By Professor Robert Thomas, Ms Mea Holm
Professor Robert Thomas: Consultant Oncologist, MRCP MD FRCR. Cranfield University, Bedford Hospital and Addenbrooke’s Hospital Cambridge University Trust. C/O The Primrose Research Unit, Bedford Hospital, Bedford MK42 9DJ, e-mail: [email protected].
Mea Holm: Research Assistant, Master of Biochemistry. C/O The Primrose Research Unit, Bedford Hospital, Bedford MK42 9DJ.
The American Society of Clinical Oncology (ASCO) Annual Meeting attracts over 25,000 delegates and over 5,000 abstract submissions representing the latest research in clinical and translational science in the areas of cancer prevention, diagnosis and treatment. The research presented often sets the standards for breast cancer care around the world.
Every year, the ASCO scientific committee selects the most significant presentations for a Best of ASCO series, and as a guide to What’s coming next in breast cancer treatment?’, these are summarised in this article under the categories of Research into adjuvant therapies, and Research into improving outcomes of metastatic breast cancer.
a) Research on Adjuvant Therapies
The papers below involved nearly sixteen and a half thousand women treated in over 100 institutions and thereby represent a major academic achievement for the medical community. Research of this quality significantly adds to our understanding of the best current management options and guides potential future treatment strategies.
i. Radiotherapy for low risk DCIS?
Several large randomised controlled trials (RCTs) comparing radiotherapy (RT) to no RT have shown significant benefits of RT in the local control of DCIS. Women in these studies had a range of prognostic features with a bias towards higher grade DCIS. This study (RTOG 9804) investigated the benefit of RT specifically in women with low risk DCIS, where low risk DCIS was defined as:
Mammographically detected disease
Low or intermediate nuclear grade
<2.5 cm size
Surgical margins 3 mm
From December 1999 to July 2006, 636 women with low risk DCIS (mean age 59 years) were randomised to receive 50 Gy RT in 5 weeks, or no RT. The median follow-up time was 6.46 years, and tamoxifen was used in 62% of the women. The results showed a significant difference in relapse rates between the RT and the no RT arms; with a 0.4% relapse rate in the RT arm and a 3.2% relapse rate in the no RT arm. There was no significant difference in overall survival, and relapse rate was not influenced by tamoxifen use. The rate of grade 1-2 toxicity was 76% in the RT arm, and 30% in the no RT arm, but rate of 3 grade toxicities were the same in both groups (4%).
Conclusions and comments: The first and probably the most important issue that this study highlights is that it is certainly possible to identify low risk DCIS from the pathology specimen following initial resection. Women with this condition can be reassured that even without RT the 5 years control rate is excellent (97%). In the UK, women with DCIS are rarely prescribed tamoxifen, as the UK DCIS trial did not demonstrate a benefit. The lack of benefit of tamoxifen for low risk DCIS in this study adds further weight to not prescribing tamoxifen in this group of women. Finally, it is doubtful whether oncologists in the UK would change their current stance and offer radiotherapy for a 3% benefit for these low risk women, as notwithstanding the resource implications, the toxicity is greater and there could be justified criticism of the over-treatment of mammographically screened women. For more information on DCIS, see www.cancernet.co.uk/breast-dcis.htm.
ii. Bone health and breast cancer outcomes?
Accelerated loss of bone density is common after cancer treatments for a variety of reasons. Patients tend to become less active unless they are fortunate enough to be treated in an area that embraces exercise rehabilitation after cancer. Men with prostate cancer often receive androgen deprivation therapy, and women may pass into menopause earlier because of chemotherapy or because of damage to the ovaries resulting from surgery. In addition, many post-menopausal women are prescribed aromatase inhibitors, which further reduce bone density. Increased bone loss may lead to osteopenia or osteoporosis, and add to the risk of fractures and vertebral height loss. For this reason, it is important to monitor bone density after cancer, and to give appropriate treatment where necessary. More recently, however, attention has turned to the effects of bone loss and its medical treatments on the risk of breast cancer relapse and overall survival. The significance of this issue is reflected in the scientific committee allocating two trials on this subject within their best of ASCO criteria.
The first trial (NCIC CTG MA.27) examined the effects of osteoporosis and osteoporosis treatments on survival after breast cancer among women taking an aromatase inhibitor. This research was essentially a sub-analysis of 7576 post-menopausal women randomised in a study comparing exemestane and anastrozole. The primary finding of this study showed no difference in effectiveness between these two well-known aromatase inhibitors. Osteoporosis was found in 17% of women, although twice as many women were treated for osteoporosis (in this case with raloxifene). The results showed that women with osteoporosis but no osteoporosis treatment had the highest relapse rate, but osteoporosis treatment significantly lowered relapse rates. The best outcomes were seen in the women with osteoporosis treatments without osteoporosis.
The second trial (AZURE - BIG 01/04) evaluated the effect of the bone hardening drug zoledronic acid (ZOL) in addition to standard adjuvant therapy in 3360 women with stage II/III breast cancer. Unlike the trial above, it included women who were also pre- and peri-menopausal. Half of the women randomised to ZOL for 5 years had improved bone health, although there was no overall improvement in disease outcome between women taking ZOL and women not taking ZOL. A more detailed analysis of the results did, however, reveal an interesting age-related effect. Women on ZOL aged <40 had significantly greater relapse rates compared to women on ZOL >5 years post-menopause. These results are in agreement with a similar effect seen in women taking aromatase inhibitors within the NCIC CTG MA.27 study, but also suggested that menopausal status is more informative than age in the selection of patients for treatment with ZOL.
Conclusions and comments: Both these studies suggest an anti-cancer benefit of bone hardening therapies among women with established menopause; an effect also seen in previous studies. The precise mechanisms are not certain, but one theory is that the increased bone re-absorption associated with osteoporosis may provide fertile soil for cancer growth, and thus preventing bone loss discourages circulating cancer cells taking root. Another theory is that these drugs have a direct anti-angiogenesis effect. Routinely giving these drugs would substantially add to the complexity and cost of adjuvant treatments, in addition to adding certain associated risks such as a rare chance of damaging the bone of the jaw. Opinions on this issue remain divided, though the general consensus among scientists at the ASCO conference was not to prescribe bone health drugs in women with normal bone, but to monitor bone density regularly and treat early if deterioration is detected. This data also adds weight to the evidence that women with breast cancer are advised to practice a lifestyle to maintain bone health, including regular exercise, sensible sun exposure and vitamin D-rich diets (see www.cancernet.co.uk/vitamin-d.htm).
iii. Do extra drugs and increased intensity of regimens improve the effect of chemotherapy?
A course of chemotherapy after surgery significantly reduces the chance of breast cancer relapse especially for women with more aggressive features, such as positive axillary lymph nodes, high-grade tumour, or HER2 gene over-expression. Over the years, improvements have been made to chemotherapy regimens as a result of the publication of well-conducted randomised controlled trials. The study presented in the Best of ASCO series (NSABP B-38) investigated whether a more intense regimen, or adding a further drug not normally used in this setting (gemcitabine), has greater benefit on cancer outcome. The study involved 4894 women who had node positive breast cancer, treated in numerous hospitals across the USA. Women were randomised to receive the chemotherapy agent adriamycin combined with cyclophosphamide every 2 weeks (instead of the usual 3 week interval) followed by weekly taxane; or the same regimen plus gemcitabine; or a standard regimen of TAC (Taxane, adriamycin and cyclophosphamide) given at 3 weekly intervals. The results, rather disappointingly, showed no difference between the regimens. The trial also investigated whether erythropoietin (EPO), a growth factor used to boost haemoglobin, had any effect on relapse rate. The results showed no significant effect.
Conclusions and comments: This trial confirmed that for this group of women, a standard 3-week regimen remains the most convenient and effective. The observation that the use of EPO does not affect relapse rates is interesting and provides reassurance that it is safe to use this useful support drug to maintain haemoglobin in women receiving adjuvant chemotherapy.
b) Research on Metastatic Breast Cancer
The next series of studies aimed at finding ways of improving the well-being and outcomes for women suffering from metastatic breast cancer. A number of well-conducted studies investigated new drugs, novel delivery systems of old drugs and the inevitable jostling for position of the established biological agents. Four trials, in particular, caught the attention of the scientific committee.
iv. Lapatinib versus transtuzumab?
The first study (NCIC CTG MA.31/ GSK EGF 108919RCT) was a real battle of the pharmaceutical titans. It aimed to discover which of the blockbuster biological agents Herceptin (Trastuzumab) or Tyverb (lapatinib) was better when combined with a taxane-based chemotherapy agent in women presenting with metastatic disease. Both these biological agents target the Epidermal Growth Factor Receptor-2 called HER2, which is over-expressed (HER2+ve) in about 20% of breast cancers. Trastuzumab is a monoclonal antibody that attaches to the extracellular domain of the HER2 receptor, whilst lapatinib is a smaller molecule that binds to the intracellular domain of the tyrosine kinase. Both agents have been shown to reduce the aggressiveness of tumours and lead to improved outcomes in previous trials. A head to head comparison of these agents had not yet been performed in this group of women.
This study involved 652 women presenting for the first time with metastatic breast cancer positive for HER2. They all received taxane-based chemotherapy (either taxotere or paclitaxel at three weekly intervals for 24 weeks), but were randomised to receive either lapatinib or trastuzumab until disease progression. The result showed that although there was no difference in overall survival between these groups, there was a significant difference in time to progression indicating a superiority of trastuzumab. The side effects of rash and diarrhoea were worse for lapatinib, and a reduction in cardiac function was noted for trastuzumab.
Conclusion and comments: This trial indicates that trastuzumab was better than lapatinib at delaying progression in this group of women. In this study, however, only 18% of women had received trastuzumab previously in the adjuvant setting, as it first started recruiting 6 years ago when this practice was less established. Currently, the majority of HER+ve patients will have received trastuzumab. The trial did not include a sub-group analysis of the women who had received prior trastuzumab, probably because the small numbers would not have been statistically valid. It is doubtful whether GlaxoSmithKline would fund another trial to prove better effectiveness in this group, so it will remain unknown. Lapatinib had a lower risk for left ventricular function so still remains the main choice if cardiac function is a concern. Likewise, it has already been established from previous studies that as it is a smaller molecule, it is better at crossing into the brain.
v. Search for new drugs
The CALGB 40502/NCCTG N063H study evaluated two chemotherapy agents; one new agent (ixabepilone) and another already established but modified agent, known as Nano Particle Albumin Bound Paclitaxel (Nab-Paclitaxel). It was thought that the albumin binding of Nab-Paclitaxel would protect normal tissues while allowing the agent to penetrate deep into tumour masses. The other agent, ixabepilone, is classed as an epothilone, which attacks the microtubules within cells and thereby prevents cell division. In total, 799 women were recruited to the study between 2008 and 2011. One third received a standard chemotherapy regimen common in the USA (weekly paclitaxel) and the others were randomised evenly between the two new agents. Many women in the trial also received additional avastin (bevacizumab), which was often given routinely to women with metastatic disease in the USA at this time. An analysis of the final results investigated the difference in the time to treatment failure, time to progression, and the overall survival between the three groups. There were no significant differences between the groups. The trend was in fact slightly in favour of standard chemotherapy, and the toxicity was slightly worse in the Nab-Paclitaxel group.
Conclusion and comments: The results were disappointing for the scientific community, and more importantly for women with this devastating condition, who were all hoping for an announcement of more effective drugs. Until new treatments emerge, the outcomes remain bleak with an average chance of survival remaining just over 2 years.
vi. Using herceptin to deliver chemotherapy
The EMILIA study was an impressive example of a technological advance in bio-engineering that has transgressed from bench to bedside. The innovative agent being investigated here (T-DM1) does not have a trade name yet, but no doubt the pharmaceutical company owning it will be keen to progress through the regulatory system. Researchers piggy-bagged (conjugated) a chemotherapy drug (Emtansine) onto a herceptin molecule. As a result, when herceptin binds specifically to the receptor on HER2+ve breast cancer cells, it delivers the chemotherapy molecule where it is needed whilst avoiding normal cells. Thereby the compound incorporates the anti-tumour activities of trastuzumab and the cytotoxic effect of the DM1. The 991 women enrolled into this study were HER2+ve, had previously received a taxane chemotherapy agent and trastuzumab either in the past or were progressing on it. Half received T-DM1 and the other half the best regimen recommended in this setting (lapatinib and capecitabine). The results showed a significant improvement in progression-free survival favouring T-DM1, although overall survival was not quite significant. Side-effect were generally lower in the T-DM1 group.
Conclusion and comments: This represents a significant technological advance for women with metastatic breast cancer but older readers may be experiencing a sense of dj vu after reading the mode of action. When monoclonal antibodies were first investigated 20 years ago, their best role was thought to be as a delivery system for a radioisotope or a poison. Later emphasis changed to the development of antibodies that target receptors, influencing downstream cellular function. Now with this agent we are back to where we started. The wheels of change certainly turn slowly but at least they are turning in the right direction.
References
RTOG 9804: A Prospective Randomized Trial for Good Risk Ductal Carcinoma in Situ (DCIS) Comparing Radiation to Observation. McCormick B et al., JCO 30, 2012 (ab 1004)
NCIC CTG MA.27: Effect of osteoporosis in postmenopausal breast cancer patients randomized to adjuvant exemestane or anastrozole. Shepherd L et al., JCO 30, 2012 (ab 501)
AZURE - BIG 01/04: Adjuvant Therapy In Early Breast Cancer With Zoledronic Acid:
Treatment Effects Are Influenced By Menopausal Status Rather Than Age. Marshall H et al., JCO 30, 2012 (ab 502) and Coleman et al. NESM 365, 2011:13961405
NSABP B-38: Randomized Adjuvant Trial Comparing Dose-dense (DD) ACPaclitaxel (P) plus Gemcitabine (G) with DD ACP and with Docetaxel, Doxorubicin, and Cyclophosphamide (TAC) in Women with Operable, Node-positive Breast Cancer. Swain S et al., JCO 30, 2012 (ab LBA1000)
CALGB 40502/NCCTG N063H: Randomized Phase III Trial of Weekly Paclitaxel compared to Weekly Nanoparticle Albumin Bound Nab-Paclitaxel or Ixabepilone +/- Bevacizumab as First-Line Therapy for Locally Recurrent or Metastatic Breast Cancer. Rugo HS, JCO 30, 2012 (ab CRA1002)
EMILIA: Phase 3 Study of Trastuzumab Emtansine (T-DM1) vs Capecitabine and Lapatinib in HER2-Positive Locally Advanced or Metastatic Breast Cancer Previously Treated With Trastuzumab and a Taxane. Blackwell K, JCO 30, 2012 (ab LBA1)