In 1987, Slamon et al. reported the role of human epidermal growth factor receptor 2 (HER2) in the pathogenesis of human breast cancer. About 20% of breast cancer patients are positive for HER2 expression. The human epidermal growth factor receptor 2 (HER2) is a member of the epidermal growth factor tyrosine kinase receptor family and is located on human chromosome 17p21. HER2 expression can be as high as 2 million, which is 10-100 times higher than that of normal cells. Prior to HER2-targeted therapy, HER2+ breast cancer heralded a poor prognosis group. 1997 FDA approval of trastuzumab therapy, a molecularly targeted anti-HER?2 drug, ushered in the era of molecularly targeted therapy for advanced breast cancer. In recent years, with the approval of three other HER2-targeted therapies – lapatinib (Tykerb), pertuzumab (Perjeta) and the antibody-coupled drug T-DM1 (Kadcyla) – the prognosis of patients with progressive HER2-positive breast cancer has been further significantly improved. Metastatic HER2+ breast cancers no longer show a rapidly progressive disease course, with an average survival time of more than 3 years. The approval of these new HER-2-targeted therapies led to the publication of ASCO’s first clinical guideline specifically targeting the systemic treatment of advanced HER2-positive breast cancer in May 2014. Because the brain is the refuge of HER2-positive breast cancer patients, and brain metastases occur in up to 50% of HER2-positive patients, ASCO also published guidelines on the management of brain metastases in this specific subset of patients at the same time.
Anti-HER2 therapy is now widely used in preoperative neoadjuvant therapy, postoperative adjuvant therapy, and palliative treatment of metastatic patients with HER2-positive breast cancer. With a large number of randomized controlled clinical studies, the oncology community has reached a consensus on the mechanism of action and clinical efficacy of anti-HER2 therapy, but some controversies also exist. For example, there is a lack of effective biological markers to predict the efficacy of anti-HER2 therapy, and the problem of drug resistance to anti-HER2 therapy is significant; the effectiveness of anti-HER2 therapy in combination with chemotherapy and endocrine therapy, as well as its optimal regimen, timing, dosing sequence, and optimal course of treatment are discussed. In this paper, the author systematically reviews and discusses the consensus and progress of anti-HER2 therapy for breast cancer.
1. Application of anti-HER2 therapy in neoadjuvant treatment of HER2-positive breast cancer
Patients who achieve pathologic complete remission (pCR) with neoadjuvant therapy have significantly lower tumor recurrence rate and significantly longer survival. Trastuzumab combined with chemotherapy for neoadjuvant therapy significantly increased the pCR rate in HER2-positive breast cancer compared with chemotherapy alone. buzdar [3] et al. reported 42 patients with HER2+ breast cancer randomized to receive either (i) paclitaxel sequential FEC chemotherapy or (ii) chemotherapy + trastuzumab. the results showed that the pCR (65% vs 26%) and 3-year DFS rate in the trastuzumab group ( The primary endpoint of the phase III NOAH [4] study of 235 patients with locally advanced breast cancer and inflammatory breast cancer treated with trastuzumab in combination or chemotherapy alone in neoadjuvant therapy was event-free survival (EFS). The results showed that the addition of trastuzumab to chemotherapy significantly increased pCR (43% vs 22%; p = 0.0007) and 3-year EFS rates (71% vs 56%, HR 0.59; p = 0.013).ACOSOG Z1041 [5] confirmed that trastuzumab in combination with anthracycline and paclitaxel-based chemotherapy regimens, either periprocedural-FEC + trastuzumab or FEC-P peri-therapy + trastuzumab, the pCR was the same in both groups (54.2% vs. 56.5%).
In the second-generation regimen of dual anti-HER2 and chemotherapy, the international multicenter open phase II NeoSphere study investigated the neoadjuvant efficacy of TH (docetaxel + trastuzumab), THP or HP regimens. 417 patients with HER2-positive (IHC3+ or FISH+) breast cancer (stage II or III, including local progression) were randomized to receive preoperative TH, THP, HP or TP for 4 cycles. TP for 4 cycles of neoadjuvant therapy, showing that the THP treatment group achieved a significantly higher pCR than the TH (P=0.0141) and TP groups (P=0.003), and patients in the docetaxel + trastuzumab combined with patuximab group achieved a significantly higher pCR rate (45.8%).
Several studies have also been published on trastuzumab + lapatinib in combination with neoadjuvant, but there were no positive results. Among them, the NeoALTTO study [6] was divided into three groups: (i) lapatinib combined with paclitaxel; (ii) trastuzumab combined with paclitaxel; and (iii) lapatinib combined with trastuzumab and paclitaxel. The pCRs for the three groups were 24.7% vs 29.5 vs 51.3%, p = 0.0001. updated results of the EFS and OS analysis presented at the 2013 San Antonio meeting showed no statistical difference in p-values. the NSABP B-41 study also yielded a negative conclusion. The other three studies CALGB 40601, CHER-LOB & TRIO B07 were small sample studies, with the TRIO B07 study showing similar pCR rates for the TCH regimen compared to H+L combined with dual targeting.
2. Anti-HER2 therapy in the adjuvant treatment of HER2-positive breast cancer
Four classic large clinical studies, NCCTG N9831, NSABP-B31, HERA, and BCIRG-006, investigated the use of anti-HER2 therapy in adjuvant therapy and all showed that trastuzumab reduced the risk of recurrence and death in breast cancer patients [7]. In the HERA [8] study, patients were randomized to the 1-year trastuzumab treatment group, the 2-year treatment group, and the observation group. The median follow-up of 2 years showed a 36% reduction in the risk of disease recurrence and a 34% reduction in the risk of death in the 1-year treatment group; patients on delayed dosing also showed a survival benefit; there was no statistically significant difference in disease-free survival on extended dosing at 2 years.The BCIRG-006 [9] study investigated (i) an AC-TH regimen; (ii) chemotherapy with the TCH regimen; and (iii) an AC-T regimen without trastuzumab in the control group. 2009 The mean follow-up of 65 months was reported in 2009: the 5-year DFS rates were 84% and 81% in the two trial groups, respectively, both significantly higher than the control group (75%); the 5-year OS rates were 92% and 91%, respectively, both significantly higher than the control group (87%). There was no significant difference in DFS and OS between the two test groups. The cardiac safety of the anthracycline-free TCH regimen was superior to that of the AC-TH regimen.
The AFFINITY study (NCT01358877) evaluated its use in adjuvant therapy. the Katherine study (N=1448) evaluated the use of pCR in patients who did not achieve pathologic remission after receiving neoadjuvant antiher2 and chemotherapy. patients in complete remission comparing the efficacy of Herceptin versus T-DM1 treatment. The trial is ongoing and is expected to be completed by the end of next year.The KAITLIN study design explores the use of T-DM1+pattuzumab instead of paclitaxel+trastuzumab+pattuzumab in adjuvant therapy. The publication of the results of these clinical studies will provide additional clinical options and rationale.
The ALTTO study is a phase III adjuvant therapy study of trastuzumab and lapatinib administered sequentially and in combination, comparing the efficacy of lapatinib alone, trastuzumab alone, and trastuzumab sequentially or in combination with lapatinib, enrolling 7,165 patients in January 2010. Selected hospitals in China also participated in this clinical trial. The results showed no increase in DFS/OS benefit with lapatinib in combination/sequential trastuzumab (T+L or T→L) compared to trastuzumab alone (T).
Neratinib is an oral irreversible pan-ErbB receptor tyrosine kinase inhibitor that effectively inhibits ErbB1 and ErbB2. data from a phase III clinical study (ExteNET) were published in July 2014. 2,812 patients with early-stage HER2-positive breast cancer were randomly assigned to receive 1 year of adjuvant treatment with neratinib or placebo after completion of adjuvant Herceptin therapy. The data showed that neratinib improved DFS by 33% compared to placebo, p=0.0046. In addition, neratinib improved the secondary endpoint of disease-free survival in ductal carcinoma in situ (DFS-DCIS) by 37%, again a statistically significant difference (p=0.0009). In April of the same year, positive data from a phase II study of neratinib (I-SPY2) also demonstrated the efficacy of neratinib in HER2-positive breast cancer with Roche Herceptin, which may become a heavyweight agent for future anti-HER2 therapy.
3. anti-HER2 therapy in the treatment of HER2-positive metastatic breast cancer
On May 6, 2014, ASCO published two clinical guidelines on the treatment of HER2-positive advanced breast cancer online in the Journal of Clinical Oncology. Experts recommend that anti-HER2-targeted therapy should be used throughout first-, second-, and multiple lines of therapy after progression on anti-HER2 therapy.
Several studies have shown additive or synergistic effects of trastuzumab with multiple chemotherapeutic agents, with trastuzumab in combination with paclitaxel being the first-line regimen of choice. The efficiency of trastuzumab in combination with vincristine, gemcitabine, capecitabine, and liposomal adriamycin ranged from 30% to 86%, respectively. A randomized controlled study comparing the efficacy of paclitaxel and vincristine in combination with trastuzumab in first-line treatment of HER2-positive advanced breast cancer, respectively, showed no statistically significant difference in efficiency (40% vs 51%) and time to disease progression (8.5m vs 6m).
Two phase III randomized controlled studies compared whether a three-drug combination regimen of paclitaxel combined with trastuzumab plus carboplatin was superior to a two-drug combination regimen. The BCIRG007 study, however, showed that the addition of carboplatin to doxorubicin in combination with trastuzumab did not result in a further improvement in efficacy, but was better tolerated by patients due to the lower dose of doxorubicin in the three-drug combination group . In conclusion, the current study shows that the trastuzumab-containing three-drug combination has a slight advantage over the two-drug combination regimen.
For the first-line treatment of advanced HER2-positive breast cancer based on the results of the CLEOPATRA phase III randomized controlled study, the combination of pertuzumab + trastuzumab + paclitaxel is recommended. Patuximab is a humanized HER2 monoclonal antibody that acts at a different site than trastuzumab and inhibits HER2 homo- and heterodimer formation.The CLEOPATRA study [10] showed that patuximab combination significantly improved PFS (18.5m vs 12.4m, p<0.001) and OS (37.6m vs not achieved, p= 0.0008), and quality of life was essentially the same in both groups. For which paclitaxel-targeted combination is currently undefined, a docetaxel 3-week regimen was used in the CLEOPATRA study, and although no data are available for paclitaxel with dual anti-HER2, it is considered to be clinically alternative, with weekly dosing combination as the optimal choice (paclitaxel weekly > three weeks dosing). In addition, we are counting on the results of the PERUSE (NCT01572038) study, which evaluated the combination of patuximab and trastuzumab with different paclitaxel classes (paclitaxel, docetaxel, or albumin-bound paclitaxel [Abraxane]) and will help to clarify which paclitaxel is the best combination treatment option. Considering cumulative toxicity, it is recommended to discontinue paclitaxel drugs and maintain dual HER2-targeted therapy after 4?6 months or when maximum clinical response is reached. Endocrine therapy can be added later in hormone receptor-positive patients. After disease progression again in the maintenance phase, paclitaxel reactivation or switch to second-line regimens may be considered.
The status of the antibody-drug coupling T-DM1 (ado-trastuzumabemtansine, Kadcyla) in first-line therapy has not been determined, and the evidence is still insufficient as only a small subgroup of the EMILIA trial compared capecitabine and lapatinib in first-line therapy compared to T-DM1. The results of the ongoing MARIANNE study (NCT01120184), which compares the efficacy of three groups of first-line: (i) T-DM1 + patuximab; (ii) paclitaxel + trastuzumab; and (iii) T-DM1 + placebo, may change the choice of first-line treatment for HER2-positive patients. If equally effective, first-line T-DM1 may provide a more optimal choice due to less side effects.
The mammalian target protein of rapamycin, mTOR, is a downstream target of the PI3k-AKT signaling pathway, and everolimus (RAD001) is able to inhibit mTOR activity. Trastuzumab resistance is associated with activation of the PI3k-AKT signaling pathway. Preclinical trials have shown that RAD001 enhances the antitumor activity of trastuzumab and reverses trastuzumab resistance. 2009 San Antonio Breast Cancer Conference reported the results of a combination analysis of two phase I clinical trials of RAD001 in combination with trastuzumab and chemotherapy agents (vincristine or paclitaxel) in 74 patients with HER2-positive metastatic breast cancer who had used multiple treatment regimens and were resistant to trastuzumab, 25 of whom had also been previously treated with lapatinib. The results showed an overall efficacy rate of 27% and a clinical benefit rate of 82.4%.
4. HR+/HER2+ breast cancer
There is still uncertainty about the optimal management of this group of patients. It is now recommended that chemotherapy plus HER2-targeted therapy be considered for the majority of patients, regardless of hormone receptor status. A study design for a separate endocrine regimen that exempts patients from chemotherapy may be considered for patients for whom HER2-targeted therapy is contraindicated or who have comorbidities, low tumor load, and slow disease progression/recurrence. However, this needs to be done with caution until large-scale evidence-based medicine is available, as the results of some previous studies have shown that disease progression occurs within a short period of time after endocrine therapy alone [11-12].
The combination of endocrine therapy with targeted is usually recommended for use after first-line paclitaxel with targeted therapy. It should be noted that previous evidence-based evidence shows that endocrine therapy in combination with anti-HER2 targeting only shows prolonged PFS without significant benefit in OS compared to endocrine therapy alone, although we can also assume that this is partly due to the result of crossover to the targeted combination group in some endocrine-treated patients. Should this population be treated with first-line target + endocrine (delayed chemotherapy) or first-line chemotherapy + target? There is also a lack of evidence-based medical evidence. HER2-positive patients can be broadly divided into two subgroups – the HR-positive group and the HR-negative group, which are two subgroups with different molecular biological behaviors, and therefore should be treated separately in clinical practice. At present, there is still a lot of space available for the study design that we need to conduct in this field.
5. Lack of effective biological markers to predict the efficacy of anti-HER2 therapy
So far, there is no better biological marker to predict the efficacy of anti-HER2 therapy than HER2. Despite the fact that two anti-HER2 therapies are sometimes used, a significant proportion of patients still have poor response rates to treatment. A more appropriate and individualized use of anti-HER2 therapy remains a hot topic of current research. in a January 5, 2015 article in J ClinOncol, Ian J. Majewski et al. of the Netherlands Cancer Institute explored the association of mutations in the gene encoding the catalytic subunit of phosphatidylinositol 3-kinase (PI3K) (PIK3CA) with neoadjuvant anti-human epidermal growth factor receptor 2 (HER2) targeted therapy in breast cancer. (HER2)-targeted therapy efficacy. PIK3CA mutations were identified in HER2-positive early-stage breast cancer patients in the NeoALTTO study. The study showed that PIK3CA mutations were found in 23% of HER2-positive tumors and were associated with poor outcomes in all treatment groups. The overall pathologic complete remission rate (pCR) in wild-type PIK3CA patients treated with trastuzumab in combination with lapatinib reached 53.1%, while dropping to 28.6% in patients with PIK3CA-activating mutated tumors. It was shown that in HER2-positive breast cancer patients, PIK3CA mutations predicted lower pCR rates after neoadjuvant anti-HER2-targeted therapy. Therefore, anti-HER2 combined with PI3K inhibitor therapy is under investigation.
6. Anti-HER2 therapy resistance is a significant problem
Although anti-HER2 therapy has achieved certain efficacy in breast cancer patients, however, its resistance is becoming more and more obvious. Some patients are primary drug resistant, while others gradually develop secondary resistance after receiving anti-HER2 therapy and obtaining efficacy. The mechanisms of resistance are complex, involving HER2 and its downstream transmission pathways, HSP90, telomerase, VEGF inhibitors, etc., and need to be further investigated.
Recently, the results of a study from Cold Spring Harbor (CSHL) in the United States are expected to bring a powerful new approach to the treatment of HER2-positive breast cancer. PTP1B is a member of the protein tyrosine phosphatase (PTPs) superfamily. This study found that when a mouse model of HER2-positive breast cancer was treated with a PTP1B inhibitor (MSI-1436 or trodusquemine), HER2 protein signaling was inhibited and tumor growth and lung metastasis were extensively suppressed. trodusquemine and related analogues are currently under development [13].
7. Other
How to combine anti-HER2 monoclonal antibodies with chemotherapy to maximize patient benefit, whether it is clinically relevant to combine with endocrine therapy, and how to combine with other targeted therapies to obtain better efficacy. More clinical trials are urgently needed to answer these questions in order to maximize the impact of anti-HER2 therapy. In addition, the duration and lifelong management of long-term anti-HER2 targeted therapy is an open question for the very small percentage of patients who achieve clinical remission after systemic systemic therapy. The clinical efficacy achieved with anti-HER2 therapy comes with expensive economic costs, necessitating the inclusion of an economic benefit analysis for this subset of patients.
The optimal regimen and sequence of subsequent therapy for HER2-positive metastatic breast cancer is still not well defined. The ongoing observational study, the SystHERS prospective cohort study (NCT01615068), will provide a good answer to the choice of treatment modality. In addition, impairment of central function during HER-2 targeted therapy is a clinical concern. the SAFE-Cardiac Trial (NCT01904903) study evaluates the cardiac safety of HER2-targeted therapy in patients with mildly reduced ejection fraction to define reliable safety parameters for the monitoring of central function during the use of these agents.