Posted on March 8th, 2009 by
The 2008 annual American Society of Clinical Oncology’s (ASCO) Breast Cancer Symposium, held this year on September 5-7 in Washington, DC, delivered results encompassing advancements in screening, diagnosis, treatment, supportive care, and individualized therapies for patients with breast cancer. This year’s meeting was jointly sponsored by ASCO, the American Society of Breast Disease, the American Society of Breast Surgeons, the American Society for Therapeutic Radiology and Oncology, the National Consortium of Breast Centers, Inc., and the Society of Surgical Oncology. The event brought together world-renowned clinicians and researchers who are dedicated to improving outcomes for those diagnosed with breast cancer.
Over the past decade, patients with metastatic breast cancer have seen a significant increase in the agents available to them for therapy, including targeted agents such as Herceptin® (trastuzumab) and Tykerb® (lapatinib), the new aromatase agents, novel chemotherapy agents, and supportive care measures. However, it has not been well established whether survival rates for these patients parallel the increase in novel therapeutic measures. To evaluate changes in survival over the decades during which newer therapeutic options have become available for patients with metastatic breast cancer, researchers from the city of Hope Comprehensive Cancer Center in Duarte, California, conducted a retrospective analysis comparing survival rates before and after the new drug era (1985 to 1994 and 1995 to 2005, respectively). The study included patients with metastatic breast cancer who were treated at their center between 1985 and 2005; 199 of whom were diagnosed between 1985 to 1994 and 159 of whom were diagnosed between 1995 to 2005.
The median overall survival was improved by 2.4 years from 1985 to 1994, while the median overall survival was improved by 3.1 years between 1995 and 2005; the difference in survival between these two time periods did not reach statistical significance (P=0.26; HR=1.14).
The researchers stated that these results were against their expectations as they assumed an improvement in survival had been achieved over the decades. However, they emphasized that these data were from a single institution and perhaps greater subgroup evaluation may identify survival differences among certain groups of patients.
Although newer agents have arrived and been integrated into standard care for breast cancer, the use of chemotherapy and radiation remain integral in the therapeutic regimen for most patients. As such, research continues to explore different schedules, doses, and combinations of chemotherapy agents among patients with this disease.
Metronomic administration of chemotherapy is an area that has been evaluated in the palliative setting for patients with breast cancer, particularly among those who are not able to tolerate significant side effects. Metronomic administration (low-dose and rapid administration) allows for lower doses of therapy to be administered without a prolonged drug-free break with lower toxicities. Laboratory analysis has indicated that metronomic administration may enhance apoptotic and anti-angiogenic effects of therapy; trials continue to evaluate the efficacy of this approach.
Researchers from the University of Ottowa recently conducted a clinical trial to further evaluate the use of metronomic chemotherapy among patients with anthracycline-resistant breast cancer. As there is no consensus statement on the treatment of anthracycline-resistant breast cancer, trials evaluating this group of patients are ongoing in an attempt to identify optimal therapies for specific subsets of these patients. This uncontrolled trial included 47 patients with HER2-negative, anthracycline-resistant, or refractory locally advanced or metastatic breast cancer, 38 of whom were evaluable for responses. Initial treatment consisted of weekly low-dose Taxotere® (docetaxel) 15 mg/m2, plus daily Xeloda® (capecitabine) 1,250 mg, and twice-daily Celebrex® (celecoxib) 200 mg. After four weeks, doses of Taxotere could be increased to 20 mg/m2 weekly if patients did not experience grades III/IV neutropenia, and at eight weeks escalation of Taxotere to 25 mg/m2 was allowed. Approximately three-fourths of patients were administered the first dose escalation, and approximately one-third were administered the second dose escalation of Taxotere. The primary endpoint of the trial was clinical benefit, defined as responses or disease stabilization for at least six months.
The lead author of the trial, Dr. Young from the University of Ottowa, stated: “Treatment given in this metronomic fashion is associated with significant anticancer activity and was well tolerated in this study. The efficacy of this regimen may be underestimated, as our study design involved a two-step escalation of docetaxel. It is possible that some patients experienced early progression prior to receiving an adequate dose of this agent….This particular dosing schedule for docetaxel and oral capecitabine should be examined further in clinical studies involving combination therapy with novel targeted therapies.”
Ixempra™ (ixabepilone), approved in October 2007, is the first epothilone approved for clinical use in the treatment of cancer. Its approval was based on the “046″ randomized clinical trial (n=752) comparing Xeloda (C) to Xeloda plus Ixempra (I+C) in anthracycline- and taxane-refractory metastatic breast cancer. Results from the “046″ trial significantly favored the I+C arm in terms of prolonged progression-free survival compared with C only. Dr. Gabriel Hortobagyi presented results at this year’s breast cancer meeting that included a combined analysis of the “046″ trial and the “048″ trial, a second, larger randomized trial (n=1221) comparing I+C to C in anthracycline- and taxane-refractory, metastatic breast cancer. The combined analysis confirmed a significant improvement in progression-free survival in the I+C arm, as well as a trend in overall survival for I+C (HR, 0.85; 95% CI, 0.75-0.98; P=0.231).The researchers also noted that I+C has a manageable safety profile. At this juncture Ixempra presents a novel chemotherapy agent for this difficult-to-treat patient population; however, due to a lack of data at present, physicians must employ its use based on the profile of the individual patient (i.e., single-agent sequential management versus combination therapy).
Identification of the estrogen and progesterone receptors, as well as the HER2 pathway, has provided perhaps some of the greatest breakthroughs leading to individualized treatment for cancer. Breast cancer patients have derived overwhelming benefit through the understanding of these biologic pathways as corresponding therapies have emerged targeting cellular components specific to each pathway. However, new findings continue to emerge that reinforce the fact that all biologic elements intrinsically possess intricate and ever-changing details that require perseverance in research to gain a greater understanding of their complexity.
As there often remains discordance between metachronous metastatic sites and primary tumor characteristics in terms of ER/PR/HER2 status, confirmation through biopsy of metastasis is often the recommendation and practice of oncologists to determine optimal treatment approaches. Dr. Alvarez and colleagues recently conducted a study to evaluate the rate of discordance between a recurrent metastatic site and the primary tumor among 961 patients with recurrent metastatic breast cancer. Patients had tumor tissue available for HER2 testing from the primary tumor and/or axillary nodes and the metastatic site by fluorescent in situ hybridization (FISH), with a median time from original diagnosis to metastasis being 33 months. No patient had received prior adjuvant Herceptin. Ninety-four percent of cases had concordant HER2 results between the metastatic and primary tumors. Of the 8% with discordant results, all patients had HER2-positive primary tumors and HER2-negative metastatic tumors.
A study was conducted by Dr. Simmons and colleagues in which HER2 status as well as ER and PR status were evaluated in both metastatic and primary tumors among 29 patients with metastatic breast cancer.
Taken together, the results of these studies indicate that a biopsy of metastasis appears appropriate so that treatment aimed at the biologic characteristics of the metastatic site(s), which are often in contrast with those of the primary tumor, can be employed to provide an effective overall systemic approach. However, the researchers cautioned that a biopsy of brain metastasis among all patients with this site of metastasis does not appear warranted at this time. The reasoning behind this is the difficulty in obtaining a biopsy through the cranium and the lack of data indicating a high rate of discordance in terms of biologic characteristics between brain metastasis and a primary breast tumor. Research is ongoing to further evaluate this issue.
To further illustrate the complexities of biologic pathways, it appears that a significant portion of primary HER2-positive tumors will convert to HER2-negative tumors following an incomplete pathologic complete response to Herceptin. Dr. Mittendorf and colleagues from the University of Texas M. D. Anderson Cancer Center conducted a study including 143 patients with HER2-positive (as ascertained by FISH) breast cancer who underwent neoadjuvant therapy with Herceptin, a taxane, and an anthracycline. Following therapy, half of the patients achieved a complete pathologic response defined as no evidence of disease in the breast or axilla. Tissue specimens for patients who did not achieve a complete response were available for 23 patients pre- and post-therapy. Post-treatment testing of tissue specimens revealed that 30.4% were no longer HER2-positive. Dr. Mittendorf stated: “We don’t yet know, on a molecular level, what causes tumors to change” and there were no other identifiable changes in the tumor cells. Although these results may need additional supportive results, it appears that patients with HER2-positive tumors who do not achieve a complete pathologic response with Herceptin may derive benefit from a post-therapy biopsy to determine subsequent HER2 status. Dr. Mittendorf also stated that optimal adjuvant regimens for this subgroup of patients need evaluation.
Dr. Subramaniam and colleagues of Georgetown University also reported on biologic changes that may occur among women with hormone-positive breast cancers. These researchers conducted a clinical trial evaluating the effectiveness of Nexavar® (sorafenib) in addition to Arimidex® (anastrozole) among women with hormone-positive breast cancer who progressed or recurred following treatment with Arimidex. As a single agent, Nexavar is considered inactive as therapy for breast cancer. However, Nexavar targets several pathways, including the ras-raf-MAPK pathway, which is implicated in resistance to therapy. Therefore, the trial evaluated the combination of Nexavar and Arimidex to determine if Nexavar could help overcome resistance to Arimidex among 27 postmenopausal patients with metastatic hormone-positive breast cancer that had stopped responding to endocrine therapy. Patients received Nexavar 400 mg twice daily plus standard doses of Arimidex.
The researchers of the study concluded that Nexavar may help to overcome resistance to endocrine therapy among postmenopausal women with hormone-positive breast cancer; results that may provide far-reaching implications into understanding how to overcome resistance of other types of therapies in several types of cancers.
Different adjuvant chemotherapy, hormone, and combination regimens continue to be compared in early breast cancer. As treatment is becoming more individualized, several studies are underway in an attempt to understand which patient and disease characteristics will influence outcomes of specific therapies.
Oncotype DX®, the reverse transcription polymerase chain reaction (RT-PCR) 21-gene assay, represents a major milestone in the progress of individualized therapy. Oncotype DX is a clinically validated test that quantitatively predicts the likelihood of breast cancer recurrence in women with newly diagnosed, early-stage invasive breast cancer and assesses the benefit these patients will achieve from chemotherapy. Oncotype DX has been included in the NCCN and ASCO guidelines for patients with estrogen-receptor positive early breast cancer to help guide treatment decisions.,
The 21-gene assay has also demonstrated the ability to determine ER/PR status, results that are now included as part of the assay’s results., More recently, researchers have been evaluating the accuracy of Oncotype DX in determining HER2 status.
It is now recommended that all breast cancer patients be tested for HER2 status before beginning treatment, as agents targeted against HER2 are available and tend to improve outcomes for patients overexpressing HER2. Standard testing for HER2 includes immunohistochemistry (IHC) and fluorescence-in-situ hybridization (FISH) testing.
Researchers recently conducted two studies to explore the accuracy of Oncotype DX in establishing HER status when compared with standard IHC or FISH testing among breast cancer patients. The first study analyzed data from 755 patients who were enrolled in the Intergroup study E2197. These patients had Stage I-III breast cancer with 0-3 three positive lymph nodes; HER2 status was compared between central IHC and central RT-PCR using a panel of 371 genes including the 21 in Oncotype DX. The concordance rate of HER2-positive status between central IHC and central RT-PCR was 95% (95% CI, 92%, 96%).
The second study evaluated data from a previous clinical trial conducted by researchers from Kaiser Permanente, the University of California-San Francisco, and PhenoPath, Inc. The study included 568 patients and compared HER2 status as tested by FISH or Oncotype DX testing. Twelve percent of patients were HER-2 positive by Oncotype DX and 11% by FISH. There was a 97% overall concordance (95% CI, 96%, 99%) between the two methods of testing. The researchers concluded that Oncotype DX possesses the ability to accurately determine HER2 status when compared to standard testing among breast cancer patients.
As of the end of September, 2008, Oncotype DX now includes ER, PR and HER2 status in all generated reports, allowing for a single test to provide results that previously required several individual tests.
Deletions and amplifications within the topoisomerase II alpha gene (TOP2A) have emerged as a predictor of an improved response to anthracycline-based therapy. Gene alterations within TOP2A are rare in hormone receptor-positive, HER2-normal cancer, while TOP2A is co amplified in approximately 65% of HER2-positive tumors. The TOP2A gene continues to be studied in trials as it appears to be an upcoming and important potential variable upon which to guide therapy.
The Eastern Cooperative Oncology Group (ECOG) conducted a study to further examine TOP2A gene alterations (amplifications or deletions) among hormone-positive, HER2-normal disease. Patients received therapy with either AC (doxorubicin, cyclophosphamide) or AT (doxorubicin, docetaxel). A computer model evaluating TOP2A expression plus the therapeutic regimen demonstrated that TOP2A expression was significantly associated with an increased risk of recurrence, even when adjusted for age, nodal status, tumor size, and grade of tumor. Patients with a low TOP2A expression trended toward an improved outcome with AC, while those with a high TOP2A expression trended toward a favored outcome with AT. Although these results themselves will not change clinical practices, they demonstrate that TOP2A continues to remain a potentially major player in deciding treatment for breast cancer.
It has been well established that younger women with breast cancer tend to have more aggressive disease than their older counterparts. Therefore, younger patients may take a more aggressive approach to reducing the risk of a recurrence or second primary, such as a contralateral prophylactic mastectomy among patients with early breast cancer. Although a prophylactic contralateral mastectomy drastically reduces the risk of a recurrence in the contralateral breast, its affect on survival is not well known.
Researchers from the University of Texas M. D. Anderson Cancer Center in Houston, Texas, recently conducted a clinical study to evaluate the association between survival and prophylactic contralateral mastectomies among women with early breast cancer. The study was a retrospective review of the Surveillance, Epidemiology, and End Results (SEER) database, including over 80,000 women with Stages I-III breast cancer diagnosed from January 1998 through December 2003. All patients were diagnosed with unilateral cancer, and nearly 8% underwent a contralateral prophylactic mastectomy. In an unadjusted comparison, contralateral prophylactic mastectomy was found to significantly improve survival (HR=0.69, P<0.001).
The researchers stated that although a prophylactic contralateral mastectomy may appear to be a radical treatment choice, younger patients with Stages I/II, ER-negative disease may derive a significant benefit from the procedure.
Another treatment issue in early breast cancer that continues to be evaluated is neoadjuvant therapy, particularly in larger tumors confined to the breast. As neoadjuvant therapy can shrink the tumor pre-operatively, allowing for breast-conserving surgery in a greater number of women, researchers attempt to identify the largest size and tumor characteristics that can still benefit from neoadjuvant therapy.
Researchers from Europe conducted the European Cooperative Trial of Operable Breast Cancer that included 1,355 patients with breast cancers greater than 2 cm. Patients were randomized to either neoadjuvant or adjuvant therapy, with the primary endpoints being relapse-free, distant relapse-free, and overall survival as well as the rate of local recurrences. Twenty percent of patients had tumors larger than 4 cm; approximately 55% were 50 years or older; and nearly 70% had hormone receptor-positive disease.
Perhaps breast-conserving therapy achieved with neoadjuvant therapy plays an even larger role than cosmesis and sexuality; also affecting long-term upper-body morbidity among patients undergoing surgery for breast cancer. Researchers from Australia conducted a study to evaluate function-limiting upper-body morbidity among 258 breast cancer patients who underwent surgery for their disease. Assessment of the upper-body symptoms and their impact on function was assessed at six months following diagnosis and every three months to 18 months and included factors such as upper-body strength and endurance, hand grip, flexibility and range of motion, and score on the Disability of the Arm, Shoulder, and Hand questionnaire.
The researchers stated that upper-body morbidity plays a long-term role in a significant portion of women undergoing surgery for breast cancer, even among those without lymphedema. Long-term morbidity issues are gaining more attention as cancer survivors are living longer, and the understanding of ways in which to minimize these morbidities is becoming paramount to maintaining a patient’s quality of life.
Although presentations from this year’s breast ASCO may not have delivered immediate practice-changing results, understanding of the biology of breast cancer, gathering information regarding specific genes and mutations and their effects on the development and course of a disease, identification of subgroups of patients who respond differently to therapies, and quality-of-life issues are all invaluable in understanding the complete picture of how to optimally treat breast cancer patients. The theme of breast cancer therapy continues towards a more individualized approach with tests such as OncotypeDX, testing of TOP2A, potential ER/PR/HER2 discordance between primary and metastatic sites, and overcoming resistance.
 Pal SK, et al “Lack of survival benefit in metastatic breast cancer with newer chemotherapy agents: The City of Hope cancer experience” ASCO Breast 2008; Abstract 95.
 Young S, et al. Phase II clinical rial examining the activity of docetaxel and oral capecitabine given in metronomic fashion and concurrently with celecoxib in patients with anthracycline-resistant metastatic breast cancer. ASCO Breast 2008; Abstract 256.
 Thomas E, Gomez HL, Li RK, et al. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. Journal of Clinical Oncology. 2007;25:5210-5217.
 Hortobagyi GN, Perez E, Vrdoljak E, et al. Analysis of overall survival (OS) among patients (pts) with metastatic breast cancer (MBC) receiving either ixabepilone (I) plus capecitabine (C) or C alone: results from two randomized phase III trials. ASCO Breast 2008. Abstract 186.
 Alvarez RH, Albarracin CT, Valero V, et al. Discordance rates of HER-2 expression between breast primary tumors and paired metastases using archived tumor specimens. ASCO Breast 2008;Abstract 121.
 Simmons C, Miller N, Geddie W, et al. Changes in breast tumor receptor status with time: a prospective study assessing the impact of obtaining confirmatory biopsy at metastatic recurrence on patient management. ASCO Breast 2008;Abstract 124.
 Mittendorf E, et al. Determination of HER2 status in patients achieving less than a pathologic complete response following neoadjuvant therapy with combination chemotherapy plus trastuzumab. ASCO Breast 2008; Abstract 150.
 Subramaniam DS, et al. Sorafenib in hormone-receptor positive (ER/PR+) metastatic breast cancer (MBC) resistant to aromatase inhibitors (AIs). ASCO Breast 2008; Abstract 162.
 National Comprehensive Cancer Network 2008 Clinical Practice Guidelines in Oncology Breast Cancer.
 ASCO publication: Journal of Clinical Oncology. 2007;25: 5287-5312.
 Badve S et al. ER and PR assessment in ECOG 2197: comparison of locally determined IHC with centrally determined IHC and quantitative RT-PCR. ASCO Breast; 2007. Abstract #87.
 Baehner FL et al. A Kaiser-Permanente population-based study of ER and PR expression by the standard method, immunohistochemistry (IHC), compared to a new method, quantitative reverse transcription polymerase chain reaction (RT-PCR). ASCO Breast 2007; Abstract #88
 Baehner F, Gray R, Childs B, et al. HER2 Concordance Between Central Laboratory Immunohistochemistry and Quantitative Reverse Transcription Polymerase Chain Reaction in Intergroup Trial E2197. ASCO Breast. 2008; Abstract #13
 Baehner FL, Achacoso, Maddala T, et al. HER2 Assessment in a Large Kaiser Permanente Case-Control Study: Comparison of FISH and Quantitative RT-PCR Performed by Central Laboratories. ASCO Breast 2008; Abstract #41
 Pritchard KI, Messersmith H, Elavathil L, et al. HER-2 and topoisomerase II as predictors of response to chemotherapy. Journal of Clinical Oncology. 2008;26:736-744.
 Iwata H, Masuda N, Rai Y, et al. Estradiol (E2) expression with monthly versus 3-monthly goserelin treatment in premenopausal patients with early breast cancer. ASCO Breast 2008; Abstract 151.
 Bedrosian I et al. Contralateral prophylactic mastectomy and survival. ASCO Breast 2008; Abstract 2.
 Eiermann W, et al. European Cooperative Trial in Operable Breast Cancer: No increased risk of local breast tumor recurrence after primary systemic therapy and conservative surgery. ASCO Breast 2008; Abstract #149.
 Hayes S, et al. Upper-body morbidity following breast cancer treatment and its relationship with quality of life. ASCO Breast 2008; Abstract 142.
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