Despite advances in the treatment options, breast cancer still remains the most frequent cancer among women, impacting 2.1 million women each year, causing the greatest number of cancer-related deaths among women. In 2018, it is estimated that 627,000 women died from breast cancer – approximately 15% of all cancer deaths among women(1). The disease is curable when is limited to the breast and local lymph nodes. Although treatable, metastatic breast cancer (MBC) remains an incurable disease, having a median overall survival (OS) of 3 years and a 5-year survival of only 25%(2,3).
MBC can be either de novo stage IV disease, or metastatic recurrence of prior stages I-III. Exposure to prior therapies becomes an important difference. De novo stage IV disease implies metastasis at or near the time of initial diagnosis and no prior therapy for the cancer. Metastatic recurrence of stage I-III breast cancer typically implies recurrence despite systemic adjuvant therapy. Both classes are considered incurable and are treated with palliative intent(4).
Approximately 20% of breast cancer tumors overexpress human epidermal growth factor receptor 2 (HER2 [ErbB2]), which is associated with a more aggressive clinical phenotype and historically portends poor prognosis(5). However, the use of HER2-targeted agents has changed the treatment paradigm of this disease(6). The inclusion of these agents into the adjuvant therapy of stage I-III HER2-positive breast cancers has significantly reduced distant metastatic recurrences and improved survival(7-9). This has resulted in overall fewer HER2-positive MBC and in a relative increase in the proportion of de novo stage IV disease among patients with HER2-positive metastatic disease. Historically, de novo stage IV breast cancer accounted for 6-20% of metastatic breast cancers across subtypes, but recent studies reported that over 50% of metastatic HER2 breast cancers today represent de novo stage IV disease(10-14).
All invasive and metastatic HER2-positive breast cancers benefit from HER2 directed therapy. Even very small cancers appear to benefit. A U.S. study evaluated the records of 965 women with small cancers that had not been treated with HER2-targeted therapy or chemotherapy. By the end of five years, 6% of women with HER2-negative breast cancer had a recurrence, compared with 23% of women with HER2-positive breast cancer(15).
The objective of this review is to present the main possibilities of treatment for patients with breast cancer and HER2-positive tests. From pivotal trials we know that trastuzumab is active when added to chemotherapy in patients with advanced metastatic breast cancer. In particular, the combination with chemotherapy significantly prolonged the median time to disease progression, the overall response rate, and improved the median survival time by approximately 25% compared with chemotherapy alone.
Monoclonal antibody therapy
Trastuzumab is a humanized monoclonal antibody that binds to the HER2 receptor. It was the first FDA approved drug to treat HER2+ breast cancer and can be used to treat all HER2+ breast cancers. In patients with MBC previously treated with chemotherapy whose tumors overexpress HER2, the administration of trastuzumab as a single agent resulted in a response rate of 21%(16).
In a phase III trial, patients with MBC were randomly assigned to receive either chemotherapy alone (doxorubicin and cyclophosphamide or paclitaxel), or the same regimen plus trastuzumab. The patients treated with chemotherapy and trastuzumab had an overall survival benefit of 25.1 months versus 20.3 months (p=0.05)(17).
Clinical trials comparing combination of trastuzumab with multiagent chemotherapy or single-agent chemotherapy have revealed conflicting results. In one clinical trial, patients with MBC treated with trastuzumab, paclitaxel and carboplatin tolerated the combination well and had a longer time to disease progression, compared with those treated with trastuzumab and paclitaxel alone(18). However, no difference in OS, time to disease progression or response rate was shown in the Breast Cancer International Research Group’s phase III trial (BCIRG-007 [NCT00047255]), which compared carboplatin and docetaxel plus trastuzumab versus docetaxel plus trastuzumab as first-line chemotherapy for MBC HER2-positive(19).
Pertuzumab is a humanized monoclonal antibody that binds to a different epitope at the HER2 extracellular domain than trastuzumab does. This binding prevents dimerization with other ligand-activated HER receptors, like HER3. The phase III clinical trial CLEOPATRA (NCT00567190) assessed the efficacy and safety of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel, in the first line of HER2-positive MBC(20,21). The median OS was 40.8 months in the control group versus 56.5 months in the pertuzumab group (HR favoring pertuzumab group, 0.68; 95% CI; 0.56-0.84; p<0.001). The median progression-free survival (PFS) per investigator assessment was improved by 6.3 months in the pertuzumab group (HR 0.68; 95% CI; 0.58-0.80). Median OS was 56.5 months in the pertuzumab group versus 40.8 months in the placebo group (HR 0.68; 95% CI; 0.57-0.84; p<0.001). The toxicity profile was similar, with no increase in cardiac toxic effects seen in the pertuzumab arm(21).
Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate incorporating the human epidermal growth factor receptor 2 (HER2)-targeted antitumor properties of trastuzumab with the cytotoxic activity of the microtubule-inhibitory agent DM1. T-DM1 allows specific intracellular drug delivery to HER2-overexpressing cells, potentially improving the therapeutic index and minimizing exposure of normal tissue.
The phase III clinical study EMILIA, or TDM4370g (NCT00829166), enrolled 991 patients with HER2-postive, unresectable, locally advanced or metastatic breast cancer who were previously treated with trastuzumab and a taxane(22). The patients were randomly assigned to receive either T-DM1, or lapatinib plus capecitabine. Median PFS was 9.6 months with T-DM1 versus 6.4 months with lapatinib plus capecitabine (HR 0.65; 95% CI; 0.55-0.77; p<0.001). The median OS was 29.9 months with trastuzumab emtansine versus 25.9 months in the lapatinib plus capecitabine group (HR 0.75; 95% CI; 0.64-0.88). Thrombocytopenia and increased serum aminotransferase levels were higher in patients who received T-DM1, but the incidences of diarrhea, nausea, vomiting and palmar-plantar syndrome were higher in the lapatinib plus capecitabine arm(23).
More evidence of T-DM1’s benefit in MBC HER2-overexpressed was shown in a randomized phase II study of T-DM1 versus trastuzumab plus docetaxel – 137 women with HER2-overexpressed MBC were randomly assigned in the first-line setting. At a median follow-up of 14 months, median PFS was 14.2 months with T-DM1, compared to only 9.2 months for trastuzumab plus docetaxel arm (HR 0.59; 95% CI; 0.36-0.97). Preliminary OS results were similar between arms. T-DM1 had a favorable safety profile, with fewer grade 3 adverse events (46.4% versus 90.9%), adverse events leading to treatment discontinuations (7.2% versus 40.9%), and serious adverse events (20.3% versus 25.8%)(24).
In the randomized phase III TH3RESA (NCT01419197) trial, it was studied the activity of T-DM1 in heavily pretreated patients with HER2-postive MBC who had received previous trastuzumab and lapatinib. T-DM1 was compared with physician’s choice of treatment(25). In this trial, 602 patients were randomly assigned in a 2:1 ratio (404 patients assigned to T-DM1 and 198 patients assigned to physician’s choice) and crossover to T-DM1 was allowed. At a median follow-up of 7.2 months in the T-DM1 group and 6.5 months in the physician’s choice group, median PFS was 6.2 months in the T-DM1 group and 3.3 months in the physician’s choice group (HR 0.528; 95% CI; 0.422-0.661; p<0.0001). OS was 22.7 months with trastuzumab emtansine versus 15.8 months the treatment of physician’s choice (HR 0.68; 95% CI; 0.54-0.85; p=0.0007)(26).
T-DM1 as first-line treatment of HER2-positive MBC was evaluated in the phase III MARIANNE (NCT01120184) trial, which assigned 1,095 patients to receive either trastuzumab plus taxane, T-DM1 plus placebo, or T-DM1 plus pertuzumab. The median PFS was 13.7 months for the trastuzumab-plus-taxane arm, 14.1 months for the T-DM1-plus-placebo arm, and 15.2 months for the T-DM1-plus-pertuzumab arm. There was no significant difference in PFS with T-DM1 plus placebo compared to trastuzumab plus taxane (HR 0.91; 97.5% CI; 0.73-1.13), or with T-DM1 plus pertuzumab compared to trastuzumab plus taxane (HR 0.87; 97.5% CI; 0.69-1.08). Therefore, neither T-DM1 plus placebo, nor T-DM1 plus pertuzumab showed PFS superiority over trastuzumab plus taxane(27).
Trastuzumab deruxtecan (DS-8201)
Trastuzumab deruxtecan is a HER2-targeting antibody drug conjugate (ADC) studied for the treatment of patients with HER2-positive cancer. FDA has approved trastuzumab deruxtecan (DS-8201) for the treatment of patients with HER2-positive metastatic breast cancer who have been treated with trastuzumab and pertuzumab and have disease progression after ado-trastuzumab (T-DM1). DS-8201 is a smart chemotherapy comprised of a humanized HER2 antibody attached to a novel topoisomerase I inhibitor (DXd) payload by a tetrapeptide linker. It is designed to deliver enhanced cell destruction upon release inside the cell and reduce systemic exposure to the cytotoxic payload (or chemotherapy) compared to the way chemotherapy is commonly delivered(28).
A Lancet Oncology publication of the phase I dose-expansion results in HER2-positive metastatic breast was reported in May 2019 and additional data were released at the San Antonio Breast Cancer Symposia in December. The results of the initial breast cancer trial reported that an objective response rate of 60% and a disease control rate of 94% were attained at the recommended expansion dose of of DS-8201. An average 20.7-month median duration of response in HER2-positive metastatic breast cancer patients previously treated with trastuzumab emtansine was reported. Patients enrolled in this part of the trial had a median of seven prior lines of treatment, including trastuzumab and trastuzumab emtansine, and in 86% of cases, pertuzumab(29).
The phase 2 DESTINY-Breast01 clinical trial results were presented at the San Antonio Breast Cancer Symposium in December 2019. The trial included 253 patients with HER2-positive metastatic breast cancer previously treated with ado-trastuzumab. The patients had received a median of six prior treatments for advanced disease, including HER2-targeted therapeutics. The overall response rate was 61%, with 6% complete responses and an average survival duration without cancer progression of 16.4 months(28).
Margetuximab is an investigational immune-enhancing monoclonal antibody that targets HER2 oncoprotein. Margetuximab and chemotherapy result is comparable to that of trastuzumab and chemotherapy and will represent another treatment option for individuals with HER2+ advanced breast cancer(30).
The SOPHIA clinical trial enrolled 536 women with HER2+ metastatic breast cancer at 200 trial sites across North America, Europe and Asia. The patients were treated with either margetuximab or trastuzumab in combination with one of four chemotherapy agents (capecitabine, eribulin, gemcitabine or vinorelbine) and directly compared. All trial patients had previously received trastuzumab and pertuzumab, and approximately 90% had previously received ado-trastuzumab emtansine. The patients treated with the combination of margetuximab plus chemotherapy, compared to trastuzumab plus chemotherapy, were initially reported to have experienced a 24% risk reduction in the duration of survival without cancer. Trial results were updated at the 2019 San Antonio Breast Cancer Symposia, and margetuximab plus chemotherapy treated patients survived without cancer progression, on average, 5.8 months compared with 4.9 months with trastuzumab. Margetuximab appeared to delay cancer progression more in patients with the CD16A genotype. Approximately 85% of patients in the study were carriers of the CD16A (FcgRIIIa) 158F allele, a biomarker which has been previously associated with a diminished clinical response to Herceptin® and other antibodies. There was a 32% risk reduction with margetuximab compared to Herceptin® in these patients(31).
Tyrosine kinase inhibitor therapy
Lapatinib is an orally administered tyrosine kinase inhibitor of both HER2/neu and the epidermal growth factor receptor. When these proteins are overexpressed among cancer cells, referred to as HER2-positive and/or EGFR-positive cancers, the proteins tend to function abnormally, resulting in unchecked replication and growth of cancerous cells.
Lapatinib plus capecitabine has shown activity in patients with HER2-positive MBC that progressed after treatment with trastuzumab. A nonblinded randomized trial (GSK-EGF100151 [NCT00078572]) compared this combination with capecitabine alone in 324 patients with locally advanced or metastatic disease which progressed after therapies that included anthracyclines, taxanes and trastuzumab. Lapatinib-plus-capecitabine arm showed a median time-to-disease-progression of 8.4 months compared with 4.4 months in the capecitabine-alone arm (HR 0.49; 95% CI; 0.34-0.71; p<0.001). There was no difference in OS (HR 0.92; 95% CI; 0.58-1.46; p=0.72). Patients on combination therapy were more likely to develop diarrhea, rash and dyspepsia(32).
Neratinib is a new tyrosine kinase inhibitor that is targeted against several biochemical pathways implicated in the growth and spread of cancer like HER1, HER2 and HER4 pathways. At this moment, neratinib is approved by FDA (in July 2017) only for the extended adjuvant treatment of adult patients with early-stage HER2-positive breast cancer following adjuvant trastuzumab-based therapy(33).
The international NALA clinical trial included 621 patients with metastatic HER2-positive breast cancer who received ≥2 previous prior anti-HER2-based treatment regimens. The patients were treated with either neratinib 240 mg once daily on days 1 through 21 plus capecitabine 750 mg/m2 twice daily on days 1 to 14 of each 21-day cycle or lapatinib 1250 mg once daily on days 1 through 21 plus capecitabine 1000 mg/m2 twice daily on days 1 to 14 of each 21-day and directly compared.
The patients who received neratinib plus capecitabine were more likely to respond to treatment, live longer and experience improvement in survival without cancer progression compared to those given Tykerb® plus Xeloda®. The 24-month survival without progression rate was 12% versus 3%, respectively(34).
Tucatinib is a tyrosine kinase inhibitor drug that is highly selective for HER2 without significant inhibition of EGFR. The inhibition of EGFR is associated with significant side effects, including skin rash and diarrhea. Tucatinib has been granted orphan drug designation by the FDA for the treatment of breast cancer patients with brain metastases.
The HER2CLIMB clinical trial compared tucatinib in combination with trastuzumab and capecitabine to the treatment with trastuzumab and capecitaine alone in patients with locally advanced or metastatic HER2-positive breast cancer who were previously treated with trastuzumab, pertuzumab and T-DM1 in 612 patients. Trial results were updated at the December 2019 San Antonio Breast Cancer Symposia. The addition of tucatinib to trastuzumab and capecitabine significantly improved the outcomes of patients with advanced HER2+ breast cancer, including in patients with brain metastases. Compared to trastuzumab and capecitabine alone arm, the addition of tucatinib resulted in a 46% reduction in the risk of disease progression or death, improved overall survival, with a 34% reduction in the risk of death. The estimated survival at two years was 45% with the addition of tucatinib compared to 27% for trastuzumab and capecitabine alone. Median survival duration was improved to 22 months compared to 17 months. Approximately 33% of tucatinib-treated patients survived one year without cancer progression compared to only 12% for trastuzumab and capecitabine(35).
Pyrotinib is a “next-generation” pan-HER receptor tyrosine kinase inhibitor that is active against HER-positive cancers in both preclinical experiments and humans. Pyrotinib plus capecitabin yielded better overall response rates and delayed cancer progression than lapatinib plus capecitabine in patients with HER2-positive MBC.
A clinical trial aimed to determine if pyrotinib’s “pan inhibiton” might produce superior results compared to standard treatment with lapatinib. In this trial, a total of 128 patients with HER2-positive relapsed or metastatic breast cancer previously treated with taxanes, anthracyclines, and/or trastuzumab were treated with either pyrotinib or lapatinib in combination with capecitabine and directly compared. Overall, 79% of pyrotinib-treated patients responded to treatment compared to only 57% for those receiving lapatinib. Pyrotinib delayed cancer progression on average with 18 months compared to 7 months for lapatinib. Both treatments were well tolerated, but caused hand-foot syndrome in 20% of patients. Pyrotinb was also more likely to cause diarrhea and a low white blood count than lapatinib. The study results demonstrated the superiority of pyrotinib over lapatinib for the treatment of advanced HER2-positive breast cancer(36).
Currently, no data support the superiority of any particular regimen. Sequential use of single agents or combinations can be used for patients with metastatic disease.
The single agents that have shown activity in MBC include the following: anthracyclines (doxorubicin, epirubicin, liposomal doxorubicin); taxanes (paclitaxel, docetaxel, albumin-bound nanoparticle paclitaxel [ABI-007 or Abraxane®]); alkylating agents (cyclophosphamide); fluoropyrimidines (capecitabine, fluorouracil [5-FU]); antimetabolites (methotrexate); vinca alkaloids (vinorelbine, vinblastine, vincristine); platinum (carboplatin, cisplatin); other (gemcitabine, mitomycin C, eribulin mesylate, ixabepilone)(37).
Combination regimens that have shown activity in metastatic breast cancer include the following: AC (doxorubicin and cyclophosphamide); EC (epirubicin and cyclophosphamide); docetaxel and doxorubicin; CAF (cyclophosphamide, doxorubicin and 5-FU); CMF (cyclophosphamide, methotrexate and 5-FU); doxorubicin and paclitaxel; docetaxel and capecitabine; vinorelbine and epirubicin; capecitabine and ixabepilone, carboplatin and gemcitabine; gemcitabine and paclitaxel(37).
There are no data suggesting that combination therapy results in an OS benefit over single-agent therapy. An Eastern Cooperative Oncology intergroup study (E-1193) randomly assigned patients to receive paclitaxel and doxorubicin, given both as a combination and sequentially(38). Although response rate and time to disease progression were both better for the combination group, survival was the same in both groups(38-40).
Combination chemotherapy is often given if there is evidence of rapidly progressive disease or visceral crisis. A systematic review of 17 randomized trials found that the addition of one or more chemotherapy drugs to a chemotherapy regimen in the attempt to intensify the treatment improved tumor response, but had no effect on OS(41).
The optimal time for patients with responsive or stable disease has been studied by several groups. For patients who attain a complete response to initial therapy, two randomized trials have shown a prolonged disease-free survival after immediate treatment with a different chemotherapy regimen compared with observation and treatment upon relapse(42,43). Neither of these studies, however, showed an improvement in OS for patients who received immediate treatment; in one of these studies(43), survival was actually worse in the group that was treated immediately. Similarly, no difference in survival was noted when patients with partial response or stable disease after initial therapy were randomly assigned to receive either a different chemotherapy versus observation(44) or a different chemotherapy regimen given at higher versus lower doses(45). However, 324 patients who achieved disease control were randomly assigned to maintenance chemotherapy or observation. Patients who received maintenance chemotherapy (paclitaxel and gemcitabine) had improved PFS at 6 months and improved OS. This was associated with an increased rate of adverse events(46). Because there is no standard approach for treating metastatic disease, patients requiring second-line regimens are good candidates for clinical trials.
Surgery may be indicated for selected patients: fungating or painful breast lesions (mastectomy), isolated lung metastases, pathologic (or impending) fractures, parenchymal brain or vertebral metastases with spinal cord compression, pleural or pericardial effusions(37).
Radiation therapy has a major role in the palliation of localized symptomatic metastases(47). The indications for external-beam radiation therapy include the following: bronchial obstruction, fungating or painful breast or chest wall lesions, after surgery for decompression of intracranial or spinal cord metastases, after fixation of pathologic fractures, painful bony metastases, unresectable central nervous system metastases (i.e., brain, meninges and spinal cord).
Strontium chloride Sr 89 – a systemically administered radionuclide – can be administered for palliation of diffuse bony metastases(48,49).
Reducing skeletal morbidity in patients with bone metastases should be considered. The results of randomized trials of pamidronate and clodronate in patients with bony metastatic disease show decreased skeletal morbidity(50-52). Zoledronate has been at least as effective as pamidronate(53).
The monoclonal antibody denosumab inhibits the receptor activator of nuclear factor kappa beta ligand (RANKL). A meta-analysis of three phase III trials (NCT00321464, NCT00321620 and NCT00330759) comparing zoledronate versus denosumab for the management of bone metastases suggests that denosumab is similar to zoledronate in reducing the risk of a first skeletal-related event(54).
After about two decades of using HER2 inhibitors in breast cancer, they have gained an important place in the therapeutic armamentarium of early and advanced stage of breast cancer. We also want to emphasize that the recent trials reveal the fact that the first results obtained in pivotal trials are not applicable in real word. In this respect, retrospective study of two populationbased cohorts of patients with metastatic breast cancer who were treated with trastuzumab revealed an overall survival in each cohort significantly worse than that reported in CLEOPATRA (trastuzumab/pertuzumab; 39.2 versus 56.4 months) and EMILIA (T-DM1; 15.4 versus 30.9 months). Another finding was that older patients and patients treated with trastuzumab/pertuzumab had significantly worse overall survival compared with younger patients. This study experience and medical thinking is as important as the evidence from clinical trials(55). n
Conflict of interests: The authors declare no conflict of interests.