute of Molecular Medicine and St James’s Institute of Oncology, recalls the limited treatment options in the early 90s for women with advanced breast cancer once their disease proved resistant to anthracycline-based chemotherapy.

“Anthracyclines were head and shoulders above other drugs at that time, and everything else, such as vinblastine and mitomycin C, were of modest benefit. So there was a feeling that the taxanes were an important class of drugs and a genuinely new and better option for patients,” he says.

From yew tree to clinic

Taxane history starts in 1962, when bark from the Pacific yew tree, Taxus brevifolia, was collected as part of the US National Cancer Institute (NCI) natural products screening programme. Samples showed cytotoxic effects and the active molecule was initially called taxol (later renamed paclitaxel). But taxol’s structure was not reported until 19711 because it proved difficult to characterise, partly because the yield from yew bark was so low.

Subsequent research showed that taxanes worked in a completely different way from other cytotoxic drugs.

They were shown to “over-stabilise” the microtubules that form the structural scaffolding of cells, preventing them from breaking down and reorganising for normal mitosis, thus inhibiting multiplication of cancer cells.2

Adverse publicity about the large numbers of Pacific yews that were beingcut down to produce paclitaxel — an estimated three mature trees to treat one cancer patient — led Bristol-Myers Squibb, which had licensed paclitaxel from the NCI, to look for other ways to produce the drug, and plant cell fermentation subsequently replaced the controversial harvesting of yew bark.

By using the needles of the more common European yew, Taxus baccata, to produce docetaxel, Rhône Poulenc Rorer (now Sanofi-Aventis) was able to avoid confrontation with environmental groups.

Although both docetaxel and paclitaxel, administered every three weeks, were investigated in advanced breast and advanced ovarian cancer, it gradually became clear that docetaxel was more effective in breast and paclitaxel in ovarian cancer.

A randomised, open-label comparison of three-weekly docetaxel versus paclitaxel in women with advanced breast cancer that had progressed after anthracycline-containing chemotherapy showed median overall survival and median time to progression were both significantly longer with docetaxel (15.4 versus 12.7 months, P=0.03, and 5.7 months versus 3.6 months, P< 0.0001, respectively).3

Docetaxel best for breasts

A key phase III trial, published in 1999, showed that more women with metastatic breast cancer previously treated with anthracyclines responded to docetaxel than mitomycin plus vinblastine (30 per cent versus 11.6 per cent; P<0.0001), and had significantly longer median time to progression and overall survival (19 versus 1 week, P=0.001, and 11.4 versus 8.7 months, P=0.0097, respectively).4 Treatments were tolerable, although neutropenia grade 3/4 was more frequent with docetaxel (93.1  per cent versus 62.5 per cent; P<0.05), while thrombocytopenia grade 3/4 was more frequent with the mitomycin-vinblastine combination (12 per cent versus 4.1 per cent; P<0.05).

“This was a striking development because it was the first properly organised study which showed that it was possible to prolong survival with cytotoxic treatment in women with metastatic breast cancer. It marked docetaxel down as a major player in advanced breast cancer and, at last, we had more than one type of drug in the locker for treating these patients,” says Professor Twelves.

He adds that, as anthracycline-based chemotherapy moved into common use at an earlier stage of breast cancer treatment, in the adjuvant setting, docetaxel took over as first-line treatment for metastatic breast cancer.

Dosing dilemmas

Although three-weekly docetaxel had the edge over paclitaxel for efficacy in the treatment of metastatic breast cancer, the perception that paclitaxel was better tolerated was confirmed in the head-to-head trial.3 Professor Twelves explains that reducing the dose of docetaxel below that used in pivotal trials has, however, made its side effects more manageable without unduly sacrificing efficacy in a “routine” population that tends to be older and less robust than trial patients. But a better understanding of the impact of the non-linear pharmacokinetics of paclitaxel has resulted in new, more effective dosing strategies for women with breast cancer.5

“The way docetaxel is given hasn’t changed greatly over 20 years, but we have found that giving paclitaxel weekly instead of three weekly enables us to give a larger total dose with better outcomes, while still retaining the good tolerability profile,” explains Professor Twelves.

The recently developed solvent-free, nanoparticle albumin-bound formulation of paclitaxel (Abraxane) allows shorter infusion times without premedication, and has demonstrated good response rates and better tolerability than with the standard formulation, and may also be given in a weekly dosing schedule.5 However, Professor Twelves explains that, although the novel formulation is proving popular in the US, British oncologists tend to use weekly schedules of conventional paclitaxel, keeping the albumin-bound formulation for exceptional circumstances.

Taxanes as adjuvant treatment

Although both docetaxel and paclitaxel are licensed for use in combination with doxorubicin and cyclophosphamide as adjuvant treatment for non-metastatic breast cancer, Professor Twelves explains that the benefits of taxanes used this way are less clear cut than for more advanced disease.

A meta-analysis of 13 studies with almost 23,000 patients with early breast cancer showed that adding a taxane to anthracycline-based treatment improved disease-free survival by 17 per cent (P<0.00001) and overall survival by 15 per cent (P<0.00001) in high-risk patients.6

But, in the well designed, randomised, open label TACT study, with over 4,000 women with early breast cancer treated in hospitals across the UK, adding docetaxel to standard treatment failed to yield any benefit in disease-free survival at five years.7

Various differences in the study populations and treatment regimens used in TACT and other early breast cancer studies may account for the differences in outcomes. Professor Twelves, who took part in TACT, points out that sequential regimens that added the taxane to other cytotoxics resulted in unequal treatment duration in many previous adjuvant breast cancer studies. So, the taxane-treated patients may have benefited partly from the longer courses of treatment.

“Despite the TACT results, many of us find it hard to believe that taxanes don’t provide any additional benefit because they are so effective in metastatic disease. Oncologists often prefer to believe the meta-analyses of all studies but, in the UK, taxanes are generally reserved for high-risk patients in the adjuvant setting,” he says.

Interestingly, TACT did suggest that benefit from docetaxel was most apparent in patients with oestrogen receptor negative, human epidermal growth factor receptor-2 positive (HER2+) disease, and Professor Twelves predicts that further investigation of patient subgroups will identify those patients most likely to benefit from taxanes.

Future trends

Taxanes have not only changed the way that patients with breast and ovarian cancer are treated, they have also triggered research into other cytotoxic drugs that work on the same target — the microtubule.
The epothilone B analogue, ixabepilone, stabilises microtubules in a similar way to taxanes. It has produced beneficial response rates and progression-free survival for women with advanced, heavily pre-treated breast cancer — both as a single agent and when combined with capecitabine. It has not, however, been shown to prolong survival and is licensed in the US, but not in Europe.

Earlier this year, results of the phase III, open label EMBRACE study with eribulin, a non-taxane inhibitor of microtubule dynamics with a distinctly different mode of interaction with microtubules, were published.8 Eribulin achieved a statistically significant and clinically meaningful improvement in overall survival compared with physician’s choice of treatment in women with heavily pre-treated metastatic breast cancer.8

Trastuzumab emtansine, which combines the anti-HER2 monoclonal antibody trastuzumab with the potent cytotoxic and antimitotic agent, mertansine, has shown promise in HER2+ metastatic breast cancer in terms of improved progression-free survival and is better tolerated that the combination of docetaxel and trastuzumab.

Professor Twelves believes that, despite the vogue for tyrosine kinase inhibitors over the past 15 years, cytotoxic treatment will remain at the heart of cancer treatment and may even be set for a resurgence: “Cytotoxics have come to be seen as a blunderbuss approach to treatment, and we have focused on more ‘targeted’ treatments. But things are perhaps not so black and white, and now that we have a better understanding of cancer biology we may be able to exploit that knowledge to use cytotoxics more effectively. Taxanes have not only improved survival for women with metastatic breast cancer, they’ve taught us the recurring lesson that a lot of drug development goes on after a drug is approved and, not least, they’ve established microtubules as a validated target for future treatment.”

References

1 Wani MC, Taylor HL, Wall ME, Coggon P, McPhail AT. Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. Journal of the American Chemical Society 1971;93:2325–7.
2 Schiff PC, Horwitz SB. Taxol stabilizes microtubules in mouse fibroblast cells. Proceeding of the National Academy of Sciences (USA) 1980;77:1561–5.
3 Jones SE, Erban J, Overmoyer B, Budd GT, Hutchins L, Lower E et al. Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. Journal of Clinical Oncology 2005;23:5542–51.
4 Nabholtz JM, Senn HJ, Bezwoda WR, Melnychuk D, Deschênes L, Douma J et al. Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy. 304 Study Group. Journal of Clinical Oncology 1999;17:1413–24.
5 Woodward EJ, Twelves C. Scheduling of taxanes: a review. Current Clinical Pharmacology 2010;5:226–31.
6 De Laurentiis M, Cancello G, D’Agostino D, Giuliano M, Giordano A, Montagna E et al. Taxane-based combinations as adjuvant chemotherapy of early breast cancer: a meta-analysis of randomized trials. Journal of Clinical Oncology 2008;26:44–53.
7 Ellis P, Barrett-Lee P, Johnson L, Cameron D, Wardley A, O’Reilly S et al. Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial. The Lancet 2009;373:1681–92.
8 Cortes J, O’Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K et al. EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice Versus E7389) investigators. Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. The Lancet 2011;377:914–23.

Citation: The Pharmaceutical Journal URI: 11084729

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Supplementary images

  • Molecular model of docetaxel: taxanes have  triggered research into other cytotoxic drugs that work on the same target — the microtubule  (Dr Tim Evans/Science photo library

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