	Two trials explored the role of lapatinib (Tykerb) as neoadjuvant therapy in early-stage HER2-positive breast cancer and concluded that its effectiveness is statistically no better than standard trastuzumab (Herceptin) therapy. Investigators said that the adverse events many patients experience while taking lapatinib--in particular, severe diarrhea-- might limit its usefulness in this setting. The Neo-ALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation), phase III study did find significant improvement in the rate of pathological complete remission (pCR) when using lapatinib and trastuzumab as a combination regimen versus either drug alone (

). In the GeparQuinto study, lapatinib combined with epirubicin and cyclophosphamide proved less effective at producing a pCR prior to surgery than trastuzumab administered with the same chemotherapy regimen.

	Neo-ALTTO enrolled 450 women with invasive, operable, HER2-positive breast cancer tumors >2 cm who had adequate cardiac function. Patients were randomized to 1 of 3 regimens for 6 weeks: 1500 mg of lapatinib per day; intravenous trastuzumab, with a 4 mg/kg loading dose followed by 2 mg/kg weekly; or 1000 mg of lapatinib daily with the same trastuzumab regimen that was given in the trastuzumab-only arm. Paclitaxel was introduced in all groups at week 6, and patients continued on neoadjuvant therapy for an additional 6 weeks.

	Following surgery, patients were assigned to 34 weeks of adjuvant therapy, with drug selection based on the neoadjuvant regimen received. Women who took single-agent lapatinib or trastuzumab with paclitaxel in the trial's neoadjuvant phase received the same drug as adjuvant therapy. Those who took lapatinib and trastuzumab together received the doublet again. Overall, the women completed 1 year of HER2- targeting treatment.

	Trial protocol required the collection of tumor tissue samples after 2 weeks of therapy. Investigators said they obtained >11,000 tissue samples through biopsy to analyze for biomarkers predictive of response or resistance to the regimens used. At the symposium, Jose Baselga, MD, chief of the Division of Hematology/Oncology and associate director of Massachusetts General Hospital Cancer Center in Boston, presented preliminary data only from the neoadjuvant phase of the Neo-ALTTO trial. The primary endpoint for this portion of the study was pCR, defined as an absence of invasive cells in the breast or noninvasive in situ cancer in the breast at surgery.

	The pCR rate in the combination arm was 51.3% compared with 24.7% in the trastuzumabonly arm (

= .0001) and 19.5% in the lapatinibonly group. The pCR rate did not differ significantly when comparing the lapatinibonly and trastuzumab-only groups. Assessing pCR as the absence of cancer cells in the breast and lymph nodes produced a rate of 46.9% in the combination arm, compared with 27.6% in the trastuzumab arm (

= .001) and 20% in the lapatinib arm. The difference was again statistically insignificant between the lapatinibonly and trastuzumab-only groups.

	Looking at pCR by hormone receptor (HR) status, the combination of lapatinib and trastuzumab provided a more robust benefit for HR-negative patients than it did for HRpositive patients (61.3% vs 41.6%, respectively). Comparing pCR rates in each arm by HR status significantly favored the combination regimen over trastuzumab alone in HR-negative patients (

	"This study shows that dual anti-HER2 blockade with lapatinib plus trastuzumab is valuable in this group of patients with breast cancer," Baselga said. In the lapatinib-only arm, 23% of patients developed grade 3 diarrhea versus 2% of patients receiving trastuzumab and 21% of patients given both drugs together. Diarrhea in the lapatinibonly group increased over time, and the rate of grade 3 diarrhea went from 11% to 22% by the end of the neoadjuvant phase of the trial. The lapatinib arm also experienced a higher rate of grade 3 neutropenia (16%) than the trastuzumab arm (3%) and the combination group (9%). The rate of grade 3 hepatic abnormalities was 13% in the lapatinib arm, with 2 patients experiencing "serious hepatic dysfunction," according to Baselga. The rate of grade 3 hepatic abnormalities only reached 1% in the trastuzumab arm and 9% in the combination arm. Both the lapatinib-only arm and the combination arm had a 7% rate of grade 3 skin disorders compared with 2% of patients taking trastuzumab alone. None of the groups demonstrated any evidence of cardiac dysfunction. Baselga said that although the increased toxicities (particularly diarrhea and liver enzyme abnormalities) were manageable in the lapatinib arm, nearly one-third of patients in this group were unable to complete treatment as planned. 

	This phase III study, led by the German Breast Group, compared outcomes associated with neoadjuvant lapatinib versus trastuzumab in patients who received an anthracyclinebased chemotherapy regimen prior to surgery. Following surgery, the women randomized to lapatinib were given trastuzumab for 12 months, and women initially assigned to trastuzumab continued on the drug for an additional 6 months. Michael Untch, MD, Multidisciplinary Breast Cancer Center, Helios Clinic, Berlin, Germany, presented results from the neoadjuvant phase of the trial for the subset of patients with HER2-positive disease.

	The trial enrolled 2500 women with untreated, primary invasive breast cancer, of which 620 were HER2-positive. Looking at disease characteristics, median tumor size was 4 cm. About 17% of patients had locally advanced disease, ~28% had multifocal disease, 69% were node-positive at baseline, 47% had high-grade, aggressive tumors, and 42% were estrogen receptor (ER)- and progesterone receptor (PR)-negative.

	Patients were randomized to 4 cycles of epirubicin and cyclophosphamide, administered concurrently with trastuzumab or lapatinib. Women randomized to trastuzumab received a loading dose of 8 mg/kg followed by 6 mg/kg every 3 weeks, and those given lapatinib received 1000 to 1250 mg per day. After the first 4 cycles, all the patients were given 4 cycles of docetaxel 100 mg/m2.

	The rate of discontinuation was 10% higher in the lapatinib arm than in the trastuzumab arm (23% vs 13%, respectively), primarily because of severe diarrhea. Partway through the trial, the investigators decided to counter the diarrhea by lowering the dose of lapatinib and administering loperamide, which Untch said reduced the incidence of grade 3 diarrhea, and he recommended giving it to all patients taking lapatinib.

	GeparQuinto applied more stringent criteria than the National Surgical Adjuvant Breast and Bowel Project (NSABP) guidelines used in the Neo-ALTTO trial for determining pCR. Untch said his group defined pCR as no microscopic evidence of invasive or noninvasive cancer cells in the breast and lymph nodes at the time of surgery. Using this strict criteria yielded a pCR rate of 31.3% in the trastuzumab arm compared with 21.7% in the lapatinib arm (

<.05). When they reanalyzed pCR data according to NSABP guidelines, the rate of pCR was still better with trastuzumab than with lapatinib (50.4% vs 35.2%, respectively; P <.05). Untch said other studies have suggested that pCR is an independent predictor of long-term outcomes. In addition, Untch noted that the women who took neoadjuvant trastuzumab were more likely to receive breast-conserving surgery than those treated with lapatinib (65.6% vs 56.0%). He said this was likely because of tumor shrinkage and hypothesized that future studies might find HER2 blockade allows some women to forgo surgery altogether. 

	Eric Winer, MD, Dana-Farber Cancer Institute, Boston, Massachusetts, who served as the formal discussant for the data presentation, pointed out that trastuzumab outperformed lapatinib in both trials. "It is not clear to what extent this is due to the patients who were not able to complete lapatinib treatment as planned," he noted.

	Winer added that because lapatinib and trastuzumab attack different targets in HER2-positive breast cancer, evidence leans toward combining them. "There are abundant data to suggest that the combination of trastuzumab plus lapatinib is better than either drug alone."

	ER-negative patients were more likely to obtain pCR regardless of the definition used by the trials, he noted. He did not concur with Untch that pCR predicts long-term outcomes. He said that while it is possible that the failure of ER-positive patients to achieve a pCR might not compromise eventual disease-free survival (DFS), longer follow-up is needed. "pCR is variable and associated with hormone receptor subtype. We need further data on anti-HER2 therapies [before using pCR as a surrogate for DFS]," Winer said.

	"The combination of lapatinib and trastuzumab plus docetaxel will be studied in the adjuvant setting. It should not be used as neoadjuvant therapy outside the setting of a clinical trial," he cautioned.

Baselga J, Bradbury I, Eidtmann H, et al. First Results of the NeoALTTO Trial (BIG 01-06 / EGF 106903): a phase III, randomized, open label, neoadjuvant study of lapatinib, trastuzumab, and their combination plus paclitaxel in women with HER2-positive primary breast cancer. Presented at: San Antonio Breast Cancer Symposium; December 8-12, 2010; San Antonio, TX

Untch M, Loibl S, Bischoff J, et al. Lapatinib vs trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy: primary efficacy endpoint analysis of the GeparQuinto study (GBG 44). Presented at: San Antonio Breast Cancer Symposium; December 8-12, 2010; San Antonio, TX.

Published in Oncology & Biotech News. January 2011.

Articles

Two trials explored the role of lapatinib (Tykerb) as neoadjuvant therapy in early-stage HER2-positive breast cancer and concluded that its effectiveness is statistically no better than standard trastuzumab (Herceptin) therapy

SABCS Coverage: Trastuzumab Superior to Lapatinib in HER2-Positive Breast Cancer, But Combination Is Best

	Investigators for Study 136 say that an additional 4 months of follow-up data have confirmed earlier findings that denosumab (Xgeva) is superior to zoledronic acid (Zometa) at preventing skeletal-related events (SRE) in patients with breast cancer that has metastasized to their bones. "This extended data analysis showed that denosumab was superior to zoledronic acid, and continued treatment with denosumab resulted in a median time to first SRE that was 5 months longer than with zoledronic acid," said Alison Stopeck, MD, lead author and an associate professor of medicine at Arizona Cancer Center in Tucson.

	Stopeck added that significantly fewer patients in the denosumab arm suffered pathologic fractures or required radiation to the bone compared with the group taking zoledronic acid. "These results reinforce the superior efficacy profile of denosumab versus zoledronic acid and provide additional reassurance of the safety profile of this drug. I feel confident that denosumab can prevent debilitating and costly bone complications [in these patients]," Stopeck said.

	The international, randomized, doubleblind, phase III trial randomized 2046 adults with advanced breast cancer and confirmed bone metastases to 120 mg of denosumab, administered subcutaneously, plus intravenous placebo every 4 weeks (n = 1026); or to 4 mg of zoledronic acid administered intravenously and placebo administered subcutaneously every 4 weeks (n = 1020). All patients were given supplemental calcium and vitamin D. The patients had not received bisphosphonate treatment prior to study onset. Unlike most breast cancer trials, which include only women, ~1% of patients in this study were men, which Stopeck said reflects the real-world incidence of breast cancer in men.

	Compared with zoledronic acid, Stopeck reported that use of denosumab extended the median time to first on-study SRE by 5 months (27.4 mo vs 32.4 mo, respectively; 

= .0096). In the subgroup of patients who experienced ?1 SRE, denosumab was associated with a 4.5% relative risk reduction at 12 months, an 11.4% relative risk reduction at 18 months, and a 15.4% relative risk reduction compared with zoledronic acid. Overall survival and disease-free progression were similar in both groups.

	In a multiple events analysis, denosumab reduced the risk of first and subsequent SREs by 22%, a difference that Stopeck said was highly statistically significant (

= .0008). Patients taking denosumab experienced 526 SREs overall, compared with 669 for patients treated with zoledronic acid. Stopeck emphasized that "the curves between the two treatment arms [for SREs] continued to separate over the 4-month extended analysis."

No new safety signals emerged over the 4-month extension study. Nearly all patients in the trial experienced at least 1 adverse event, and similar proportions in each arm experienced a serious adverse event (

). The zoledronic acid arm had nearly double the rate of adverse events related to renal toxicity compared with the denosumab group. The zoledronic acid group also had a higher rate of hypocalcemia compared with the denosumab group, whereas osteonecrosis of the jaw was more common in the denosumab arm than the zoledronic acid arm (

= .29). The rate of acute phase reactions, such as bone pain and flu-like symptoms, was much higher in the zoledronic acid arm than in the denosumab arm. Stopeck pointed out that while 15% of patients taking zoledronic acid missed a dose or had a dose reduction to manage an adverse event, no patient taking denosumab missed any doses during the trial because of toxicity.

	A subanalysis of Study 136 showed that patients taking denosumab experienced less pain than those taking zoledronic acid, based on data from a patient-completed Brief Pain Inventory. Patients randomized to denosumab said it took 70 days for the drug to reduce pain levels to where they no longer interfered with daily activities compared with 86 days for zoledronic acid (

= .09). Pain took a median of 394 days to worsen for the patients given denosumab versus 310 days for those receiving zoledronic acid (

	Investigators are also looking to see whether denosumab can prevent bone metastases in patients with cancer. "We want to manipulate the bone microenvironment to prevent metastases," Stopeck said. D-CARE, a placebo-controlled trial that is looking at adjuvant therapy in breast cancer, has started to enroll high-risk patients with early-stage disease and will evaluate denosumab's effect on disease-free survival and bone metastasis-free survival. "I feel confident that Xgeva can provide patients with advanced breast cancer that have developed a bone metastases an excellent option to prevent debilitating and costly bone complications," Stopeck concluded.

	The FDA approved denosumab on November 18, 2010, to prevent SREs in patients with bone metastases from solid tumors. It has not been approved for patients with multiple myeloma. Stopeck disclosed that her potential conflicts of interest include Amgen and Novartis, makers of these two drugs.

	____________________________________________

Abstracts P6-14-01 and P1-13-05. Stopeck A, Martin M, Ritchie D, et al. Effect of denosumab versus zoledronic acid treatment in patients with breast cancer and bone metastases: results from the extended blinded treatment phase. Paper presented at: 33rd Annual San Antonio Breast Cancer Symposium; December 8-12, 2010; San Antonio, TX.

Investigators for Study 136 say that an additional 4 months of follow-up data have confirmed earlier findings that denosumab (Xgeva) is superior to zoledronic acid (Zometa) at preventing skeletal-related events

SABCS Coverage: Denosumab Bests Zoledronic Acid at Preventing Bone Complications in Patients With Breast Cancer

	Adjuvant treatment of stage II and III breast cancer with zoledronic acid (Zometa) failed to improve disease-free survival (DFS) in the large, randomized AZURE (Adjuvant Zoledronic Acid to Reduce Recurrence) trial, contrary to expectations of the investigators. AZURE was the largest study conducted of bisphosphonate use with adjuvant therapy for women with breast cancer, and it is highly unlikely that this conclusion will change with further follow-up, the authors said.

	At the time the AZURE trial began, investigators were aware that momentum was growing to use zoledronic acid in the adjuvant setting. "We were surprised by the overall finding of AZURE," said lead author, Robert Coleman, MD, Academic Unit of Clinical Oncology, Weston Park Hospital, Sheffield, United Kingdom, said at a press conference.

	AZURE results contrast with those of the large randomized ABCSG (Austrian Breast and Colorectal Study Group)-12 trial, which did demonstrate a survival benefit with use of adjuvant zoledronic acid in patients who have earlier-stage breast cancer (stage I and II); those patients were younger and had been given goserelin to induce premature menopause. ABCSG-12 findings prompted some oncologists to consider giving zoledronic acid as a routine component of adjuvant therapy for women with breast cancer.

	According to Coleman, "One intriguing finding of a prespecified subgroup analysis of AZURE was a significant DFS benefit for zoledronic acid confined to women who were more than 5 years' postmenopausal or older than age 60, so presumably in menopause for several years." He added that the P value of .001 for this observation was "rarely seen in a subgroup analysis" and called the finding "hypothesis-generating."

	AZURE enrolled 3360 women with stage II and stage III breast cancer who did not have metastases and had not received bisphosphonates in the previous year. Treatment arms were well balanced in terms of disease characteristics. Patients were randomized to standard therapy (investigator's choice of chemotherapy, endocrine therapy, and/or surgery) with placebo or with 4 mg of zoledronic acid. Over 5 years, Zoledronic acid was given in 6 doses every 3 or 4 weeks and later in 8 doses every 3 months followed by 5 doses every 6 months. Both arms had similar percentages of patients Zoledronic Acid Improves Disease-Free Survival in Postmenopausal or Older Women Only who used systemic chemotherapy and endocrine therapy, and the types of therapy received were similar in both groups. More than 95% of patients in the study were treated with chemotherapy--97% with an anthracycline and 24% with a taxane. In addition, 74% of patients received a combination of chemotherapy and endocrine therapy.

	At a median follow-up of ~59 months, the rate of serious adverse events was similar between the treatment arms, with the exception of osteonecrosis of the jaw (ONJ). Investigators reported 17 confirmed cases of ONJ in the zoledronic arm and 9 potential cases; no cases occurred in the control arm. "At 5 years, 1.5% of patients on zoledronic acid developed ONJ," Coleman noted.

	Disease-free survival and invasive DFS were identical in the trial arms. The types of recurrences were similar and arose with similar frequency in both groups of patients. About two-thirds of recurrences were distant metastases, ~16% were loco-regional recurrences, ~6% were ipsilateral recurrences, and ~3% were contralateral recurrences. Approximately 6% of patients in each arm developed new primary cancers.

	Patients treated with zoledronic acid were 15% less likely to die than patients in the control arm (hazard ratio, 0.85; 

= .07), but this was not significant. When overall survival was analyzed according to menopausal status, older postmenopausal women who received zoledronic acid were 29% less likely to die of breast cancer than premenopausal women (

	"This trial will not be the last word," said Sharon H. Giordano, MD, University of Texas M.D. Anderson Cancer Center, Houston, Texas. "Other studies are planned or are ongoing to look at the role of bisphosphonates in breast cancer. Routine use of zoledronic acid to prevent recurrence of breast cancer is not indicated, but bisphosphonates do have an important role in treating bone loss among women with breast cancer to prevent skeletal-related events," she said. Giordano called the differences in outcome by menopausal status in AZURE "intriguing but not definitive." Novartis, which manufactures zoledronic acid, said the company is withdrawing applications in the United States and Europe that sought approval for the drug as part of adjuvant therapy while it analyzes data from this study.

	_______________________________________________

Abstract P5-11-02. Gnant M, Mlineritsch B, Stoeger H, et al. The carryover effect of adjuvant zoledronic acid: comparison of 48- and 62-month analyses of ABCSG-12 suggests that the benefits of combining zoledronic acid with adjuvant endocrine therapy persist long after completion of therapy. Paper presented at: 33rd Annual San Antonio Breast Cancer Symposium; December 8-12, 2010; San Antonio, TX.

Adjuvant treatment of stage II and III breast cancer with zoledronic acid (Zometa) failed to improve disease-free survival (DFS) in the large

SABCS Coverage: Zoledronic Acid Improves Disease-Free Survival in Postmenopausal or Older Women Only

	Women with untreated advanced breast cancer had a trend toward greater clinical benefit with fulvestrant (Faslodex) versus anastrozole (Arimidex) as first-line hormonal therapy, according to results from the FIRST (Fulvestrant First-Line Study Comparing Endocrine Treatments) randomized trial (

). The clinical benefit rate (CBR) was 72.5% for patients treated with fulvestrant compared with 67% for patients taking anastrozole. This translated to a 30% increase in the odds for clinical benefit, which did not reach statistical significance (

 = .386). Fulvestrant was associated with a 36% reduction in the hazard for progression, however, which was significantly better than anastrozole (

	"The time-to- progression benefit for fulvestrant was consistent in all predefined subgroups," said James F. R. Robertson, MD, a breast oncologist at the University of Nottingham in England. "Patients who progress on either fulvestrant or anastrozole remain sensitive to subsequent endocrine treatments." Earlier trials evaluated a 250-mg dose of fulvestrant as second-line endocrine therapy, which failed to slow breast cancer progression compared with anastrozole or tamoxifen, said Robertson. A recent randomized trial, however, found that a 500-mg dose of fulvestrant was associated with significant improvement in progression-free survival compared with 250 mg of fulvestrant as second-line endocrine therapy (

	Those results led to a randomized, open-label comparison of a 500-mg dose of fulvestrant with a 1-mg dose of anastrozole as first-line endocrine therapy for postmenopausal women (N = 205) with advanced, estrogen receptor-positive breast cancer. The primary endpoint was CBR (objective response plus prolonged stable disease); secondary endpoints included objective response rate, time to progression, duration of response, duration of clinical benefit, and safety.

	The first planned analysis occurred after a median follow-up of 8.0 months in the fulvestrant arm and 5.9 months in the anastrozole arm, at which point 36% of patients had progressed. The analysis also showed a disparity in progression between the groups: 29.4% taking fulvestrant progressed compared with 41.7% given anastrozole (

	An updated analysis, performed after a median follow-up of 19 months in the fulvestrant arm and 13 months in the anastrozole group, showed that 69% of patients had progressed. The disparity in rates of progression between the groups that was reported in the first analysis persisted, with a 61.8% rate of progression for the fulvestrant arm compared with a 76.7% rate of progression for the anastrozole group; this translates to a 34% difference in the hazard for progression favoring fulvestrant (

= .01). The median time to progression was 23.4 months for patients treated with fulvestrant compared with 13.1 months for patients taking anastrozole. Adjustment for predefined covariates resulted in a hazard ratio of 0.64 and a 36% reduction in favor of fulvestrant, identical to the advantage shown in the first analysis.

	Robertson said 34 patients in the fulvestrant arm and 50 in the anastrozole arm who progressed received additional hormonal therapy, which benefitted several patients. Of these women, 14 (41.2%) from the fulvestrant group and 21 (42%) from the anastrozole arm had an objective response or stable disease for >/=24 weeks.

	The safety analysis showed no significant differences between the treatment groups for any prespecified adverse events. Additionally, 14 patients (7 in each group) experienced a cumulative 22 serious adverse events.

	The results of the study compare favorably with other published phase III randomized trials of aromatase inhibitors versus tamoxifen as first-line endocrine therapy, said Robertson. In one study, anastrozole resulted in a time to progression of 8.5 months, an overall response rate of 29%, and a CBR of 57.1% (

. 2001;92:2247-2258). A similar study involving letrozole (Femara) showed a time to progression of 9.4 months, a response rate of 30.2%, and a CBR of 48.8% (

	_____________________________________________

Robertson JFR, Lindemann JPO, Llombart-Cussac A, et al. A comparison of fulvestrant 500-mg with anastrozole as first-line treatment for advanced breast cancer: Followup analysis from the FIRST study. Paper presented at: San Antonio Breast Cancer Symposium; December 8-12, 2010; San Antonio, TX.

Women with untreated advanced breast cancer had a trend toward greater clinical benefit with fulvestrant (Faslodex) versus anastrozole (Arimidex) as first-line hormonal therapy

SABCS Coverage: Fulvestrant Prolongs Time to Progression in Breast Cancer

	Aromatase inhibitor use appears to increase the risk of cardiotoxicity in women with early-stage breast cancer, albeit slightly. Investigators said the risk is similar in magnitude to the risks of venous thromboembolism and endometrial cancer associated with 5 years of tamoxifen use. In at-risk patients, such as women with ischemic heart disease at the time of a cancer diagnosis, aromatase inhibitors are associated with an approximately 7% increase in cardiovascular events. In addition, said Eitan Amir, MD, senior fellow, Division of Medical Oncology and Hematology, Princess Margaret Hospital, Toronto, Canada, women who switch from tamoxifen to aromatase inhibitors have a reduced risk of deaths unrelated to breast cancer compared with women whose adjuvant therapy includes an aromatase inhibitor from the outset.

	"It is important to emphasize that the risk is more substantial in at-risk patients [ie, those with cardiovascular risk factors at baseline]," said Amir. "The cardiotoxic effects of aromatase inhibitors include myocardial infarction, angina, and heart failure." One implication of this study is that clinicians should include an assessment of baseline cardiovascular risk, he added.

	According to Amir, several large clinical trials show improved survival in breast cancer, including disease-free survival (DFS), when a "switch" strategy is employed (ie, starting on tamoxifen, then switching to an aromatase inhibitor) versus initiating women on aromatase inhibitors up front. "The lack of improvement [in survival] with upfront aromatase inhibitors may be related to the [cardiac] toxicity," Amir said.

	He and his colleagues at Princess Margaret Hospital conducted a systematic review of data from 7 large randomized clinical trials that assessed primary adjuvant endocrine therapy in >30,000 postmenopausal women with breast cancer. They stratified the women into 2 groups: those who received monotherapy with an aromatase inhibitor and those who received tamoxifen monotherapy or tamoxifen followed by a short period of aromatase inhibitor use.

	They found that women in the aromatase inhibitor group had a 26% higher risk of cardiovascular events (ie, myocardial infarction, angina, and congestive heart failure) than women in the tamoxifen arm (

>.01). The number needed to harm (NNH), which signifies how many patients must be treated for 1 cardiovascular event to occur, was 132 in the aromatase inhibitor group. Looking only at data for at-risk patients taking aromatase inhibitors, Amir noted the absolute risk was 7% and the NNH increased to 14. The increased risk of cardiovascular events for women across the whole study taking aromatase inhibitors was relatively low, ranging from 3.4% to 4.2%, but this was still significant. Amir said the findings suggest women with an elevated risk of heart disease might want to limit their use of aromatase inhibitors.

	In addition to the increased cardiovascular risks, women taking aromatase inhibitors had a 47% higher rate of fracture than women who received tamoxifen. The rate of serious adverse events was similar whether women started on aromatase inhibitors or switched to them after taking tamoxifen. Women on tamoxifen had higher rates of secondary endometrial cancer and deep vein thrombosis.

	The investigators analyzed death without recurrence in the patients and found that upfront use of aromatase inhibitors was associated with a nonsignificant increased risk, whereas switching was not. "It appears that switching from one drug to another may be the best approach," Amir theorized. 

Amir E, Ocana A, Niraula S, et al. Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients. Paper presented at: 33rd Annual San Antonio Breast Cancer Symposium; December 8-12, 2010; San Antonio, TX.

Aromatase inhibitor use appears to increase the risk of cardiotoxicity in women with early-stage breast cancer, albeit slightly.

Bonnie Gillis

Articles

SABCS Coverage: Trastuzumab Superior to Lapatinib in HER2-Positive Breast Cancer, But Combination Is Best

SABCS Coverage: Denosumab Bests Zoledronic Acid at Preventing Bone Complications in Patients With Breast Cancer

SABCS Coverage: Zoledronic Acid Improves Disease-Free Survival in Postmenopausal or Older Women Only

SABCS Coverage: Fulvestrant Prolongs Time to Progression in Breast Cancer

SABCS Coverage: Aromatase Inhibitors Increase Cardiotoxicity Risk in Women With Pre-existing Heart Disease