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Report from the San Antonio Breast Cancer Symposium

Breast canceradVaNces iN the maNagemeNt Of metastatic her2-pOsitiVe aNd tripLe-NegatiVe breast caNcer

Jeffrey Sulpher, MD, FRCPC, cardiac Oncology fellow, the Ottawa hospital cancer centre; and Susan Dent, MD, FRCPC, medical Oncologist, the Ottawa hospital cancer centre

TRial SuMMaRy: EFS and OS results from NeoalTTOpiccart-gebhart m, holmes ap, de azambuja e, et al. the association between event-free survival and pathologic complete response to neo-adjuvant lapatinib, trastuzumab or their combination in her2-positive breast cancer. survival followup analysis of the NeoaLttO study (big 1-06) s1-01.

In NeoALTTO, 455 patients with HER2+ breast cancer (BC) were randomized to receive either neoadjuvant lapatinib, trastuzumab, or the combination for 6 weeks, then the same targeted therapy plus weekly paclitaxel until definitive surgery. Postoperatively, patients received 3 cycles of adjuvant FEC (fluorouracil, epirubicin, cyclophosphamide) followed by the same targeted therapy for a further 34 weeks.

FiNDiNgSThere was a significantly higher breast pathologic complete response (pCR) (NSABP definition: ypT0/is) with dual HER2 blockade using lapatinib and trastuzumab, compared with either agent alone. There were no significant differences between trastuzumab and combination treatment arms in event-free survival (EFS) (HR=0.78, 95% CI 0.47–1.28; p=0.33) or overall survival (OS) (HR=0.62, 95% CI 0.3–1.25, p=0.19). Patients who achieved pCR had better outcomes irrespective of treatment arm (HR=0.38, 95% CI 0.22–0.63, p=0.0003). Subgroup analyses by hormone receptor status revealed a larger divergence in outcomes for patients with hormone receptor-negative disease who achieved pCR for both EFS (HR=0.34, 95% CI 0.17–0.63, p=0.001) and OS (HR=0.29, 95% CI 0.11–0.62, p=0.003).

TRial SuMMaRy: BCiRg006 4-drug combination in neoadjuvant settinghurvitz sa, miller Jm, dichmann r, perez at, 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 lapa-tinib in patients with her2+ breast cancer (triO-us b07) s1-02.

This trial was designed to evaluate the clinical and molecular effects of neoadjuvant TC (docetaxel/carboplatin) plus trastuzumab (H) and/or lapatinib (Ty) in HER2+ BC.

Patients with stage I-III operable BC were randomized to 1 of 3 arms: TCH, TCTy or TCHTy. Patients received a run-in cycle of Ty (1000 mg/d days 1-21) and/or H (8 mg/kg IV),

followed by 6 cycles of q3-wkly TC (T: 75 mg/m2, C: AUC 5 or 6) plus H (6 mg/kg) and/or Ty (1000 mg/d d1-21). The primary endpoint was pCR.

FiNDiNgSIn 106 (of 130 patients): hormone receptors were negative (HR–) in 43 (41%) and were ER and/or PR positive (HR+) in 63 (59%). The overall pCR was 42% (45/106), including 43% (13/30) in Arm 1, 25% (7/28) in Arm 2 and 52% (25/48) in Arm 3 (chi-square test p=0.069). Using a pairwise comparison, pCR was significantly lower in Arm 2 than in Arm 3 (p=0.021) but no difference was detected between Arms 1 and 2 (p=0.14) or 1 and 3 (p=0.45) The pCR in HR+ and HR– tumours were 33% HR+ vs 58% HR– for Arm 1, 13% HR+ vs 42% HR– for Arm 2, and 41% HR+ vs 68% HR– for Arm 3.

TRial SuMMaRy: BETH: addition of bevacizumab shows no OS or iDFS benefitslamon dJ, swain sm, buyse m, martin et al. primary results from beth, a phase iii controlled study of adjuvant chemotherapy and trastuzumab ± bevacizumab in patients with her2-positive, node-positive or high-risk node-negative breast cancer. s1-03.

BETH is a randomized, phase III, open-label study evaluating the addition of bevacizumab (B) to 2 different trastuzumab (H) chemo regimens. Patients had HER2+ BC, Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0–1, unilateral invasive breast adenocarcinoma, and left ventricular ejection fraction (LVEF) ≥55%. Patients were stratified by center, hormone receptor status (ER and/or PR-positive, ER/PR-negative), and axillary lymph node status (0, 1–3, 4+) before inclusion into 1 of 2 chemo cohorts, and then randomized. The primary endpoint was invasive disease-free survival (IDFS) for B-containing vs non-B-containing regimens. Secondary endpoints included: IDFS within chemo cohorts, DFS, OS, recurrence-free interval (RFI), distant RFI, safety including specific cardiac assessments, and the identification of predictive biomarkers for B response.

FiNDiNgSThere was no significant benefit from the addition of beva-cizumab to chemotherapy in either IDFS (HR=0.99, 95% CI 0.79–1.25, p=0.9610) or OS (HR=0.87, 95% CI 0.60–1.25, p=0.4387). The secondary endpoint of IDFS within chemotherapy cohorts was also nonsignificant.

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TRial SuMMaRy: CalgB 40603 shows benefit from adding carboplatin or bevacizumab to standard NaC in TNBCsikov Wm, berry da, perou cm, et al. impact of the addition of carbo-platin (cb) and/or bevacizumab (b) to neoadjuvant weekly paclitaxel (p) followed by dose-dense ac on pathologic complete response (pcr) rates in triple-negative breast cancer (tNbc): caLgb 40603 (alliance). s5-01.

CALGB 40603 is a 2x2 randomized phase II study designed to evaluate the impact of the addition of either carboplatin (Cb) or bevacizumab (B) to neoadjuvant chemotherapy (NAC) on pCR rates in triple-negative breast cancer (TNBC). Secondary endpoints include toxicities, adverse events (AEs), RFS and OS.

In 454 patients, median age was 48, stage II 68%/stage III 32%. Of 354 patients with treatment data, 59 did not com-plete NAC, 30 withdrew due to AEs, more often with B vs not (11.5% vs 3.5%). B was discontinued in 23% of assigned patients vs 6–13% for other agents. Grade 3–4 neutropenia (56% vs 20%) and thrombocytopenia (22% vs 4%) were more common with Cb vs not, while grade 3 hypertension was more common with B vs not (11% vs <1%). Febrile neutropenia, usually during ddAC (dose-dense doxorubicin + cyclophosphamide), was more common in those who received both Cb and B (19% vs others 7%). Unaudited pCR results for the first 369 patients, with effects reported as increments in pCR (95% CI), assuming no interaction, are shown in Table 1. Preliminary results suggest that adding Cb or B to standard NAC significantly increases pCR rates in stage II–III TNBC. These increases are additive, with pCR (breast) in 60.6% and pCR (breast/axilla) in 50% of patients who received both.

COMMENTaRy: Over the past decade, advances in the management of patients with HER2-positive breast cancer have significantly improved patient outcomes, mainly due to the use of targeted therapies such as trastuzumab.1-5 Unfortunately, similar gains have not been achieved in patients with triple-negative (i.e. ER/PR-negative, HER2-negative) disease, which has no known biologic target.

In HER2-positive disease, there is now growing interest in targeting the HER2-neu receptor pathway with multiple agents (usually in combination with trastuzumab), including the monoclonal antibody pertuzumab and the tyrosine kinase inhibitor lapatinib. Clinical trials of dual blockade have demonstrated clinical benefit in both the metastatic and neoadjuvant setting. In CLEOPATRA, an international phase III randomized controlled trial, women with HER2-positive metastatic breast cancer demonstrated a superior DFS and OS when treated with pertuzumab/trastuzumab and docetaxel, compared with trastuzumab and docetaxel alone (PFS HR 0.62, p<0.001, OS HR 0.64, p=0.005), leading to the approval and widespread adoption of this approach in the metastatic setting.6 Dual blockade has also been shown to be efficacious in the neoadjuvant setting, with higher pathologic complete response (pCR) rates achieved in patients treated with trastuzumab/pertuzumab

Table 1. Pathologic complete response (pCR)

pCR (breast) pCR (breast/axilla)

No Cb Cb B effect No Cb Cb B effect

No B 30/89 33.7%

44/94 47.8%

14.9% (4.8–25.0%)

25/89 28.2%

39/92 42.4%

10.5% (0.5–20.5%)

B 48/94 51.1%

57/94 60.6% p=0.004 40/94

42.6%47/94 50.0% p=0.031

Cb effect

11.7% (1.6–21.8%) p=0.022

10.3% (0.3–20.3%) p=0.034

B=bevacizumab; Cb=carboplatin*95% confidence interval

and docetaxel, compared with trastuzumab and docetaxel alone (45.8 % vs 29.0%, p=0.0141),7 leading to the approval of this combination by the FDA in September 2013. Similar results were demonstrated in the NeoALTTO trial, with improved rates of pCR with dual blockade with trastuzumab and lapatinib vs. trastuzumab alone (51.3% vs 29.5%, p=0.0001).8 Whether such promising results will translate into long-term improvements in DFS or OS is unclear.

At SABCS 2013, the 4-year followup data of NeoALLTO demonstrated again that pCR is associated with both EFS (time from randomization) and OS, irrespective of treatment arm.9 The majority of patients achieving pCR were in the HER2-positive, hormone receptor-negative subgroup (pCR 61.3%). It is important to bear in mind that Neo-ALTTO was powered to detect differences in pCR and not EFS or OS. This question is being addressed in the larger phase III adjuvant study (ALTTO, NCT00490139), a 3-arm trial examining the impact of dual blockade on DFS. The benefit of dual blockade should be evaluated in the context of potential for additional toxicity. In NeoALTTO, the rate of adverse events (such as diarrhea) was higher in patients receiving trastuzumab and lapatinib.8 Although these results show promise, they have not yet changed the standard of care in the management of early-stage HER2-positive breast cancer, which remains adjuvant chemotherapy and trastuzumab. Hopefully the results of APHINITY (NCT01358877), a phase III trial investigating chemo/trastuzumab +/– pertuzumab (recently completed accrual), will shed additional light on the role of dual HER2 blockade in the early-stage setting.

The use of platinum agents in HER2-positive breast cancer has also shown promising results, with the recently published BCIRG006 trial demonstrating comparable rates of DFS/OS and reduced adverse events with adjuvant docetaxel, carbo-platin and trastuzumab (TCH), compared with anthracycline, taxane and trastuzumab combination therapy (AC-TH).5 The addition of lapatinib to TCH to further improve rates of pCR was also recently assessed in a phase II trial (TRIO-US B07), the results of which were presented at SABCS.10 Unfortunately, this strategy led to an increase in treatment toxicity, resulting in lower rates of treatment completion in the combination arm (73% in the combination TCH + lapatinib

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arm vs 100% in the TCH arm).10 As a consequence, pCR rates between TCH + lapatinib and TCH study arms were comparable (52% vs 47%), perhaps as a result of lower treat-ment intensity in the combination arm. For these reasons, the addition of lapatinib to standard TCH or AC-TH regi-mens in the neoadjuvant setting cannot be recommended at this time.

In 2011, the FDA revoked approval for the use of beva-cizumab in combination with chemotherapy for first-line treatment of metastatic HER2-negative breast cancer, due to lack of efficacy (FDA Docket # 2010-N-0621). However, the role of bevacizumab in both HER2-positive (adjuvant/neoadjuvant) and triple-negative breast cancer patients remains unclear. Slamon and colleagues recently reported results from the BETH trial, investigating the role of adju-vant bevacizumab in women with HER2-positive early-stage

breast cancer (high-risk node-negative or node-positive).11 In this trial, the addition of bevacizumab to conventional chemotherapy (TCH or TH/FEC followed by H) failed to prolong DFS (HR=0.99, CI 0.79–1.25), and increased the risk of treatment-related toxicity, such as hypertension and proteinuria. These results are in line with the previously pub-lished phase III adjuvant BEATRICE trial, which demon-strated no improvement in IDFS or OS when bevacizumab was combined with standard chemo therapy in triple-negative disease.12 Therefore at this time, there remains no role for bevacizumab in the adjuvant setting.

However, there may be a role for bevacizumab the man-agement of triple-negative breast cancer in the neoadjuvant setting. In the phase II neoadjuvant CALGB 40603 trial, women were treated with weekly paclitaxel x 12 +/– carbo-platin +/– bevacizumab followed by AC (q2 weeks x 4 cycles).13 Higher rates of pCR were observed in patients receiving bevacizumab as part of their neoadjuvant therapy. This improvement was additive when bevacizumab was combined with carboplatin (breast pCR rates were 33.7% using paclitaxel alone, 47.8% with combination carboplatin, and 60.6% with combination carboplatin and bevacizumab). While these results are encouraging, TNBC represents a heterogeneous group of patients, and it is currently unknown which molecular subtypes respond best to a taxane and platinum chemotherapy combination. A definitive phase III trial will be needed to clarify if bevacizumab has a role in the treatment of women with triple-negative breast cancer in the neoadjuvant setting.

References1. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al.

Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. NEJM 2001;344(11):783-92.

2. Perez EA, Romond EH, Suman VJ, Jeong JH, Davidson NE, Geyer CE, Jr., et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analy-sis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol 2011;29(25):3366-73.

3. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. NEJM 2005;353(16):1659-72.

4. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, et al. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. NEJM 2006;354(8):809-20.

5. Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, et al. Adjuvant trastuzumab in HER2-positive breast cancer. NEJM 2011;365(14):1273-83.

6. Baselga J, Cortes J, Kim SB, Im SA, Hegg R, Im YH, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. NEJM 2012;366(2):109-19.

7. Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 2012;13(1):25-32.

8. Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet 2012;379(9816):633-40.

9. Piccart-Gebhart M, Holmes AP, de Azambuja E, Di Cosimo S, Swaby R, Untch M, 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). San Antonio Breast Cancer Symposium; December 2013; San Antonio, Texas.

In BrIEFalready known• Agents targeting the HER2-neu receptor pathway in

her2 positive disease, such as pertuzumab and lapatinib have been shown to increase rates of pathological complete remission (pcr) in women with metastatic disease when taken in addition to trastuzumab and docetaxel.

• In 2011, the FDA revoked approval for bevacizumab in combination with chemotherapy for first-line treatment of metastatic her2 negative breast cancer due to lack of efficacy.

What these studies showed• Four-year followup data from NeoALTTO demonstrated

that pcr is associated with event-free survival (efs) and overall survival (Os).

• Toxicity was a concern with lapatanib when it was added to docetaxel, carboplatin and trastuzumab in the phase ii triO-us b07 trial.

• The BETH trial demonstrated additional toxicity and no improvement in invasive disease-free survival with the addition of bevacizumab to chemotherapy in her2 positive early stage breast cancer.

• The CALGB 40603 trial suggested there may be a role for neoadjuvant bevacizumab in triple negative cancer.

Next steps• A definitive phase III trial is needed to confirm beva-

cizumab’s role in triple negative cancer.• Wait for results from the APHINITY phase III trial

investigating chemo/trastuzumab +/- pertuzumab in early stage her2 positive cancer.

• Wait for disease-free survival (DFS) results from the phase iii aLttO study to confirm lapatinib’s role in metastatic her2 positive disease.

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10. Hurvitz SA, Miller JM, Dichmann R, Perez AT, Patel R, Zehngebot LM, 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). San Antonio Breast Cancer Symposium; December, 2013; San Antonio, Texas.

11. Slamon DJ, Swain SM, Buyse M, Martin M, Geyer CE, Im Y-H, et al. Primary results from BETH, a phase 3 controlled study of adjuvant chemotherapy and trastuzumab ± bevacizumab in patients with HER2-positive, node-positive or high risk node-negative breast cancer. San Antonio Breast Cancer Symposium; December 2013; San Antonio, Texas.

12. Cameron D, Brown J, Dent R, Jackisch C, Mackey J, Pivot X, et al. Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial. Lancet Oncology. 2013;14(10): 933-42.

13. Sikov WM, Berry DA, Perou CM, Singh B, Cirrincione C, Tolaney S, et al. Impact of the addition of carboplatin (Cb) and/or bevacizumab (B) to neoadjuvant weekly paclitaxel (P) followed by dose-dense AC on pathologic complete response (pCR) rates in triple-negative breast cancer (TNBC): CALGB 40603 (Alliance). San Antonio Breast Cancer Symposium; December 2013; San Antonio, Texas.

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