About the Author
Dr. Lee Schwartzberg is a senior partner at The West Clinic in Memphis, Tennessee. He did a residency in Internal Medicine at Cornell University and fellowship training in Hematology and Oncology at Memorial Sloan-Kettering Cancer Center where he was chief resident in Medicine. He is a Clinical Professor of Medicine at The University of Tennessee College of Medicine. He serves as the Medical Director of the Baptist Cancer Institute-Stem Cell Transplant Program and the Cancer Assessment Risk Evaluation and Surveillance (CARES) Genetics Program. Dr. Schwartzberg has authored over fifty research papers and serves as the Director of Research for The West Clinic.
While there was no overriding theme to breast cancer presentations at ASCO 2008, it is clear that progress continues to be steadily made in defining optimal chemotherapeutic regimens in the adjuvant setting, extending our knowledge of biological therapy, and improving HER2-directed therapy in metastatic breast cancer (MBC). Provocative results were presented regarding use of bisphosphonate therapy for improvement in breast cancer-specific endpoints, changes in phenotype during the course of the disease, and linking breast cancer outcome to nutritional status.
There are many standard regimens to choose from in deciding chemotherapy for the adjuvant treatment of breast cancer. Among the most firmly established are anthracycline-based and/or taxane-based programs. Studies launched during the past few years have attempted to extend the value of chemotherapy by exploring different regimens, either more intensive therapy to improve efficacy or, conversely, reduction of intensity to improve tolerance in special populations.
The more intensive approach was explored in the TanGo trial, which added gemcitabine (G) to paclitaxel (T) after epirubicin and cyclophosphamide (EC) 1. The rationale for this combination was a Phase III study in the metastatic setting that demonstrated improvement in both progression-free survival and overall survival for the combination 2. TanGo is a large multinational study that explores increased efficacy in the adjuvant setting. This trial randomized 3,141 women, predominantly node positive (77%), to receive EC followed sequentially by T or EC followed by GT. At 34.9 months of follow-up, there was no difference in DFS with EC-GT compared with EC-T, hazard ratio (HR) 1.0 (95% CI 0.8-1.2, p=.96), or in overall survival, HR 1.1 (95% CI 0.9-1.4 p=.5). While GT was generally well tolerated, quality of life was worse with more intensive therapy during treatment but showed no difference by one year after therapy. A similar approach is being tested in NSABP-B38, and those results are awaited with great interest. At this point there is no benefit detected in using more than three chemotherapeutic agents in the adjuvant setting.
A different question was asked by CALGB 49907: Would elderly women do as well with single-agent capecitabine as with combination therapy with a standard oral CMF or AC program? 3 Elderly was defined as > 65, and one-third of patients enrolled were 65-69 years of age. The relapse-free survival was inferior for capecitabine: 80% versus 89% (p=.0009) at a median follow up of 2.4 years. In addition, overall survival was reduced from 93% to 88% (p=0.019). A significant association with HR status was noted with HR-negative patients having a fourfold greater risk of relapse when treated with capecitabine compared with all other patients. In general, the toxicity was moderate in both regimens with more Grade 3/4 hematologic toxicity in the CMF/AC arms but no treatment-related deaths. The study not only demonstrates the inferiority of capecitabine but also the good tolerance and efficacy of CMF or AC in this elderly population and offers reassurance about giving adjuvant chemotherapy in this setting. Based on the findings from this year’s ASCO, no changes in established chemotherapy programs were identified for general usage.
HER2-positive Breast Cancer
Remarkable advances continue to be made for patients with overexpression of HER2/neu protein; a testimony to the power of defining a subgroup of patients with a validated biologically important target and multiple approaches to inhibition. One question that has vexed clinicians since the approval of trastuzumab 10 years ago is whether there is the benefit to continuing trastuzumab past first-line progression. Unfortunately, the American oncology community was unable to muster support for a clinical trial to answer this question. This year what is likely to be the last word on the subject was provided by a Breast International Group/German Breast Group study, which compared capecitabine alone with capecitabine plus trastuzumab in HER2-positive patients progressing on trastuzumab. While the trial closed early due to poor accrual, Von Minckwitz and associates were able to compare 156 patients randomized to the two strategies 4. The overall response rate increased from 27.0% to 48.0% with the combination (P=.011) with clinical benefit extending to 75.3% for capecitabine plus trastuzumab compared with 54.0% for capecitabine alone (p=.0068). The primary endpoint, median time to progression (TTP), increased from 5.6 months to 8.2 months, HR.69, p=.034. Overall survival was numerically increased to 25.5 months compared with 20.4 months. In terms of toxicity, mild to moderate anemia and hand/foot syndrome were seen more commonly with the combination, but capecitabine plus trastuzumab was otherwise well tolerated. Coupled with extensive retrospective analyses and anecdotal evidence, clinicians can now be very comfortable with continuing anti-HER2 therapy past the first line of therapy with an expectation of meaningful benefit for many patients.
A second anti-HER2 therapy, the oral small molecule tyrosine kinase inhibitor lapatinib, was approved by the FDA in 2007 in combination with capecitabine for HER2-positive patients progressing after trastuzumab. O’Shaughnessy, et al, presented a study at ASCO 2008 comparing lapatinib alone with lapatinib with trastuzumab in heavily pretreated patients progressing after a taxane, anthracycline, and trastuzumab 5. These HER2-positive patients had received a median of three trastuzumab regimens and four to five prior chemotherapy regimens. The median PFS was improved 27% from 8.2 weeks to 12.1 weeks (p=.008), and the percentage of patients progression-free at six months improved from 13% with lapatinib alone to 28% for the combination of lapatinib and trastuzumab. The clinical benefit rate was doubled from 12.4 % to 24.7% for the combination, HR 2.2, p=.01, and the one-year overall survival for the combination was 45% compared with 36% for lapatinib alone. The only significant increase in toxicity was diarrhea. Such results are impressive for this heavily pretreated group, suggesting that trastuzumab resistance is relative rather than absolute. Most importantly, this study establishes proof of principle that targeting the HER2 receptor both at the extracullar and intracellular level simultaneously can be beneficial.
Anti-angiogenic Therapy in MBC
The FDA recently approved bevacizumab for use in MBC, based on the results of the cooperative group trial E2100, which randomized MBC patients receiving first-line chemotherapy to weekly paclitaxel alone versus. paclitaxel and bevacizumab dosed at 15 mg/kg every three weeks 6. Mature results demonstrated a nearly doubling of PFS to 11.3 months compared with 5.6 months for paclitaxel alone. Response rate was similarly doubled, although overall survival was not significantly increased. Corroborative data were eagerly awaited and were presented at this year’s ASCO.
The AVADO trial is a Phase III double-blind randomized study conducted in 26 countries in first-line MBC patients 7. Patients were randomized to receive full dose of docetaxel at 100 mg/m2 with placebo; low-dose bevacizumab, 7.5 mg/kg; or higher dose bevacizumab at 15 mg/kg every three weeks. Seven-hundred-thirty-six patients were randomized with two-thirds having received prior adjuvant chemotherapy but only 15% prior taxane. Three-quarters of the patients were hormone receptor-positive and nearly half had three or more metastatic sites. The median follow up for this trial remains short at only 10.2 months at the time of reporting. By this time, however, the progression-free survival is superior in the bevacizumab arms at 18.2/18.8 months for the low dose/high dose as compared to 8.0 months for placebo with HR of 0.79 (95% CI 0.63-0.98) p=.0318 or HR 0.72 (0.57-0.90) p=.0099. In addition, the overall response rate was higher: 55/63% compared with 44% for placebo. Incremental toxicity was modest. These results support the use of bevacizumab in the first-line treatment of MBC, although the magnitude of the benefit and optimal dose of bevacizumab in MBC remains to be determined.
Another approach to anti-angiogenesis has been explored through the use of small-molecule oral tyrosine kinase inhibitors, which inhibit the VEGF receptor. Pazopanib is one such agent in active development. Slamon, et al, reported preliminary results of a study of lapatinib plus pazopanib, which demonstrated higher response rates and longer PFS, as assessed by investigators at 12 weeks on study 8. Safety was acceptable, although there was some increase in adverse events with the combination, including some reversible cardiac symptomatology. Longer follow-up on this study is eagerly awaited.
Moving Beyond Hormonal Therapy
Perhaps the most intriguing study in breast cancer at ASCO 2008 was the presentation of the Austrian Breast Cancer Study Group trial-12, which deserved its presence at the plenary session 9. This trial asked two main questions: 1) Was there benefit to using an aromatase inhibitor (in this case anastrazole) instead of tamoxifen along with ovarian suppression in premenopausal women with hormone receptor-positive breast cancer?; and 2) Was there any breast cancer-specific effect from adding adjuvant bisphosphonate therapy (in this case the potent intravenous zoledronic acid [ZA]), to the endocrine regimen? Why ask these questions? There is a strong history of adjuvant endocrine therapy studies by this group, who have previously documented the benefit of ovarian suppression plus tamoxifen being superior to CMF chemotherapy in hormone positive-breast cancer 10. However, ovarian suppression may be associated with reductions in bone mineral density. Bisphosphonates can be expected to improve bone density in women who have reduction in estradiol levels, either by ovarian suppression in the premenopausal setting or by aromatase inhibition in the postmenopausal setting. In fact, the secondary endpoint of ABCSG-12-the effects of ZA on bone density-was reported at San Antonio in December 2007 11. The addition of the bisphosphonate improved bone density at 36 months. Such results have been confirmed in other studies using similar designs, including bisphosphonates in adjuvant endocrine trials.
Gnant, et al, presented the primary endpoint results of ABCSG-12, a 2 x 2, open label, Phase III trial of 1,800 women with hormone receptor-positive, Stage I-II breast cancer. At a median follow-up of 60 months, there was no difference in DFS between patients who received tamoxifen and those who received anastrozole, nor was there a significant difference in relapse-free survival or overall survival. Of note, the five-year DFS for the entire study group was 94% and the overall survival was 98.2%, superb results for a group of patients who did not receive chemotherapy. For the endpoint of the addition of ZA given intravenously every six months, there was a significant improvement in DFS, HR=0.643, p=.011; an improvement in relapse-free survival, HR=0.653, p=.014; and a trend towards improvement in overall survival, HR=0.595, p=.101. Interestingly, ZA-treated patients had not only fewer bone metastases but also fewer local-regional recurrences, contralateral breast cancers, and non-bone distant metastases. Toxicity patterns varied by agent; those women receiving anastrazole had more arthralgia, bone pain, and fever, particularly when they also received ZA. With regard to serious adverse events, uterine polyps and thrombosis were statistically more common in the tamoxifen groups, with no serious events more common in the anastrazole arms. Both the presenter and the discussant at ASCO proffered theories as to why an agent like ZA might have anticancer properties, with the leading possibility being a change in the microenvironment of the bone, well known as the most common site of metastases in hormone receptor-positive breast cancer. Certainly, these results are very provocative, and give a potential new approach to adding to our armamentarium of drugs that improve the lot of women treated after primary surgery.
Prognostic and Predictive Analysis
It is now well accepted that gene expression profiling is valuable in breast cancer to determine both the intrinsic prognosis of a given tumor and to predict benefit of both hormonal treatment and chemotherapy. Indeed, the use of commercially available tests such as the OncotypeDX® test, which uses RT-PCR analysis of 21 genes from formalin-fixed, paraffin embedded tissue, has proven quite useful clinically. As of yet, there is no validated gene expression test that can determine the best types of chemotherapy to use for a given tumor, although there is strong evidence that sensitivity to anthracyclines is dependent on expression of topoisomerase II and that taxanes may be more effective in the presence of HER2 over expression. Goldstein, et al, presented further analysis of the E2197 study 12, a trial that compared doxorubicin and cyclophosphamide (AC) with doxorubicin and docetaxel (AT) to look for genes by RT-PCR that might distinguish differential chemotherapy benefit. They utilized both the 21gene recurrence score set as well as an additional pool of 371 genes. Although the recurrence score set by itself did not distinguish outcome by regimen, in the intermediate and high-risk groups (recurrence score >18), there were a number of genes that predicted differential benefit. These could be grouped to determine a set that predicted better outcome for AC and a group that predicted better outcome for AT.
Simon, et al, used a similar approach to expand the predictive value of the recurrence score by exploring a gene expression profile of 384 genes in addition to those used in the recurrence score in a group of hormone receptor patients treated with neoadjuvant chemotherapy 13. They identified a model that identified a small set of novel genes, which, when combined with clinical covariates, improved prediction of benefit from chemotherapy over that seen with clinical covariates or recurrence score alone. These results need to be externally validated, but appear to point the way towards a hopefully near future where genetic expression assays will help guide our chemotherapy treatment decisions in the adjuvant and metastatic settings.
New Concepts in Breast Cancer
Previous studies ranging from in vitro experiments to epidemiologic trials have suggested a link between breast cancer and Vitamin D. This vitamin has increasingly been found to play an important role in cell differentiation and could be a regulator of cancer progression. Goodwin, et al examined a cohort of women from Canada who were diagnosed with early-stage breast cancer more than 10 years ago and had archived blood samples taken after surgery and before systemic therapy 14.
In 512 women tested for 25-OH Vitamin D levels, they found 37.5% with deficient levels, 38.5% with insufficient and 24% with sufficient levels. These levels correlated significantly with age, BMI, Vitamin D supplementation, other vitamin levels, and diet. Vitamin D deficiency was associated with an increased risk of distant recurrence and death, while patients with insufficient and sufficient Vitamin D levels had similar outcomes. These intriguing results raise many questions, including whether or not they are representative of women living in lower latitudes with more sunlight exposure and whether Vitamin D supplementation might impact breast cancer-specific survival. Corroborative evidence is eagerly awaited.
One of the dogmas of clinical breast cancer is to treat metastases as if they are phenotypically the same as the primary tumor from which they derived. Therefore, patients with an ER-positive primary tumor typically receive hormonal therapy in the metastatic setting. This belief is now be challenged by results reported at the ASCO 2008 breast cancer Clinical Science Symposium. Investigators from British Columbia compared tumor samples from primary tumors and metastatic lesions collected in a tumor microarray repository 15. They found that receptor status was different in 45/160 (28%) of tumors studied, of which 14 were considered possible new ipsilateral lesions. Receptor gain and loss, as well as, less commonly, HER2 gain or loss, were seen in the face of various systemic therapy. Another study, presented by Leidlke on behalf of Broglio et al, demonstrated 55/237 (23.8%) discordance rate between primary and metastatic lesions, with a poorer survival in tumors changing phenotype to triple negative status 16. These results, considered along with previous small studies showing similar findings suggest that clinicians should more aggressively biopsy metastatic disease to confirm the molecular phenotype, particularly when the clinical presentation is at odds with the expected findings (e.g., early visceral relapse after small ER+, PR+ primary tumor).
As usual, ASCO presentations raised many more questions than they answered, but in aggregate greatly add to our rapidly growing knowledge base of breast cancer. Given the continued yearly fall in the death rate from this disease, the evidence is strong that the enormous efforts of clinical trial patient participants and investigators reported at ASCO and other scientific meetings result in tangible progress for current and future breast cancer patients.
1 Poole CJ, Hiller L, Howard HC, et al. tAnGo: a randomized phase III trail of gemcitabine (gem) in paclitaxel-containing, epirubicin/cyclophosphamide-based, adjuvant chemotherapy (CT) for women with early-stage breast cancer (EBC). Journal of Clinical Oncology, May, 2008; Vol. 26 (15S). Abstract 506.
2 Melemed AS, O’Shaughnessy J, Nag S, et al. Phase III study of gemcitabine plus paclitaxel compared with paclitaxel alone in patients with unresectable, locally recurrent, or metastatic breast cancer. Journal of Clinical Oncology, May 2008; Vol 26 (15S) Abstract 150.
3 Muss HB, Berry DL, Cirrincione C, et al. Standard chemotherapy (CMF or AC) versus capecitabine in early-stage breast cancer (BC) in patients aged 65 and older: results of CALGB/CTSU 49907. Journal of Clinical Oncology, May 2008; Vol 26 (15S) Abstract 507.
4 Von Minckwitz G, Zielinski C, Maarteense E, et al. Capecitabine vs. capecitabine + trastuzumab in patients with HER2-positive metastatic breast cancer progressing during trastuzumab treatment: the TBP phase III study (GBG 26/BIG 3-05). Journal of Clinical Oncology Annual Meeting; May 2008; Vol 26 (15S) Abstract 1025.
5 O’Shaughnessy J, Blackwell KL, Burstein H. et al. A randomized study of lapatinib alone or in combination with trastuzumab in heavily pretreated HER2+metastatic breast cancer progressing on trastuzumab therapy. Journal of Clinical Oncology, May 2008; Vol 26 (15S) Abstract 101.
6 Miller K, Wang M, Gralow J, et al. Paclitaxel plus Bevacizumab versus Paclitaxel alone for Metastatic Breast Cancer. New England Journal of Medicine 2007; Vol 357 (26): 2666-2676, December 27, 2007.
7 Miles D, Chan A, Romieu G, et al. Randomized, double-blind, placebo-controlled, phase III study of bevacizumab with docetaxel or docetaxel with placebo as first-line therapy for patients with locally recurrent or metastatic breast cancer (mBC): AVADO. Journal of Clinical Oncology, May, 2008; Vol 26 (15S). Abstract LBA1011.
8 Slamon D, Gomez HL, Kabbinavar FF, et al. Randomized study of pazopanib + lapatinib vs. lapatinib alone in patients with HER2-positive advanced or metastatic breast cancer. Journal of Clinical Oncology, May 2008; Vol 26 (15S) Abstract 1016.
9 Gnant M. Mlineritsch B, Schippinger W, et al. Adjuvant ovarian suppression combined with tamoxifen or anastrozole, alone or in combination with zoledronic acid, in premenopausal women with hormone-response, stage I and II breast cancer: first efficacy results from ABCSG-12. Journal of Clinical Oncology, May, 2008; Vol. 26 (15S). Abstract LBA4.
10 Jakesz R, Hausmaninger H, Kubista E et al. Randomized adjuvant trial of tamoxifen and goserelin versus cyclophosphamide, methotrexate, and fluorouracil: evidence for the superiority of treatment with endocrine blockade in premenopausal patients with hormone-responsive breast cancer–Austrian Breast and Colorectal Cancer Study Group Trial 5. Journal of Clinical Oncology, 2002; 20 (24): 4621-7.
11 Gnant M. Mlineritsch B, Luschin-Ebengreuth G, et. al. Bone mineral density (BMD) at 5 years after diagnosis in premenopausal patients with endocrine-responsive breast cancer after 3 years of adjuvant endocrine treatment with goserelin and tamoxifen or anastrazole or both treatments in combination with zoledronic acid-new results from ABCSG-12. San Antonio Breast Cancer Symposium, 2007, Abst. 26
12 Goldstein LJ, Gray RJ, Bugarini R, et al. Predictive utility of progesterone receptor (PR) and multigene expression in identifying benefit from adjuvant doxorubicin plus Cyclophosphamide (AC) or docetaxel (AT) in intergroup trial E2197. Journal of Clinical Oncology, May, 2008; Vol 26 (15S) Abstract 557.
13 Simon R, Bianchini G, Zambetti M, et al. Outcome prediction in estrogen-receptor positive chemotherapy-and tamoxifen-treated patients with locally advanced breast cancer. Journal of Clinical Oncology, May, 2008; Vol 26 (15S). Abstract 11104.
14 Goodwin PJ,Ennis M,.Pritchard K. I, et al. Frequency of vitamin D (Vit D) deficiency at breast cancer (BC) diagnosis and association with risk of distant recurrence and death in a prospective cohort study of T1-3, N0-1, M0 BC. Journal of Clinical Oncology, May, 2008; Vol 26 (15S) Abstract 511.
15 MacFarlane R, Speers C, Masoudi H, Chia S. Molecular changes in the primary breast cancer versus the relapsed/metastatic lesion from a large population-based database and tissue microarray series. J of clinical Oncology May 2008, Vol 26 (15S). Abstract 1000
16 Broglio K, MOulder SL, Hsu L, et al. Prognostic impact of discordance/concordance of triple-receptor expression between primary tumor and metastasis in patients with metastatic breast cancer. J of Clinical Oncology May 2008, Vol 26 (15S) Abstract 1001