Highlights from the 36th Annual CTRC-AACR San Antonio Breast Cancer Symposium (SABCS)
Bobbie Quach, PharmD Student
Meghana V. Trivedi, PharmD PhD BCOP
University of Houston College of Pharmacy, Houston, TX
Bisphosphonates in Breast Cancer
Adjuvant Bisphosphonate Reduces Bone Recurrence and Improves Survival in Postmenopausal Women with Early Breast Cancer1
During the past 15 years, numerous randomized controlled trials have shown conflicting clinical benefits in the use of adjuvant bisphosphonate therapy in breast cancer. To address this, a meta-analysis of 36 randomized controlled trials was conducted to compare bisphosphonate versus no bisphosphonate in the adjuvant setting. The primary outcomes were time to recurrence, time to first distant recurrence, and mortality. In all 17,709 women (pre- and postmenopausal) included in the study, a significant reduction in bone recurrence (10-year gain: 1.5%) was observed with the use of bisphosphonates. When the analysis was restricted to 11,306 postmenopausal women, the reduction in bone recurrence with bisphosphonate therapy was even higher (10-year gain: 2.9%). In the analysis of bone recurrence by menopausal status, use of adjuvant bisphosphonates significantly reduced bone recurrence in postmenopausal women (hazard ratio [HR] = 0.66) but not in premenopausal women (HR = 0.93). There was a significant delay in breast cancer recurrence and non-bone distant recurrence in postmenopausal women taking bisphosphonates; this difference was not seen when premenopausal women were also included in the analysis. In evaluating mortality in postmenopausal women, adjuvant bisphosphonate use significantly reduced breast cancer mortality (10-year gain: 3.1%) and all-cause mortality (10-year gain: 2.3%). Although the difference in breast cancer mortality was significant with bisphosphonates in all women, this was primarily driven by the majority of postmenopausal women. In summary, adjuvant bisphosphonates in postmenopausal women significantly reduced the risk of bone recurrence (risk reduction of 34%) and improved survival (risk reduction of 17%) irrespective of the type of bisphosphonate and osteoporosis versus cancer dose, ER positivity, node status, and presence/absence of chemotherapy.
No Advantage of Postneoadjuvant Zoledronic Acid in Primary Breast Cancer2
The NaTaN (Neo-Adjuvant Trial Add-On) study evaluated the effects of postneoadjuvant treatment with zoledronic acid in patients without pathological complete response (pCR) after antracycline-taxane- based chemotherapy for primary breast cancer. Patients were randomized within 3 months, 1 year, 2 years, or 3 years after surgery to receive intravenous (IV) zoledronic acid 4 mg with 1,000 mg calcium and 880 international unit (IU) vitamin D daily versus observation. For the first 6 months, zoledronic acid was administered every 4 weeks for the first six doses, every 3 months for the following 2 years (eight doses), and every 6 months for the last 2.5 years (five doses). Primary outcome was event- free survival (EFS); reported secondary outcomes were overall survival (OS), EFS in subgroups, and toxicity. An interim analysis was conducted with a nonprotocolled Bayesian futility analysis with a 15% futility boundary for the likelihood the results will become statistically significant. The probability of success was <6%; therefore, results were considered final and released. No EFS improvements were seen for patients given 5-year zoledronic acid postneoadjuvant therapy (HR = 0.960, 95% confidence interval [CI]: 0.709–1.30; p = .7885) in comparison to the control group. EFS benefits were not seen in any of the subgroup analyses. Similarly, no significant difference in OS (p = .4082) was noted. In addition, serious adverse events occurred more often in the treatment group (60 events) compared with the observation group (21 events). Although this first randomized postneoadjuvant zoledronic acid treatment study did not improve outcomes in patients without pCR after neoadjuvant chemotherapy, several postneoadjuvant treatment options are currently under investigation, such as rucaparib (PARP-inhibitor) in triple-negative breast cancer (BRE09-146), trastuzumab emtansine in HER2+ disease (OT1-1-06), and palbocicilib in HR+/ HER2- disease (OT2-6-11).
Aromatase Inhibitors (AIs): Breast Cancer Prevention
Anastrozole for Prevention in Postmenopausal Women at High Risk3
The International Breast Cancer Intervention Study II (IBIS-II) trial, a multicenter, randomized, placebo-controlled study, assessed the efficacy of anastrozole versus placebo in 3,864 postmenopausal women who do not have breast cancer but have an increased risk of developing breast cancer. Increased risk was determined by age, family history, type (atypia/lobular carcinoma in situ), breast density, or if the Tyrer-Cuzick model indicated a 10-year risk of breast cancer greater than 5%. The updated data with a median follow-up of 5 years were presented at the meeting. A 53% reduction in breast cancer was seen in the anastrozole treatment group (95% CI: 0.32–0.68; p < .0001). In addition, significant reductions were also seen in ductal carcinoma in situ (DCIS; 70% reduction, HR =0.30 [0.12–0.74]), all invasive breast cancer (50% reduction, HR = 0.50 [0.32–0.76]), and ER+ invasive breast cancer (58% reduction, HR = 0.42 [0.25–0.71]), but not in ER-invasive breast cancer. Compliance was similar in anastrozole and placebo groups with few dropouts due to side effects. Musculoskeletal events (63.9% versus 57.8%) and vasomotor/gynecological adverse effects (56.8% versus 49.4%) were common and significantly higher in the anastrozole group compared with placebo. Currently, the IBIS-II trial provides evidence to support the use of anastrozole for prevention in high-risk postmenopausal women. The long- term follow-up of these patients will determine the full scope of benefits and risks of anastrozole.
AI: Adverse Effects Management
Exercise Interventions to Alleviate Aromatase Inhibitors’ Arthalgia4
AIs are standard of care for hormone receptor-positive breast cancer; however, side effects, such as arthralgia, result in poor adherence and early discontinuation. The HOPE (Hormone and Physical Exercise) study examined 121 postmenopausal stage I-IIIC breast cancer patients who were taking an AI for at least 6 months and experienced at least mild arthralgia defined by pain score >3 on the Brief Pain Inventory-Short Form (BPI). The BPI measured worst pain, pain severity, and pain interference at baseline, 6, and 12 months reported on a scale of 0–10 (mild pain = 3–4, moderate pain = 5–7, severe pain = 8–10). The patients were randomized to the exercise group (n = 61) or usual care group (n = 60). The year-long exercise program consisted of a twice weekly supervised strength training session comprising six common strength-training exercises (8–12 repetitions, three sets) and 2.5 hours/week of moderate aerobic exercise with heart rate monitors to determine intensity. At baseline both controls and exercisers reported similar BPI scores with the worst pain at a pain score of 6 (moderate pain). After 12 months, women randomized to exercise had a significant (20%) decrease in their worst joint pain score, while the usual care control group had only a 3% decrease (p = .017). Women who had 80% or higher adherence to the exercise plan had greater benefits compared with women who had <80% adherence to exercise plans. This preliminary study showed clinical benefit with the use of exercise to reduce pain level from AI-induced arthralgias in breast cancer survivors; therefore, this regimen may lead to improvements in AI adherence, quality of life, and mortality risks. Additional analyses are in progress to further evaluate the benefits of this exercise intervention.
AIs: Preemptive Symptom Management May Improve Adherence5
The COBRA (Consortium on Breast Cancer Pharmacogenomics) investigators analyzed the patient-reported symptoms prior to AI initiation and after discontinuation to determine if a patient’s baseline symptoms may impact persistence with AI treatment. The ELPh (Ex- emestane and Letrozole Pharmacogenetics) trial randomized 503 postmenopausal women with early stage ER+ breast cancer to ex-emestane 25 mg PO daily (n = 248) or letrozole 2.5 mg PO daily (n= 252) for 2 years. Every 1, 3, 6, 12, and 24 months, quality of life and serum hormone concentration data were collected. Quality of life assessments evaluated depression (CESD), anxiety (HADS-A), sleep (PSQI), and symptoms (BCPT). Overall, 31.2% participants discontinued treatment due to toxicity (60 patients taking letrozole and 80 patients on exemestane). Poor sleep (45%, OR = 1.91, p = .002), feeling tired (58%, OR = 1.76, p < .001), and forgetfulness (46%, OR = 1.66, p= .015) were significant adverse effects associated with early AI treatment discontinuation. A significant correlation (p = .007) was seen between baseline symptom burden and AI discontinuation in 1 year. In conclusion, the ELPh study suggested that up-front evaluation and management of initial symptoms might help improve adherence to AI therapy by managing these symptoms before they become problematic and also identifying patients at higher risk of treatment discontinuation in order to enable appropriate interventions.
HER2+ Breast Cancer
Pathological Complete Response (pCR) Correlates with Survival Advantage in HER2+ Breast Cancer6
The initial findings of the Neo-Adjuvant Lapatinib and/or Trastu- zumab Treatment Optimisation (NeoALTTO) trial presented at SABCS in 2011 showed that the pCR rate was significantly higher in the combination lapatinib plus trastuzumab arm compared with the single therapy with either lapatinib or trastuzumab. The updated survival analyses presented at the 2013 meeting demonstrated that patients who achieved pCR had significantly better EFS and OS compared with no pCR irrespective of treatment arm. At a median follow-up of 4 years, there was a significant increase in EFS in patients who experienced pCR in comparison to no pCR (HR = 0.8 [0.22–0.63], p =.0003). In evaluating OS, a 65% reduction (HR = 0.35 [0.15–0.70], p =.005) in death risk was seen in patients who had pCR compared with patients who did not. A greater difference in EFS and OS between pCR and no pCR was seen for hormone receptor-negative breast cancer. No differences in EFS or OS were noted between the treatment arms; however, the NeoALTTO study was not powered to detect modest differences in survival. This question will be addressed by the ALTTO trial, which will be presented next year. Although the data are promising, it might be still premature to use the combination anti-HER2 therapy as a standard of care because of increased risk of adverse effects and lower adherence to therapy with the combination therapy even in hormone receptor-negative cancer. The standard of care in the neoadjuvant setting still remains chemotherapy and trastuzumab. Follow-up analysis will occur over the next 2.5 years. The results from this study also support the FDA’s accelerated approval process in the neoadjuvant setting based on the pCR data.
Neoadjuvant Lapatinib Plus Trastuzumab in Combination with Chemotherapy: Similar pCR Rates, More Toxicities, and Less Adherence Compared with Trastuzumab Only7
The TRIO-US B07 was a randomized phase 2 trial comparing the efficacy and safety of neoadjuvant lapatinib plus trastuzumab, lapatinib alone, and trastuzumab alone in HER2+ stage I–III breast cancer. Women were randomized into three treatment arms: trastuzumab (n = 34), lapatinib (n = 36), or combination lapatinib plus trastuzumab (n = 58) for 21 days followed by six cycles of Docetaxel 75 mg/m2 and carboplatin AUC 6 IV every 3 weeks. Biopsies were collected at baseline, after run-in cycle, and at surgery, with pCR rate as the primary endpoint. Although pCR was higher in lapatinib plus trastuzumab arm (52%) compared with trastuzumab (47%) or lapatinib (25%) arms as shown by other groups, the difference was only statistically significant when comparing the combination with lapatinib. Combination therapy was associated with higher incidence of diarrhea compared with trastuzumab; whereas cardiac events were not significantly different in lapatinib plus trastuzumab arm compared with trastuzumab only. Completion of therapy was significantly lower in the combination therapy (73%) and lapatinib (72%) groups compared with trastuzumab (100%). The lack of benefit from the combination therapy over the trastuzumab only arm, which has been observed in several other studies (e.g., NeoALTTO, TBCRC 006), may be due to a short therapy with anti-HER2 agents.
Novel Agents in Breast Cancer
Src Inhibitor: Dasatinib8
In a randomized study, 120 patients with ER+, HER2- breast cancer were treated with either letrozole plus dasatinib or letrozole alone as first-line therapy for metastatic disease. Time to progression was doubled from 9.7 months to 20.1 months when dasatinib was added to letrozole. This was despite no clinical benefit based on tumor size and symptoms. These findings suggest a role of dasatinib in overcoming resistance to AIs. Dasatinib might be an attractive candidate for further investigation in this setting because it also did not greatly increase the toxicity profile of the AI.
Anti-VEGF Receptor-2 Antibodies: Ramucirumab9
Ramucirumab, a recombinant human IgG1 monoclonal antibody that binds the extracellular domain of VEGF receptor-2, was investigated as a first-line therapy in combination with docetaxel for HER2- metastatic breast cancer. Progression-free survival was not significantly better in docetaxel plus ramucirumab compared with docetaxel alone (HR = 0.88; p = .08). Ongoing molecular analysis from this study may reveal biomarkers for ramucirumab response.
PARP Inhibitors: Veliparib10,11 and BMN 67312
Veliparib plus carboplatin every 3 weeks plus weekly paclitaxel therapy for a total of 12 weeks followed by AC (four cycles of doxorubicin plus cyclophosphamide [every 2–3 weeks]) regimen was tested in comparison to weekly paclitaxel followed by AC in an adaptive trial with 116 high-risk HER2- patients.10 There was a significant increase in the estimated pCR rate from 22% to 33% when veliparib plus paclitaxel were added to the neoadjuvant regimen. The increase in the estimated pCR rate was primarily observed in triple negative breast cancer (26% versus 52%) and not in hormone receptor-positive and HER2- breast cancer (14% versus 19%). Unfortunately, the relative contributions of veliparib and carboplatin could not be determined based on the study design. In a second smaller study, veliparib was tested in 20 stage IV breast cancer patients who were BRCA 1 or 2 carriers.11 At least partial response was seen in 14 of 20 patients. Another PARP inhibitor, BMN 673, was also tested in patients with deleterious germline BRCA 1 and 2 mutations.12 Partial response was achieved in 8 of 18 patients treated with BMN 673. Both veliparib and BMN 673 remain attractive candidates for further investigation in breast cancer.
1. Coleman R, Gnant M, Paterson A, et al. Effects of bisphosphonate treatment on recurrence and cause-specific mortality in women with early breast cancer: A meta-analysis of individual patient data from randomised trials. Presented at San Antonio Breast Cancer Symposium, Dec 10-Dec 14, 2013: Abstract [S4-07].
2. von Minckwitz G, Rezai M, Eidtmann H, et al. Postneoadjuvant treatment with zoledronate in patients with tumor residuals after anthracyclines-taxane-based chemotherapy for primary breast cancer—The phase III NATAN study (GBG 36/ABCSG XX). Presented at San Antonio Breast Cancer Symposium, Dec 10-Dec 14, 2013: Abstract [S5-05].
3. Cuzick J, Sestak I, Forbes JF, et al. Breast cancer prevention using anastrozole in postmenopausal women at high risk. Presented at San Antonio Breast Cancer Symposium, Dec 10-Dec 14, 2013: Abstract [S3-01].
4. Irwin ML, Cartmel B, Gross C, et al. Randomized trial of exercise vs. usual care on aromatase inhibitor-associated arthralgias in women with breast cancer: The hormones and physical exercise (HOPE) study. Presented at San Antonio Breast Cancer Symposium, Dec 10-Dec 14, 2013: Abstract [S3-03].
5. Henry NL, Kidwell K, Hayes DF, et al. Associations between baseline patient-reported symptoms and discontinuation of adjuvant aromatase inhibitor (AI) therapy. Presented at San Antonio Breast Cancer Symposium, Dec 10-Dec 14, 2013: Abstract [S3-02].
6. Piccart-Gebhart M, Holmes AP, de Azambuja E, et al. The association between event-free survival and pathological complete response to neoadjuvant lapatinib, trastuzumab or their combination in HER2-positive breast cancer. Survival follow-up analysis of the NeoALTTO study (BIG 1-06). Presented at San Antonio Breast Cancer Symposium, Dec 10-Dec 14, 2013: Abstract [S1-01].
7. Hurvitz SA, Miller JM, Dichmann R, et al. Final analysis of a phase II 3-arm randomized trial of neoadjuvant trastuzumab or lapatinib or the combination of trastuzumab and lapatinib, followed by six cycles of docetaxel and carboplatin with trastuzumab and/or lapatinib in patients with HER2+ breast cancer (TRIO-US B07). Presented at San Antonio Breast Cancer Symposium, Dec 10-Dec 14, 2013: Abstract [S1-02].
8. Paul D, Vukelja SJ, Holmes FA, et al. Letrozole plus dasatinib improves progression-free survival (PFS) in hormone receptor- positive, HER2-negative postmenopausal metastatic breast cancer (MBC) patients receiving first-line aromatase inhibitor (AI) therapy. Presented at San Antonio Breast Cancer Symposium, Dec 10-Dec 14, 2013: Abstract [S3-07].
9. Mackey JR, Ramos-Vazquez M, Lipatov O, et al. Primary results of ROSE/ TRIO-12, a randomized placebo controlled phase III trial evaluating the addition of ramucirumab to first-line docetaxel chemotherapy in metastatic breast cancer. Presented at San Antonio Breast Cancer Symposium, Dec 10-Dec 14, 2013: Abstract [S5-04].
10. Rugo HS, Olopade O, DeMichele A, et al. Veliparib/carboplatin plus standard neoadjuvant therapy for high-risk breast cancer: First efficacy results from the I-SPY 2 TRIAL. Presented at San Antonio Breast Cancer Symposium, Dec 10-Dec 14, 2013: Abstract [S5-02].
11. Somlo G, Frankel P, Luu T, et al. Efficacy of ABT-888 (veliparib) in patients with BRCA-associated breast cancer. Presented at San Antonio Breast Cancer Symposium, Dec 10-Dec 14, 2013: Abstract [P2-16-05].
12. Mina LA, Ramanathan RK, Wainberg ZA, et al. BMN 673 is a PARP inhibitor in clinical development for the treatment of breast cancer patients with deleterious germline BRCA 1 and 2 mutations. Presented at San Antonio Breast Cancer Symposium, Dec 10-Dec 14, 2013: Abstract [P2-09-02].