HER2-Positive Breast Cancer

This article provides a comprehensive summary of the knowledge gained from recent neoadjuvant trials conducted with agents targeting HER2, and will put them into perspective with current treatment recommendations from American and European guidelines.

Bevacizumab (Avastin) improved progression-free survival (PFS) in women with HER2-positive locally recurrent or metastatic breast cancer by an average of 3 months when added to standard treatment as first-line therapy in the multinational, randomized, phase III AVEREL study.

Addition of pertuzumab to a standard chemotherapy combination of trastuzumab and docetaxel led to a 38% reduction in risk of disease worsening or death in patients with HER2-positive metastatic breast cancer, reported investigators from the randomized, double-blind, placebo-controlled phase III CLEOPATRA study.

Scientists at the NCI have designed a novel protein, HER2-Affitoxin, aimed to treat HER2-positive breast cancer. In vitro experiments and mouse breast cancer models show that the agent is highly effective in eradication of HER2-over expressing cancer cell as well as tumors in mice.

Results from a prospective study of 1023 newly-diagnosed HER2-positive metastatic breast cancer patients show that treatment with trastuzumab (Herceptin) and chemotherapy independently resulted in statistically significant improvement in median overall survival from the time central nervous system (CNS) metastases were diagnosed.

In 2004, Dr. Leisha Emens and I reviewed the use of trastuzumab (Herceptin), the monoclonal antibody directed against the HER2 protein, in the treatment of breast cancer.

A model example of personalized cancer therapy that has demonstrated improved patient outcomes is the use of anti-HER2 treatment. Breast cancer patients screened via molecular diagnostics and identified as having amplification of the HER2 gene generally have a poorer prognosis, but show better responses to anti-HER2 treatment.

For the first time, a series of metastatic melanoma (MM) patients have been genetically tested for the constitutively activating BRAF mutation and assessed for its prognostic significance as is routinely done for breast cancer (HER2) and chronic myeloid leukemia (ABL).

Impressive results from an ongoing study of an anti-HER2 antibody-drug conjugate in HER2-positive metastatic breast cancer has already fast-tracked a phase III trial.Trastuzumab-DM1 (T-DM1) has demonstrated comparable results to standard treatment but with much less grade 3-4 toxicity in phase II trial results.

Jose Baselga, MD, PhD, and Michael Untch, MD, shared results from the NeoALLTO and GeparQuinto trials, respectively. NeoALLTO is a phase III, randomized, open-label, neoadjuvant study of lapatinib (Tykerb), trastuzumab (Herceptin), and their combination plus paclitaxel in women with HER2-positive primary breast cancer. GeparQuinto (GBG 44) is evaluating lapatinib vs trastuzumab in combination with neoadjuvant anthracycline- and taxane-based chemotherapy.

Trastuzumab (Herceptin) has dramatically changed the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer.

This review explores the use of several such agents, including lapatinib (Tykerb), HSP90 inhibitors, T-DM1, and other tyrosine kinase inhibitors. Emerging data from trials of these agents indicate that the HER2 pathway remains a valid therapeutic target following disease progression on trastuzumab.

Researchers in the U.S. and Italy report that women with HER2-positive breast cancers that are 1 cm or less in diameter and are node-negative have a risk of recurrence that is two to five times greater than that of women with HER2-negative breast cancers (J Clin Oncol online, November 2, 2009).

Final results from a phase II study of an enhanced version of Herceptin upheld the emerging benefits previously seen with this novel approach in HER2-positive breast cancer.

Historically, breast tumor classification and therapeutic decisions have relied on immunohistochemical (IHC) techniques for characterizing biomarkers such as estrogen receptor (ER), progesterone receptor (PR), and the epidermal growth factor receptor 2 (HER2), as described in the review by Ma and colleagues. However, these markers have been found to be inadequate for fully predicting a patient’s response to a given breast cancer treatment such as endocrine therapy.

Insight into the molecular workings of HER2-positive breast cancer has paved the way for targeted agents that are showing great promise in clinical trials, according to a presentation at SABCS 2008. José Baselga, MD, from Barcelona, offers a primer on pertuzumab, trastuzumab-DM1, heat shock protein 90, and other agents that will provide “tremendous opportunity” in HER2-positive cancer treatment.

WASHINGTON-Loss of HER2 positivity is common among women with initially HER2-positive breast cancer who do not have a pathologic complete response (pCR) to neoadjuvant chemotherapy with trastuzumab (Herceptin), according to a report at the ASCO 2008 Breast Cancer Symposium (abstract 150).

The human epidermal growth factor receptor 2 (HER2) is a transmembrane receptor with tyrosine kinase activity overexpressed in about 20% to 25% of invasive carcinomas of the breast.

CHICAGO-The addition of trastuzumab (Herceptin) to the arsenal of breast cancer agents has elevated the prognosis of HER2-positive patients to that of HER2-negative patients, according to an institutional review from M.D. Anderson Cancer Center.

The Cancer International Research Group (CIRG), a division of TRIO (Translational Research in Oncology) announced that, based on its study BCIRG 006, the US Food and Drug Administration (FDA) has approved a new regimen known as TCH (docetaxel [Taxotere] and carboplatin combined with trastuzumab [Herceptin]) for the adjuvant treatment of HER2-positive early breast cancer. The AC-TH regimen (doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab), also investigated in the BCIRG 006 study, received approval at the same time. This is the first taxane-based non–anthracycline-containing chemotherapy combined with trastuzumab to receive FDA approval.

New data presented as part of a late-breaking plenary session at the 6th European Breast Cancer Conference in Berlin showed that neoadjuvant trastuzumab (Herceptin) in combination with standard chemotherapy produced a pathological complete response rate in 45.5% of women with HER2-positive early breast cancer.

A HER2/neu peptide–based T-cell immunotherapy that reduces recurrences in low HER2 expressors could be important for patients ineligible for trastuzumab.

About one-third of metastatic breast cancer patients with HER2 overexpression develop metastases to the brain, compared with 5% to 20% of the general metastatic breast cancer population, according to findings from a large observational study in newly diagnosed HER2-positive breast cancer.

The HER2-positive breast cancer population appears to be a heterogeneous group with a wide variation in response to trastuzumab (Herceptin). Higher levels of HER2 expression as well as HER2:HER2 dimerization were independently correlated with high response rates and longer time to progression in a study reported at the 2007 San Antonio Breast Cancer Symposium (abstract 2007).

Studies show that thousands of women may be receiving the wrong breast cancer treatment because of faulty laboratory reports. More disturbing, this trend was identified years ago. A 2006 study led by Genentech found 14% to 16% of HER2 tests were false positive and 18% to 23% were false negative.

Clinical trials have shown significant improvements in disease-free survival when trastuzumab (Herceptin) is added to standard adjuvant chemotherapy in HER2-positive breast cancer patients, but is it appropriate for all such patients, specifically low-risk patients with tumors 1 cm or smaller in size?

A widely publicized study shows that paclitaxel administered after adjuvant chemotherapy with doxorubicin plus cyclophosphamide (AC-T) provides no or only slight benefit to women with HER2-negative, ER-positive, node-positive breast cancer.

Lapuleucel-T (Neuvenge, Dendreon Corporation), an autologous active cellular immunotherapy designed to stimulate cellular immune responses against HER2/neu, proved feasible and well tolerated with evidence of anticancer activity in a phase I trial.

Recent data suggest that HER2 positivity predicts for the development of CNS metastases in breast cancer patients. Studies presented at the ASCO 2007 annual meeting found that risk of brain metastases is indeed increased in HER2-positive patients but does not appear to compromise survival.

A first-in-class HER2 antibody-drug conjugate may represent an effective new strategy in breast cancer therapy, according to phase I data