Improving survival and limiting toxicity: latest advances in treating human epidermal growth factor receptor 2 overexpressing breast cancer

Abstract

In recent years, new strategies for the treatment of breast cancer have focused on extensive target identification and understanding the expression, regulation and function of critical signaling pathways involved in breast cancer initiation and progression. This has led to significant progress in developing and understanding human epidermal growth factor receptor 2 (HER2)-targeted therapies, which in turn, has translated into significant increases in median survival for patients with HER2-overexpressing breast cancer. It is becoming increasingly difficult to make specific recommendations for the optimal treatment of HER2-overexpressing breast cancer since the field is evolving so rapidly. However, despite the many randomized trials that have been undertaken showing improvement in survival, the current standard treatment for HER2-overexpressing breast cancer continues to revolve around the addition of chemotherapy to a HER2-targeted agent, which in turn, carries substantial toxicities. This article reviews agents that have recently been investigated to treat HER2-overexpressing breast cancers. The goal is ultimately to increase the magnitude and duration of response to trastuzumab-based treatment while minimizing toxicity. Studies addressing length of therapy duration, the superiority and side-effect profile of the different biological drug combinations, and determination of biomarkers of resistance to HER2 therapy will be instrumental in decreasing morbidity and mortality for patients with HER2-overexpressing breast cancer.

Introduction

Trastuzumab (Herceptin, Genentech, San Francisco, CA), a humanized monoclonal antibody that binds the ectodomain of the human epidermal growth factor receptor 2 (HER2), has been approved by the United States Food and Drug Administration (FDA) for the treatment of HER2-overexpressing breast cancer in the adjuvant and metastatic settings [Piccart-Gebhart et al. 2005; Romond et al. 2005; Smith et al. 2007]. Despite initial encouraging results, the response rate to trastuzumab is ≤40% as single agent in the first-line treatment of metastatic breast cancer, and the median duration of response is between 9 and 12 months [Baselga, 2001; Burstein et al. 2001; Vogel et al. 2002]. This suggests that de novo and acquired resistance to trastuzumab occur.

A major focus in the treatment of HER2-overexpressing breast cancer in recent years has been on developing therapeutic agents to either potentiate the effect of trastuzumab or to target cells which have become resistant to trastuzumab. Although many randomized trials in recent years have shown improvement in overall survival (OS) of patients with HER2-overexpressing metastatic breast cancer, almost all have included a chemotherapy backbone and the current standard of care treatment for HER2-overexpressing breast cancer still revolves around the addition of chemotherapy to a HER2-targeted agent, which in turn carries substantial toxicities. This article will review agents that have been recently added to the repertoire of drugs available to treat HER2-overexpressing breast cancers. Through unique mechanisms of action and synergistic combinations of targeted agents, the magnitude and duration of response to trastuzumab-based treatment may be increased while achieving a less toxic side-effect profile.

HER2-targeted agents

Lapatinib

Besides trastuzumab, the only other HER2-targeting therapy which has received FDA approval is lapatinib (Tykerb, GlaxoSmithKline, Philadelphia, PA). Lapatinib is a dual adenosine triphosphate competitive, small molecule tyrosine kinase inhibitor which targets epidermal growth factor receptor and HER2 [Rusnak et al. 2001]. Lapatinib inhibits the catalytic activity of p95HER2 [Scaltriti et al. 2007], a mechanism of action which is especially relevant in some HER2-overexpressing tumors in which oncogene product is expressed as a kinase active 95 kDa cytosolic fragment which lacks the trastuzumab binding epitope and can thus potentially serve as a resistance mechanism to trastuzumab.

Lapatinib has been found to be active against HER2-overexpressing breast cancers, as first-line therapy and in tumors which have developed resistance to trastuzumab [Geyer et al. 2006; Gomez et al. 2008]. In the study that led to its approval by the FDA, women with HER2-overexpressing, locally advanced or metastatic breast cancer that had progressed after treatment with anthracyclines, taxanes and trastuzumab were randomized to capecitabine with or without lapatinib. In tumors with confirmation of HER2 overexpression by central review, progression-free survival (PFS) and time to progression (TTP) were almost doubled from 4.4 months to 8.4 months in the lapatinib arm [hazard ratio (HR) 0.49, 95% confidence interval (CI) 0.34–0.7, p < 0.001) [Geyer et al. 2006]. This improvement occurred without any increase in serious adverse events in the combination arm. Another randomized trial of paclitaxel with or without lapatinib in patients receiving first-line therapy for metastatic breast cancer demonstrated an improvement in median TTP from 5.8 months to 8.1 months in the lapatinib-containing arm [Di Leo et al. 2007].

In an effort to investigate preclinical studies which showed synergism between lapatinib and trastuzumab, a study of lapatinib alone or in combination with trastuzumab in patients with HER2-overexpressing and trastuzumab-refractory metastatic breast cancer was initiated [Blackwell et al. 2010]. Patients had received a median of three prior trastuzumab-containing regimens and the primary endpoint was PFS. In the 296 patients included in the intent-to-treat analysis, the combination of lapatinib and trastuzumab resulted in a PFS improvement of 12 weeks compared with 8 weeks for the lapatinib alone arm (HR 0.73, 95% CI 0.57–0.93, p = 0.008). A trend toward an improvement in OS was seen (HR 0.5, 95% CI 0.53–1.07, p = 0.106) despite the fact that 49% of women who were randomized to the lapatinib alone arm crossed over to the combination arm after 4 weeks of therapy. The safety profile was acceptable with diarrhea, rash, nausea, and fatigue being the most common toxicities. Only diarrhea was more significant in the combination arm, and as expected, neutropenia and febrile neutropenia were not factors in this chemotherapy-free treatment regimen. This study confirmed the hypothesis that dual blockade of HER2 is more effective than single therapy and set the stage for future studies to omit chemotherapy and/or to include dual target inhibition.

The combination of lapatinib and trastuzumab has also been evaluated in the neoadjuvant setting for patients with locally advanced HER2-overexpressing breast cancer [Chang et al. 2011]. In a recent phase II study (TBCRC006), patients received weekly trastuzumab and daily lapatinib for 12 weeks, and patients who were estrogen receptor (ER) and/or progesterone receptor (PR) positive also received letrozole (with goserelin if premenopausal) [Chang et al. 2011]. The median tumor size was 6 cm, with almost two-thirds of patients having tumors greater than 5 cm in size. The primary endpoint was pathologic complete response (pCR) in the breast plus near pCR, defined as residual tumor in the breast less than 1 cm. In the 64 evaluable patients, the pCR rate was 28% and the pCR plus the near pCR rate was 53%. The therapy was well tolerated with the main toxicities being grade 1 diarrhea, nausea, and acneiform rash. The only grade 3 or 4 toxicity was abnormal liver function tests which reverted to normal after discontinuation of therapy; this occurred in less than 5% of the patients. In a population of locally advanced HER2-overexpressing breast cancers, achieving pathologic tumor size of less than 1 cm in over 50% of patients without chemotherapy and without significant toxicity is a remarkable achievement. Whether extending treatment will further increase the pCR will be evaluated in future studies.

Two other large studies, NeoALTTO (neo-Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization) and the GeparQuinto trials, examined the role of trastuzumab, lapatinib, or the combination in early-stage breast cancer as adjuvant therapy. GeparQuinto (GBG 44) [Untch et al. 2010] was a randomized phase III study aimed to determine the pCR rate (defined as no invasive or non-invasive tumor residuals in breast and nodes) of the addition of trastuzumab or lapatinib to an anthracycline- and taxane-based chemotherapy regimen (epirubicin/cyclophosphamide followed by docetaxel) for patients with high-risk (> T2 or clinically or pathologically confirmed lymph node involvement) HER2-overexpressing breast cancer. Median tumor size was 4 cm. Trastuzumab or lapatinib was administered throughout all cycles of chemotherapy. The trastuzumab combination arm yielded a significantly higher pCR rate (31%) compared with the lapatinib arm (22%). Balselga and colleagues evaluated the efficacy of neoadjuvant paclitaxel with trastuzumab versus paclitaxel with lapatinib or paclitaxel with lapatinib and trastuzumab [Baselga et al. 2010a]. Eligible patients had operable HER2-overexpressing breast cancer. Patients received the targeted agent(s) alone for 6 weeks after which paclitaxel was added for 12 weeks. After surgery, patients received adjuvant FEC (5-fluorouracil, epirubicin, and cyclophosphamide) followed by the same targeted therapy they had received prior to surgery to complete 1 year of anti-HER2 therapy. The primary endpoint was pCR in the breast. The targeted therapy combination arm yielded a significantly higher pCR rate (51%) compared with 25% in the lapatinib arm and 29.5% in the trastuzumab arm. The total locoregional pCR rate, which included lymph nodes, was also significantly higher in the trastuzumab/lapatinib arm. In both GeparQuinto and NeoALTTO studies, the lapatinib-containing arms were associated with significantly more grade 3 and higher toxicity than the trastuzumab alone arms, including diarrhea, hepatic toxicity, neutropenia, and skin disorders. In the NeoALTTO study, the toxicity led to reduced treatment exposure, with only 61% of patients in the lapatinib/ trastuzumab arm completing therapy compared with 92% in the trastuzumab arm. Despite this decrease in exposure, the combination still had a much higher pCR rate, indicating that dual inhibition is important, but the dosing of lapatinib needs to be modified for future studies. Adverse events including diarrhea can also be controlled more effectively with prophylactic measures and strict dosing reduction guidelines in future studies.

ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization [ClinicalTrials.gov Identifier: NCT00490139]), a randomized, open-label multi-centre phase III study comparing the activity of lapatinib alone versus trastuzumab alone versus trastuzumab followed by lapatinib versus lapatinib concomitantly with trastuzumab in the adjuvant treatment of patients with ErbB2-overexpressing breast cancer has recently completed accrual and final results are pending. However, the study’s independent data monitoring committee recently reported that the comparison of lapatinib alone versus trastuzumab alone crossed the futility boundary, indicating that the lapatinib alone arm was unlikely to meet the prespecified criteria to demonstrate non-inferiority to trastuzumab alone with respect to disease-free survival (DFS). The study will continue the other three arms (trastuzumab alone, sequential trastuzumab/lapatinib, and the combination arm) as planned.

Initial trials of adjuvant chemotherapy with trastuzumab or placebo in early-stage HER2-positive patients showed that the brain as the first site of relapse was significantly higher in the trastuzumab arm, confirming the hypothesis that the brain could serve as a sanctuary site for patients receiving trastuzumab [Romond et al. 2005]. Unlike trastuzumab, lapatinib and other small molecule HER2-kinase inhibitors have the potential to cross the blood–brain barrier. In lapatinib’s phase III registration study, central nervous system metastases occurred in fewer women in the lapatinib/capecitabine arm compared with the capecitabine alone arm [Geyer et al. 2006]. This trend was evaluated in a phase II study of 39 patients with HER2-positive breast cancer and brain metastases [Lin et al. 2008]. The results further demonstrated evidence of some activity of lapatinib in the brain with one partial response in the brain and 18% PFS at 16 weeks. The ALTTO study, in addition to determining lapatinib’s place in the adjuvant treatment of HER2-overexpressing breast cancer in regards to systemic control, will also provide insights into whether a small molecule can improve DFS and OS by preventing CNS relapses.

Trastuzumab emtansine

Trastuzumab emtansine (T-DM1) is a novel HER2 antibody–drug conjugate in which trastuzumab is bound to the highly potent antimicrotubule agent (DM1) which is derived from the toxic chemotherapy, maytansine. T-DM1 binds to HER2 with affinity similar to that of trastuzumab and delivers its antitumor activity to HER2-overexpressing cells by combining the action of trastuzumab with receptor-mediated internalization and intercellular release of maytansine [Widdison et al. 2006]. A phase II study of 112 patients receiving single-agent T-DMI showed an overall response rate (ORR) of 26% [Vogel et al. 2009]. To confirm the finding of the first phase II study in a more homogenous population, another open-label phase II study of 110 patients who had received a prior anthracycline, taxane, capecitabine, trastuzumab and lapatinib was performed. This study demonstrated an ORR of 32.7% by independent radiology assessment and 39.5% in centrally confirmed HER2-positive patients [Krop et al. 2009]. Patients on study had received a median of seven prior agents for metastatic disease (range 1–15). T-DM1 was generally well tolerated, with the most common toxicities being fatigue, nausea, and reversible thrombocytopenia.

A randomized phase II trial of T-DM1 in patients receiving first-line treatment for metastatic breast cancer compared T-DM1 with trastuzumab plus docetaxel [Perez et al. 2010]. There were 137 patients with newly diagnosed metastatic disease who were randomized to one of the two study arms. After a median follow up of 6 months, the ORR in the T-DM1 arm was 48%, compared with 41% in the trastuzumab/docetaxel arm. Most importantly, the rates of clinically adverse events were 37% in the T-DM1 arm compared with 75% in the chemotherapy-containing arm. The development of therapies such as T-DM1, which provide significant benefit while reducing toxicity, is of utmost importance in patients with metastatic disease. T-DM1 is now being evaluated in early-stage breast cancer and in combination with chemotherapy and with other targeted agents as discussed below.

Pertuzumab

Pertuzumab (Omnitarg, Genentech, San Francisco, CA) is a humanized monoclonal antibody that binds to an epitope in the dimerization domain of the HER2 receptor that is different from the binding site of trastuzumab and prevents signaling secondary to heterodimerization with HER3. In a phase II study of patients with HER2-positive metastatic breast cancer progressing on trastuzumab, the combination of trastuzumab and pertuzumab showed an ORR of 24% and a clinical benefit rate (CBR) of 50%, with five patients (7.6%) experiencing a complete response [Baselga et al. 2010b]. This combination was extremely well tolerated with diarrhea, fatigue, and nausea being the most common adverse events. Only four patients experienced grade 3 treatment-related adverse events, including diarrhea, which was controlled with medication in two patients, one central line infection, and one episode of pruritic rash after injection of contrast prior to pertuzumab. All of the adverse events resolved and treatment was continued. The concept of treating breast cancer through the use of two targeted therapies was verified with trastuzumab and lapatinib, but this study is the first to show a benefit for combining two monoclonal antibodies without affecting toxicity.

Building on the success of the pertuzumab/trastuzumab study, a phase III study of pertuzumab and trastuzumab with docetaxel versus trastuzumab/docetaxel, known as CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab), met its primary endpoint of PFS benefit for the pertuzumab/trastuzumab/docetaxel arm [Baselga et al. 2011]. CLEOPATRA was a randomized, placebo-controlled study which included 808 patients with HER2-positive metastatic breast cancer from 19 countries in their first line of treatment for metastatic disease. The median PFS was 18.5 months in the pertuzumab group compared with 12.4 months in the control group (HR 0.62, 95% CI 0.51–0.75, p < 0.001). Final OS results are pending, but an interim analysis did show a strong trend in favor of the pertuzumab group. No new safety signals were noted and adverse events were consistent with prior studies combining trastuzumab and pertuzumab. Importantly, no increase in cardiac toxic events was noted with the combination of the two antibodies.

Pertuzumab has also been evaluated in the neoadjuvant setting in patients with HER2-overexpressing cancer whose primary tumors were larger than 2 cm. NeoSphere (Efficacy and Safety of Neoadjuvant Pertuzumab and Trastuzumab in Women with Locally Advanced, Inflammatory, or Early HER2-positive Breast Cancer Trial) was a four-arm phase II study of 417 patients designed to compare neoadjuvant docetaxel given concurrently with trastuzumab, or pertuzumab, or the combination of trastuzumab and pertuzumab, or trastuzumab and pertuzumab without chemotherapy [Gianni et al. 2010b]. The primary endpoint was pCR rate, and secondary endpoints included CBR, DFS and breast conservation rate. The combination of docetaxel/trastuzumab/pertuzumab yielded a pCR rate of 46% compared with 29% for docetaxel/trastuzumab, 24% for docetaxel/pertuzumab, and 17% for trastuzumab/pertuzumab. The CBR rate was similar between all four arms. The primary grade 3 and higher toxicities occurred in the docetaxel arms and included neutropenia, febrile neutropenia, leucopenia, and diarrhea. These appeared to be due to docetaxel as the toxicities among the three docetaxel arms were similar and the addition of a second biological drug did not change the adverse effects. The only grade 3 and higher toxicity reported in the trastuzumab/pertuzumab arm was a 1% rate of neutropenia. This study confirmed the activity of the two monoclonal antibodies in combination, but suggested that chemotherapy is still necessary in at least a subset of the population to achieve maximum response.

The MARIANNE study, a phase III randomized study of T-DM1 with or without pertuzumab compared with trastuzumab plus a taxane for first-line treatment of HER2-overexpressing metastatic breast cancer is an ongoing study which is the first to evaluate the efficacy of a targeted antibody and an antibody–drug conjugate [Ellis et al. 2011]. The primary endpoint is PFS, and target enrollment is ahead of schedule. If positive, this study may change treatment paradigms completely for HER2-overexpressing metastatic breast cancer by eliminating nontargeted cytotoxic chemotherapy in the first line. T-DM1 is also being explored in the second-line setting in a randomized phase III study comparing it with lapatinib and capecitabine. This study (EMILIA) will again serve to potentially challenge a standard treatment in HER2-overexpressing breast cancer. Table 1 includes a list of ongoing phase III clinical trials with novel agents for patients with HER2-overexpressing metastatic breast cancer.

Table 1.

Ongoing randomized phase III trials in human epidermal growth factor receptor 2 overexpressing metastatic breast cancer.

Clinical trial	Study arms	Trial endpoint	Data expected
NEFERTT (N = 1200) First-line metastatic	Neratinib + Paclitaxel	PFS, OS	2012
	Trastuzumab + Paclitaxel
BO22589 (N = 1092) First-line metastatic	Herceptin + taxane	PFS	2012
	T-DM1
	T-DM1 + pertuzumab
EMILIA (N = 580) Locally advanced or metastatic	T-DM1	PFS, OS, ORR	2013
	Capecitabine + lapatinib
	Docetaxel + trastuzumab + pertuzumab
PHEREXA (N = 450) Second-line after trastuzumab	Capecitabine + trastuzumab	PFS, TTP, TTF, ORR, CBR	2015
	Capecitabine + trastuzumab + Pertuzumab
BOLERO-1 (N = 717) First-line metastatic	Pertuzumab + trastuzumab	PFS, OS, ORR, CBR, TTR	2012
	Pertuzumab + trastuzumab + everolimus
BOLERO-3 (N = 572)	Vinorelbine + trastuzumab	PFS, OS, ORR, CBR	2012
Resistant to trastuzumab	Vinorelbine + trastuzumab + everolimus

CBR, clinical benefit rate; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; TTF, time to treatment failure; TTP, time to progression; TTR, time in treatment range.

Conclusion

In the case of treatment targeted against HER2-positive breast cancers, there are no biomarkers reliably predicting lack of benefit from trastuzumab that can be used for either clinical trial development or individual therapeutic decisions. Although there are many drugs (such as phosphoinositide 3-kinase/Akt pathway inhibitors, antiangiogenics, cell cycle regulators, or insulin-like growth factor 1 inhibitors) that might be rationally combined with trastuzumab or any other HER2 inhibitor, we do not have a formal process that allows prioritization or triaging of those combinations in a way that will accelerate the approval of the most effective ones.

The study of biomarkers of drug exposure and sensitivity in metastatic tumors, although feasible, is not easy due to the inherent difficulty of obtaining sequential tumor samples only for research purposes. One approach to circumvent this difficulty consists of the administration of novel therapies in the neoadjuvant setting. The incorporation of presurgical targeted-development clinical trials that focus on extensive agent characterization and target-assay development in a limited number of patients could yield results that would optimally inform and expedite subsequent development and approval of molecularly targeted agents, providing a platform for prioritization of novel combinations [Kummar et al. 2007]. By allowing the collection of both diagnostic and surgical tumor material, these studies have the added benefit of providing paired pre- and post-therapy tumor tissues with pharmacodynamic endpoints in 100% of subjects enrolled, hence providing a goldmine for discovery of resistance mechanisms and a platform for better identification of patients who may do well with less toxic treatment.

The results of recent neoadjuvant clinical trials for patients with HER2-overexpressing breast cancer (summarized in Table 2) show that the combination of chemotherapy and dual HER2 blockade (i.e. trastuzumab plus lapatinib or trastuzumab plus pertuzumab) clearly promotes higher rates of pCR, whereas the combination of chemotherapy and single-agent lapatinib or single-agent pertuzumab in general performs worse than chemo/single agent trastuzumab-containing regimens. Furthermore, lapatinib single-agent arms (1500 mg) tend to be more toxic, and result in inability to complete a full course of treatment. Subset analysis of pCR rates in HER2+/ER− and HER2+/ER+ breast cancers consistently show higher pCR rates in HER2+/ER− tumors. However, long-term follow up supports that HER2+/ER+ tumors may have similar (if not better) prognosis.

Table 2.

Pathological complete responses (pCRs) in neoadjuvant clinical trials for patients with human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer.

Clinical trial	Study arms	pCR (%)
NeoSphere (Gianni et al. 2010b) (N ~ 400)	Trastuzumab + docetaxel	29
	Pertuzumab + docetaxel	24
	Pertuzumab + trastuzumab + docetaxel	46
	Trastuzumab + pertuzumab	17
NeoALTTO (Baselga et al. 2010a) (N ~ 450)	Trastuzumab → trastuzumab + paclitaxel	30
	Lapatinib → lapatinib + paclitaxel	25
	Trastuzumab + lapatinib → lapatinib + trastuzumab + paclitaxel	51
GeparQunito (Untch et al. 2010) (N ~ 600)	EC + trastuzumab → trastuzumab + docetaxel	31
	EC + lapatinib → lapatinib + docetaxel	22
TBCRC006 (Chang et al. 2011) (N ~ 60)	Trastuzumab + lapatinib (ER−)	46
	Trastuzumab + lapatinib + letrozole (ER+)	21

EC, epirubicin + cyclophosphamide; ER, estrogen receptor; NeoSphere, Efficacy and Safety of Neoadjuvant Pertuzumab and Trastuzumab in Women with Locally Advanced, Inflammatory, or Early HER2-positive Breast Cancer Trial; NeoALTTO, neo-Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization Trial.

Overall, the addition of anthracyclines and/or longer duration of neoadjuvant treatment did not significantly increase pCR rates. This was to be expected following the results of the Breast Cancer International Research Group 006 (BCIRG006) multicenter phase III randomized trial. This trial compared doxorubicin and cyclophosphamide followed by docetaxel (ACT) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (ACTH) and with docetaxel, carboplatin and trastuzumab (TCH) in the adjuvant treatment of node-positive and high-risk node-negative patients with operable HER2-overexpressing breast cancer [Slamon et al. 2009]. The results showed that the benefit of trastuzumab addition to an anthracycline-based (ACTH) and a non-anthracycline-based (TCH) chemotherapy regimen was very similar in terms of DFS and OS at 65 months of follow up, with much less cardiac toxicity seen in the nonanthracycline-based (TCH) arm.

The similarities in the direction of the outcomes of certain ‘paired’ adjuvant/neoadjuvant clinical trials are certainly intriguing, and suggest the possibility that neoadjuvant studies with cellular and molecular endpoints in addition to clinical endpoints can ‘predict’ the outcome of larger clinical studies in the adjuvant or metastatic setting and thus provide a novel platform for the prioritization of new drugs and/or combinations. This was certainly the case in the adjuvant ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial [Howell et al. 2005] and the neoadjuvant IMPACT (Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen) trial [Dowsett et al. 2003, 2005; Smith et al. 2005], both of which compared the use of tamoxifen with the third-generation aromatase inhibitor, anastrozole, and the combination. In the neoadjuvant NOAH (Neo-Adjuvant Herceptin) trial [Gianni et al. 2010a] and the adjuvant NSABP (National Surgical Adjuvant Breast and Bowel Project) B-31/NCCTG N9831 trial [Romond et al. 2005], survival benefit was shown from the addition of trastuzumab to chemotherapy. More recently, the NeoALTTO study [Baselga et al. 2010a] showed that the single-agent lapatinib arm had a lower pCR rate than the trastuzumab and combination arms, which seem to have accurately predicted the outcome of the lapatinib only arm in the ALTTO study.

However, as tempting as it is to speculate, due to variable outcomes, pCR rate may not be a 100% reliable surrogate in all cases (i.e. HER2+/ER+ breast cancer), and validation in the adjuvant setting may still be required. Despite its small sample size, the TBCRC006 trial, in which patients with stage II and III HER2-overexpressing breast cancers were treated with a trastuzumab and lapatinib combination, showed that neoadjuvant treatment without a chemotherapy backbone is feasible and potentially sufficient for a selected patient population. Such neoadjuvant studies, in which tissue is collected prior to treatment and at surgery, new molecular markers can be investigated to identify subsets of patients who are the best candidates for chemotherapy-free regimens. Confirmatory studies addressing length of therapy duration, the superiority and side-effect profile of the different biological drug combinations (i.e. trastuzumab plus lapatinib, trastuzumab plus pertuzumab, T-DM1) and determination of biomarkers of HER2 therapy resistance will be instrumental in decreasing morbidity and mortality for patients with HER2-overexpressing breast cancer.