The November Oncofacts will center on some interesting presentations delivered at the ECCO 15th and 34th ESMO Multidisciplinary Congress held September 20 - 24 in Berlin, Germany, and the Breast Cancer Symposium held October 8 - 10 in San Francisco, California.

Reports from ECCO/ESMO

Bone Metastases Management:
The manufacturer of denosumab, has not yet filed with the US Food and Drug Administration (FDA) for an indication for the treatment of bone metastases.

Two separate denosumab trials were presented in patients with bone metastases. Denosumab is a fully human monoclonal antibody that specifically targets a ligand known as RANKL (that binds to a receptor known as RANK) that is a key mediator of osteoclast formation, function, and survival. Denosumab is being studied across a range of conditions including osteoporosis, treatment-induced bone loss, bone metastases, multiple myeloma, and rheumatoid arthritis.

The current standard of care for patients with metastatic breast cancer to the bone is the use of intravenous zoledronic acid for at least 2 years. Denosumab, which is given as a subcutaneous injection, was evaluated in a phase III clinical trial in comparison to this standard. The denosumab 136 trial was conducted as a phase III randomized, double-blinded trial in 2046 patients with metastatic breast cancer and bone metastases. Patients received either zoledronic acid 4 mg IV every 4 weeks, or denosumab 120 mg subcutaneously every 4 weeks. Statistical endpoints that were reported included time to a skeletal-related event (SRE), time to subsequent SREs and toxicity. An SRE was defined as 1 of the following: fracture, radiation to the bone, surgery to bone, or spinal cord compression. Results: The median time to first SRE for zoledronic acid was 26.5 months, and this endpoint was not yet reached for the patients receiving denosumab (P = .01; HR 0.82). Denosumab also significantly delayed the time to first and subsequent SREs with 474 events in the denosumab arm and 608 in the zoledronic acid arm (P = .001; HR 0.77). A prespecified exploratory analysis suggested that the 2 drugs were similar in time to pain improvement, but that denosumab was superior with regards to the delay in the development of worsened pain (88 versus 64 days) with a P-value of .009 and a HR of 0.87. With regards to safety comparisons, renal failure was seen more often in those patients receiving zoledronic acid versus denosumab (25 patients versus 2 patients), as was acute renal failure (7 patients versus 1 patient). However, osteonecrosis of the jaw (ONJ) was seen more frequently in those patients receiving denosumab versus zoledronic acid (20 patients versus 14 patients). Clinicians had been hoping that denosumab would not cause the ONJ seen with zoledronic acid. This would suggest that the mechanism for ONJ is related to the inhibition of osteoclastic activity rather than any anti-angiogenic property that has been suggested for the bisphosphonates.

Subsequently, the denosumab 244 trial was presented that enrolled 1776 advanced cancer patients with either multiple myeloma or solid tumors, which excluded breast and prostate cancer. The results of this trial failed to show a superiority of denosumab over zoledronic acid. The median time to first SRE was 20.6 months for denosumab versus 16.3 months for zoledronic acid (P = .06). There were 392 first and subsequent SREs with denosumab versus 436 episodes with zoledronic acid (non-significant). Renal failure was similar for the 2 groups as well: 20 in the denosumab arm versus 25 in the zoledronic acid arm. There were also no reported differences in rates of infection, secondary neoplasms, or ONJ. Overall survival and disease progression were not different between the 2 groups as well.

There is a third trial in patients with metastatic prostate cancer whose data has not yet been presented.

Sorafenib and Breast Cancer:
The use of an anti-angiogenic compound given concurrently with chemotherapy has become a standard of care in patients receiving front-line chemotherapy for metastatic breast cancer. This is based on the E-2100 trial showing a significant improvement in progression-free survival in women receiving weekly paclitaxel plus bevacizumab versus the chemotherapy alone. This finding was also recently verified by the Ribbon-1 trial, which randomized similar patients to non-paclitaxel chemotherapy with or without bevacizumab. Sorafenib is a small molecule inhibitor that targets multiple tyrosine kinases and currently is approved in the United States for patients with advanced renal cell carcinoma and unresectable liver cancer. The SOLTI-0701 trial is a phase IIb randomized trial which included 229 women with locally advanced or metastatic, HER2-negative breast cancer who had failed 1 or 2 previous chemotherapy regimens. Patients were randomly allocated to receive sorafenib and capecitabine or capecitabine and placebo. Women received capecitabine 1000 mg/m² twice daily for 14 of every 21 days +/- sorafenib 400 mg twice daily. Overall response rate was 38% for the sorafenib-capecitabine group and 31% for capecitabine-placebo group. Progression-free survival was 6.4 months for the sorafenib-capecitabine group and 4.1 months for the capecitabine-placebo group (P = .0006). The benefits were seen in the first-line (HR 0.5; P = .002) and second-line (HR 0.65; P = .03).

Toxicity was significant in the trial. Hand-foot syndrome of all grades occurred in 89% of the patients receiving sorafenib and 63% of patients receiving capecitabine alone. This is likely due to the high initial capecitabine dose. Grade 3 events occurred in 45% and 13% of patients, respectively, and dose reductions occurred in 75% of patients.

Ongoing research from this trial includes evaluation of survival, the differential effect of the therapy for different molecular subgroups of breast cancer, and quality of life. Other ongoing clinical trials are evaluating the use of sorafenib with other chemotherapy and hormone therapy agents for women with advanced breast cancer.

Reports from the 2009 Breast Cancer Symposium

The 2009 Breast Cancer Symposium was jointly sponsored this year by the American Society of Clinical Oncology (ASCO), American Society of Therapeutic Radiation and Oncology (ASTRO), Society of Surgical Oncology (SSO), American Society of Breast Surgeons (ASBS), American Society of Breast Disease (ASBD), and the National Consortium of Breast Centers (NCBC). Although much of the symposium centers on multidisciplinary educational sessions, original research is also presented in the form of oral abstracts and posters. Two interesting abstracts were presented that address the current management of women being screened for breast cancer and for women receiving adjuvant therapy for early breast cancer.

Mammograms and breast cancer:
Despite the fact that over the last several decades multiple large mammographic screening trials have shown a significant reduction in breast cancer mortality, the benefit of screening continues to be challenged. Cady and colleagues sought information on the specifics of how screening can impact the risk of breast cancer death in a defined population of women. The authors reported that 6997 invasive breast cancer diagnoses were found among patients in a large Massachusetts hospital consortium between 1990 and 1999. The patients were followed for causes of death through 2007. All breast cancer deaths were verified through an actual review of hospital and outpatient records. The records were also reviewed for evidence of breast cancer screening. Regular screening was defined as 2 or more screening mammograms at intervals of 2 years or less in asymptomatic women. The data from the 1995 Behavioural Risk Factor Surveillance System suggests that approximately 79% of Massachusetts’s women aged 40 years or older were in mammographic screening programs in 1995. Results: After 12.5 years of median follow-up, 461 deaths from breast cancer were found and confirmed. Of these 461 women who died, 116 (25.2%) deaths were in women who were regularly screened. This included 72 deaths from nonpalpable cancers found on screening mammogram, and 44 (9.6%) from palpable cancers found in the interval between screening mammograms. Of the deaths, 322 (69.9%) occurred in women who had never had a screening mammogram, and 23 deaths (5%) occurred after 1 or more previous mammograms, but not within the 2-year window of their diagnosis. The authors thus concluded that 75% of the breast cancer deaths occurred in the 20% of women not routinely screened, while 25% of the deaths occurred in the 80% of patients routinely screened. Dr Cady concluded that if the 13-year mortality rate is 15% in the nearly 200,000 women diagnosed with invasive breast cancer in 2009, regularly screened women will have a 13-year breast cancer mortality rate of 5% while unscreened women will have a 56% mortality rate.

Adjuvant chemotherapy and molecular profiling

The Cancer and Leukemia Group B (CALGB) 9344 trial randomized 3121 women with lymph node positive, early breast cancer to receive adjuvant doxorubicin and cyclophosphamide followed by paclitaxel or no further chemotherapy. It has previously been reported that there was a 5% absolute improvement in disease-free survival in those women randomized to receive the paclitaxel. It has previously also been reported that women whose tumors are ER-positive and HER2-negative, there is no benefit from the addition of paclitaxel. However, prior studies have also suggested that more enhanced molecular profiling either by reverse transcription polymerase chain reaction (RT-PCR) or microarray analysis can further divide tumors into more detailed biologic sub classification. Tissue microarrays were constructed from 2039 of the 3121 trial patients’ cancers. Immunohistochemistry for ER, HER2, Ki67, cytokeratin 5/6, and epidermal growth factor receptor (EGFR) was performed, and thus allowed each individual tumor to be intrinsically subtyped. Luminal A breast cancer is ER-positive and HER2-negative and has low levels of Ki67 protein. Luminal B breast cancer is also ER-positive and is either HER2-positive or has high Ki67 levels. Core basal breast cancer is ER-negative, HER2-negative, and positive for cytokeratin 5/6 or EGFR. The cases were assigned as follows: 790 luminal A, 340 luminal B, 221 HER2-enriched, 444 core basal, and 93 ER-negative/HER2-negative/nonbasal. Findings: The use of paclitaxel was associated with a 25% improvement in relapse-free survival in women with core basal breast cancer, a 31% improvement in women with luminal B breast cancer, and a 43% improvement in women with HER2-positive, ER-negative breast cancer. Patients with luminal A breast cancer received no benefit from the addition of paclitaxel. Thus, this trial suggests that all women with ER-positive breast cancer are not alike, and even though a woman has lymph node positive breast cancer, there may be a lack of effectiveness of either specific or all chemotherapy drugs for women with luminal A subtype.

Literature Review: Exercise and Lymphedema

The risk of lymphedema after breast cancer axillary surgery ranges in the literature between 6% and 70%, depending upon the criteria used and the length of follow-up. For decades, women with axillary surgery have been warned against excessive use of the surgical arm, including the prevention of hefty lifting, the avoidance of carrying bags on the affected arm, etc. As reported in the August 13 issue of the New England Journal of Medicine, Kathryn Schmitz and colleagues enrolled 141 women with a history of breast cancer and current lymphedema between October 2005 and March 2007. Women were required to have a body mass index (BMI) of 50 kg/m² or less, were not actively trying to lose weight, and had no medical condition that would preclude exercise. Seventy-one women were randomized to a weight-lifting group, and 70 women were randomized to control. The 71 women in the weight-lifting group received a free 1-year membership to a community fitness center, and under the guidance of certified fitness trainers, began twice weekly, whole body resistance training that was then slowly increased at each subsequent session. After 13 weeks, the subjects continued twice-weekly unsupervised exercise for an additional 39 weeks.

The statistical endpoint was the proportion of patients with an absolute increase of 5% or more in arm and hand swelling at 1 year. Results: There was no significant difference between groups in the proportion of women who had a change in limb swelling of 5% or more. Of the 130 women who had no recurrence of their cancer and were no lost to follow-up, 23 in the control group and 20 in the weight-lifting group were evaluated for exacerbation of their lymphedema. Of these, 19 (83%) and 9 (45%) were found to have an exacerbation.

Thus, the authors concluded that the study reduced concerns that weight lifting worsens arm and hand swelling in breast cancer patients with lymphedema.

Best of the DaySM from the 2009 Breast Cancer Symposium

Topics include:

I hope you have enjoyed this edition of OncoFacts.

OncoFacts™ Editor:

Christy Russell, MD

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