Management of small HER2-positive breast cancers

Trastuzumab has revolutionised the treatment of HER2-positive early-stage breast cancer and is now standard of care in combination with chemotherapy for patients with tumours larger than 1 cm. However, 5 years after publication of the landmark trials establishing the efficacy of the drug, the management of small (≤1 cm), HER2-positive tumours remains difficult. Most small breast cancers have a good prognosis and adjuvant chemotherapy is not routinely recommended. However, retrospective data suggest that some small HER2-positive cancers might have a worse clinical outcome than others. This notion raises the key clinical question of whether patients with small HER2-positive cancers should be offered adjuvant trastuzumab and chemotherapy. The pivotal adjuvant trastuzumab trials did not include patients with tumours smaller than 1 cm, but a subset analysis of one trial showed that patients with tumours 1-2 cm in size derived at least as much clinical benefit from 1 year of adjuvant trastuzumab as did the overall cohort. Clinicians face the dilemma of whether the potential reduction in risk of recurrence in this patient group warrants the toxic effects and risks of adjuvant chemotherapy and trastuzumab. In this review, we discuss the evidence for prognosis of small HER2-positive cancers, and for possible benefit from adjuvant trastuzumab. We suggest potential treatment strategies and clinical trial designs to address this important issue. On the basis of present evidence, we recommend that the benefits and risks of adjuvant trastuzumab should be discussed with patients with small, HER2-positive breast cancer.     

T-cell metagene predicts a favorable prognosis in estrogen receptor-negative and HER2-positive breast cancers

Introduction

Lymphocyte infiltration (LI) is often seen in breast cancer but its importance remains controversial. A positive correlation of human epidermal growth factor receptor 2 (HER2) amplification and LI has been described, which was associated with a more favorable outcome. However, specific lymphocytes might also promote tumor progression by shifting the cytokine milieu in the tumor.

Methods

Affymetrix HG-U133A microarray data of 1,781 primary breast cancer samples from 12 datasets were included. The correlation of immune system-related metagenes with different immune cells, clinical parameters, and survival was analyzed.

Results

A large cluster of nearly 600 genes with functions in immune cells was consistently obtained in all datasets. Seven robust metagenes from this cluster can act as surrogate markers for the amount of different immune cell types in the breast cancer sample. An IgG metagene as a marker for B cells had no significant prognostic value. In contrast, a strong positive prognostic value for the T-cell surrogate marker (lymphocyte-specific kinase (LCK) metagene) was observed among all estrogen receptor (ER)-negative tumors and those ER-positive tumors with a HER2 overexpression. Moreover ER-negative tumors with high expression of both IgG and LCK metagenes seem to respond better to neoadjuvant chemotherapy.

Conclusions

Precise definitions of the specific subtypes of immune cells in the tumor can be accomplished from microarray data. These surrogate markers define subgroups of tumors with different prognosis. Importantly, all known prognostic gene signatures uniformly assign poor prognosis to all ER-negative tumors. In contrast, the LCK metagene actually separates the ER-negative group into better or worse prognosis.     

A major role of p95/611-CTF, a carboxy-terminal fragment of HER2, in the down-modulation of the estrogen receptor in HER2-positive breast cancers

Current classification of breast cancers depends in great part on the expression of human epidermal growth factor receptor 2 (HER2), a cell surface tyrosine kinase receptor, and estrogen receptor (ER), the nuclear receptor for estrogen. In addition to reliable biomarkers, these receptors are targets of effective and widely used antitumor drugs. During malignant progression, HER2 and ER can establish an intricate cross-talk. In some cases, HER2 overexpression leads to the downregulation of ER and undermining of anti-ER therapies. A subgroup of HER2-positive breast cancer patients with poor prognosis expresses a heterogeneous collection of HER2 carboxy-terminal fragments (CTF) collectively known as p95HER2. One of these fragments, 611-CTF, is oncogenic in a variety of preclinical models. However, because of the lack of an appropriate tool to specifically analyze its levels in the clinical setting, the value of 611-CTF as a biomarker has not been established yet. Here, we show that 611-CTF induces resistance to antiestrogen therapy and a more pronounced down-modulation of ER than that induced by full-length HER2. To validate this effect in breast cancer samples, we developed specific anti-611-CTF antibodies. With these antibodies, we showed that, whereas the frequency of ER positivity in HER2-positive/611-CTF-negative tumors (72.6%) is similar to that reported for HER2-negative tumors (70-80%), the number of ER-positive tumors in the 611-CTF-positive subgroup is very low (31.2%). These results reveal a mechanism of ER regulation mediated by HER2, which suggests a new strategy to improve responses to endocrine therapy in breast cancer.     

HER2-positive advanced breast cancer

It is important when treating a patient who has advanced breast cancer to establish the biologic characteristics of the tumor. In addition to knowing the hormone receptor status (estrogen and progesterone), human epidermal receptor 2 (HER2) should be evaluated. The measurement of this parameter is essential to optimizing the systemic management. This article reviews the biology of HER2, testing for HER2, clinical studies evaluating HER2-based therapies, side effects (specifically cardiotoxicity), and strategies for HER2-based therapies.     

Dual HER2-targeted approaches in HER2-positive breast cancer

Approximately 15–20% of all breast cancers are human epidermal growth factor receptor 2 (HER2) positive, with clinical studies having validated the HER2 receptor tyrosine kinase pathway as an important therapeutic target. Presently, two HER2-targeted therapies are approved by the Food and Drug Administration for treatment of HER2-positive breast cancer: the HER2-targeted humanized monoclonal antibody trastuzumab and the small-molecule tyrosine kinase inhibitor lapatinib. Despite use of these HER2-targeted agents, many patients still experience disease progression. For this reason, numerous new agents and therapeutic strategies are under investigation. Based on preclinical data suggesting synergistic effects from dual therapy targeting HER2, clinical trials that test the effects of combining anti-HER2 agents have been conducted and are ongoing. Here, we review recently presented data from several clinical trials, which indicate that the strategy of combining HER2 blockade therapies can offer greater clinical efficacy, with adverse effects of varying degrees. Specifically, we review new data reported at the 2010 San Antonio Breast Cancer Symposium (SABCS 2010), including the phase II NeoSphere and phase III NeoALTTO clinical trials, and data from three clinical trials reported at the 2011 American Society of Clinical Oncology (ASCO 2011) meeting. Together these trials elucidate the potential role of combining trastuzumab with lapatinib or pertuzumab. We also discuss additional ongoing studies that will help further define the role of dual HER2 blockade therapies and its impact on clinical practice.     

Simultaneous targeting of estrogen receptor and HER2 in breast cancer

Approximately 50% of HER2-positive breast cancers express estrogen receptor (ER) and these tumors are characterized by short-lived responses to hormonal agents. Preclinical models have shown that dual targeting of ER and HER2 could reverse and delay the development of drug resistance. Two studies (TAnDEM & EGF3008) have recently been published addressing the combined use of an aromatase inhibitor (AI) and an anti-HER2-targeted agent. Both studies showed that the combined approach is associated with improvement in response rate and progression-free survival compared with an AI alone with an acceptable toxicity profile. These results would indeed extend the treatment options for patients with ER/HER2-positive metastatic breast cancer. In this article, we discuss how the improved understanding of the complex cross-talk between ER and HER2 has resulted in better clinical outcomes. We analyze clinical evidence regarding the combined use of AIs and anti-HER2-targeted agents. We also touch on possible mechanisms of resistance and ways to improve research in this field.     

Different mechanisms for resistance to trastuzumab versus lapatinib in HER2- positive breast cancers -- role of estrogen receptor and HER2 reactivation

Introduction

The human epidermal growth factor receptor 2 (HER2)-targeted therapies trastuzumab (T) and lapatinib (L) show high efficacy in patients with HER2-positive breast cancer, but resistance is prevalent. Here we investigate resistance mechanisms to each drug alone, or to their combination using a large panel of HER2-positive cell lines made resistant to these drugs.

Methods

Response to L + T treatment was characterized in a panel of 13 HER2-positive cell lines to identify lines that were de novo resistant. Acquired resistant lines were then established by long-term exposure to increasing drug concentrations. Levels and activity of HER2 and estrogen receptor (ER) pathways were determined by qRT-PCR, immunohistochemistry, and immunoblotting assays. Cell growth, proliferation, and apoptosis in parental cells and resistant derivatives were assessed in response to inhibition of HER or ER pathways, either pharmacologically (L, T, L + T, or fulvestrant) or by using siRNAs. Efficacy of combined endocrine and anti-HER2 therapies was studied in vivo using UACC-812 xenografts.

Results

ER or its downstream products increased in four out of the five ER+/HER2+ lines, and was evident in one of the two intrinsically resistant lines. In UACC-812 and BT474 parental and resistant derivatives, HER2 inhibition by T reactivated HER network activity to promote resistance. T-resistant lines remained sensitive to HER2 inhibition by either L or HER2 siRNA. With more complete HER2 blockade, resistance to L-containing regimens required the activation of a redundant survival pathway, ER, which was up-regulated and promoted survival via various Bcl2 family members. These L- and L + T-resistant lines were responsive to fulvestrant and to ER siRNA. However, after prolonged treatment with L, but not L + T, BT474 cells switched from depending on ER as a survival pathway, to relying again on the HER network (increased HER2, HER3, and receptor ligands) to overcome L's effects. The combination of endocrine and L + T HER2-targeted therapies achieved complete tumor regression and prevented development of resistance in UACC-812 xenografts.

Conclusions

Combined L + T treatment provides a more complete and stable inhibition of the HER network. With sustained HER2 inhibition, ER functions as a key escape/survival pathway in ER-positive/HER2-positive cells. Complete blockade of the HER network, together with ER inhibition, may provide optimal therapy in selected patients.     

Triple-negative and HER2-positive breast cancers found by mammography screening show excellent prognosis

Breast Cancer Research and Treatment - Our purpose was to explore the prognosis of aggressive breast cancers of the HER2 oncogene amplification (HER2?+) and triple-negative (TN) subtypes...     

HER2 mutation status in Japanese HER2-positive breast cancer patients

Background

Human epidermal growth factor receptor 2 (HER2) gene amplification/overexpression is a major therapeutic target in breast cancer, and has been introduced as a predictive biomarker to identify patients who may benefit from therapy with anti-HER2 agents. HER2 somatic mutations have been reported, and these may influence the effect of HER2-targeted drugs.

Methods

Here, we sought HER2 mutations in a group of 135 Japanese breast cancer patients with HER2-positive tumors. We analyzed HER2 mutations by direct Sanger sequencing of two major areas, the extracellular domain at position 309–310 and the kinase domain between 755 and 781.

Results

Two patients with the HER2 somatic mutation S310F in the extracellular domain were found in this series. One patient with the S310F mutation had a node-negative invasive ductal carcinoma classified as HER2 2+ by the HercepTest and fluorescence in situ hybridization (FISH) positive, and which was estrogen receptor (ER)-negative and progesterone receptor (PgR)-negative. Another patient with the S310F mutation had an apocrine carcinoma with seven lymph nodes positive for metastasis, classified as HER2 3+ by the HercepTest, but which was FISH-negative, as well as ER-negative and PgR-negative. Both patients had received adjuvant single-agent trastuzumab therapy, and had no local recurrence or distant metastasis for five and three years after surgery, respectively.

Conclusions

Our data show that HER2 mutations are rare in HER2-positive Japanese breast cancer patients. The two mutations found in this study were identical, S310F. We suggest that in vitro experiments to determine whether the S310F mutation could be involved in resistance to anti-HER2 drugs are worthwhile in future.

     

Increased pathologic complete response are expected in HER2-positive and triple-negative locally advanced breast cancers

To The Editor I want to congratulate Dr. Tan and colleagues for theirarticle entitled "Weekly taxane-anthracycline combinationregimen versus tri-weekly anthracycline-based regimenfor the treatment of locally advanced breast cancer:a randomized controlled trial" [1]. The pathologic completeresponse (pCR) rate was similar in the two arms(10.61% vs. 12.31%, P = 0.665). However, the authorsdid not stratify patients according to molecular subtypessuch as luminal A and B, human epidermal growth factorreceptor 2 (HER2)-positive and triple-negative breastcancers (TNBC). Rouzier et al. [2] reported that thepatients in TNBC and HER2-positive subgroups had thehighest rates of pCR (45% and 45%), whereas the patientswith luminal tumors had a pCR rate of 6% after neoadjuvantchemotherapy. Since HER2-positive and TNBCsubgroups of tumors are more sensitive to chemotherapy,pCR rates in these tumors are expected to be more than20%–25%. Taken all together, the evaluation of pCR ratesafter chemotherapy in locally advanced breast cancerpatients would be better evaluated according to molecularsubtypes.     

WEE1 inhibition reverses trastuzumab resistance in HER2-positive cancers

Gastric Cancer - To date, many efforts have been made to understand the resistance mechanism of trastuzumab in human epidermal growth factor receptor 2 (HER2)-positive breast and gastric cancer....     

Treatment strategy for HER2-positive breast cancer

HER2-positive tumors account for approximately 18–20% of all breast cancers. These tumors tend to be more aggressive than HER2-negative tumors and are associated with a poorer prognosis. HER2 overexpression, as determined by either 3+ immunohistochemical staining for HER2 protein or HER2 gene amplification by fluorescence in situ hybridization, should be used to select patients for anti-HER2 therapy. Trastuzumab-containing regimens as first-line therapy should be recommended to women with HER2-positive metastatic breast cancer. The continuation of trastuzumab plus capecitabine provided a significant clinical benefit compared with capecitabine alone in women who experienced progression during trastuzumab treatment. An adjuvant trastuzumab-containing regimen should be also recommended to all intermediate- or high-risk women with HER2-positive early breast cancer. Cardiac function should be serially monitored during this treatment. Many anti-HER2 drugs against breast cancer are being developed. The basic mechanisms of their action and resistance emergence are being clarified step by step. Over the mid- or long term, clinical trials comparing these drugs will be conducted until drugs that are clinically effective and easy to use in the true sense survive. Biomarkers are being aggressively searched for concerning individual drugs under development. A position of the “proper drug for the proper patient” will be more firmly established.