Triple-Negative Breast Cancer: What Is Known About It?
Triple-Negative Breast Cancer: What Is Known About It?
Therapeutic options available for TNBC range from primary surgery to adjuvant chemotherapy, radiotherapy, hormonal therapy, or targeted therapy (de Ruijter et al., 2011). Prior to beginning systemic therapy, a central venous access device is surgically implanted to safely deliver chemotherapy. The standard chemotherapeutic treatment for women with early-stage TNBC currently involves an anthracycline and taxane-based combination chemotherapy regimen (Telli & Ford, 2010). Anthracycline-based regimens include AC (doxorubicin, cyclophosphamide) followed by T (docetaxel) or TAC (docetaxel, doxorubicin, and cyclophosphamide) (Connolly & Stearns, 2010). According to the 2005 Early Breast Cancer Trialists' Collaborative Group, meta-analysis studies revealed a survival advantage and a reduction of recurrence risk with anthracycline-based therapies compared to nonanthracycline-based therapies (Gajria, Seidman, & Dang, 2010).
TAC is given via IV every 21 days, with a total of four cycles given, which takes three months to complete the prescribed regimen (Cancer Research UK, 2012; Health Canada, 2007). Rare, but serious, long-term effects of anthracycline-based regimens include congestive heart failure and secondary malignancies (Gajria et al., 2010). The more common side effects of a TAC regimen include neutropenia, anemia, nausea, diarrhea, vomiting, fatigue, stomatitis, nail changes, fever, hair loss, fluid retention, rash, nerve pain, and swelling at the injection site (Cancer Research UK, 2012; Health Canada, 2007).
Locoregional treatment of TNBC does not differ from other invasive breast carcinomas (Brouckaert, Wildiers, Floris, & Neven, 2012). Breast-conserving surgery followed by radiation therapy is the standard treatment; however, mastectomy may be recommended for extensive or multifocal disease (Maughan, Lutterbie, & Ham, 2010). Radiation therapy following lumpectomy decreases local recurrence and improves cancer-specific survival rates to survival rates equivalent to mastectomy (Maughan et al., 2010). One distinct factor concerning locoregional treatment in TNBC is the choice for contralateral prophylactic mastectomy in patients with BRCA1 mutations (Brouckaert et al., 2012). The benefits of contralateral prophylactic mastectomy compared to chemoprevention are uncertain because no prospective, randomized trials comparing the two treatment protocols exist (Lostumbo, Carbine, & Wallace, 2010).
Several clinical trials have been investigating a variety of newer therapies to treat TNBC. Poly (ADP-ribose) polymerase (PARP) inhibitors, platinum salts, angiogenesis inhibitors, epidermal growth factor receptor (EGFR) inhibitors, vascular endothelial growth factor receptor (VGFR) inhibitors, Rous sarcoma virus (SRC) inhibitors, vaccines, high-dose chemotherapy, mammalian target of rapamycin (mTOR) inhibitors, notch or secretase inhibitors, heat-shock protein 90 (HSP90) inhibitors, marine natural product DNA-damaging agents, histone deacetylase (HDAC-I), and interleukin-6/Janus kinase 2 (JAK1 and JAK2) inhibitors are among those investigational treatments.
According to Crown, O'Shaughnessy, and Gullo (2012) and Joensuu and Gligorov (2012), PARP inhibitors that are showing promise in clinical trials against TNBC include olaparib, veliparib, MK-4827, and PF-01367338. The phase III trials of the once-classified PARP iniparib demonstrated no difference in overall survival or progression-free survival in patients with TNBC (Crown et al., 2012). However, Liedtke and Kiesel (2012) reported that iniparib may have a role in second- or third-line treatment for metastatic breast cancer.
Cisplatin appears to have superior disease-free and overall survival rates as compared to carboplatin in the platinum salts class of chemotherapeutic drugs (Gelmon et al., 2012). Telli and Ford (2010) noted that five clinical trials testing platinum salts in neoadjuvant regimens reported increased pathologic complete response over the regimens without the platinum salts.
Potential for the EGFR inhibitors cetuximab, erlotinib, lapatinib, and panitumumab in combination with taxanes or platinum salts also has been noted in trials (Crown et al., 2012; Gelmon et al., 2012; Joensuu & Gligorov, 2012; Telli & Ford, 2010).
Vascular endothelial growth factor receptor (VEGFR) or angiogenesis inhibitors like bevacizumab have been reported by many to show promise in progression-free survival in metastatic TNBC and increasing pathologic complete response in early TNBC neoadjuvant therapy (Gelmon et al., 2012; Joensuu & Gligorov, 2012; Liedtke & Kiesel, 2012). Crown et al. (2012) mentioned that a newer VEGFR, ramucirumab, is in phase III clinical trials with docetaxel for metastatic HER2-negative breast cancer, and Hudis and Gianni (2011) reported the initial outcome of trials testing sunitinib had an overall response rate of 15%.
Everolimus, an mTOR inhibitor, has demonstrated mixed results according to Gelmon et al. (2012). In one study conducted by Andre et al. (2010), combining it with paclitaxel revealed encouraging results; however, another randomized trial did not display significant increase in pathologic complete response (Gelmon et al., 2012). Crown et al. (2012) indicated that among the many clinical trials occurring with mTOR inhibitors, no preliminary data revealed their efficacy in breast cancer treatment.
Some interventions are too new for data reporting, such as notch or secretase inhibitors, marine natural product DNA-damaging agents, and HDAC-I. HSP90 inhibitors have demonstrated anticancer properties in preliminary testing, as well. In addition, JAK1 and JAK2 inhibitors have been identified as possibly having therapeutic benefits in breast cancer and are being trialed in solid malignancies (Crown et al., 2012).
Treatment
Therapeutic options available for TNBC range from primary surgery to adjuvant chemotherapy, radiotherapy, hormonal therapy, or targeted therapy (de Ruijter et al., 2011). Prior to beginning systemic therapy, a central venous access device is surgically implanted to safely deliver chemotherapy. The standard chemotherapeutic treatment for women with early-stage TNBC currently involves an anthracycline and taxane-based combination chemotherapy regimen (Telli & Ford, 2010). Anthracycline-based regimens include AC (doxorubicin, cyclophosphamide) followed by T (docetaxel) or TAC (docetaxel, doxorubicin, and cyclophosphamide) (Connolly & Stearns, 2010). According to the 2005 Early Breast Cancer Trialists' Collaborative Group, meta-analysis studies revealed a survival advantage and a reduction of recurrence risk with anthracycline-based therapies compared to nonanthracycline-based therapies (Gajria, Seidman, & Dang, 2010).
TAC is given via IV every 21 days, with a total of four cycles given, which takes three months to complete the prescribed regimen (Cancer Research UK, 2012; Health Canada, 2007). Rare, but serious, long-term effects of anthracycline-based regimens include congestive heart failure and secondary malignancies (Gajria et al., 2010). The more common side effects of a TAC regimen include neutropenia, anemia, nausea, diarrhea, vomiting, fatigue, stomatitis, nail changes, fever, hair loss, fluid retention, rash, nerve pain, and swelling at the injection site (Cancer Research UK, 2012; Health Canada, 2007).
Locoregional treatment of TNBC does not differ from other invasive breast carcinomas (Brouckaert, Wildiers, Floris, & Neven, 2012). Breast-conserving surgery followed by radiation therapy is the standard treatment; however, mastectomy may be recommended for extensive or multifocal disease (Maughan, Lutterbie, & Ham, 2010). Radiation therapy following lumpectomy decreases local recurrence and improves cancer-specific survival rates to survival rates equivalent to mastectomy (Maughan et al., 2010). One distinct factor concerning locoregional treatment in TNBC is the choice for contralateral prophylactic mastectomy in patients with BRCA1 mutations (Brouckaert et al., 2012). The benefits of contralateral prophylactic mastectomy compared to chemoprevention are uncertain because no prospective, randomized trials comparing the two treatment protocols exist (Lostumbo, Carbine, & Wallace, 2010).
Therapies Under Investigation
Several clinical trials have been investigating a variety of newer therapies to treat TNBC. Poly (ADP-ribose) polymerase (PARP) inhibitors, platinum salts, angiogenesis inhibitors, epidermal growth factor receptor (EGFR) inhibitors, vascular endothelial growth factor receptor (VGFR) inhibitors, Rous sarcoma virus (SRC) inhibitors, vaccines, high-dose chemotherapy, mammalian target of rapamycin (mTOR) inhibitors, notch or secretase inhibitors, heat-shock protein 90 (HSP90) inhibitors, marine natural product DNA-damaging agents, histone deacetylase (HDAC-I), and interleukin-6/Janus kinase 2 (JAK1 and JAK2) inhibitors are among those investigational treatments.
According to Crown, O'Shaughnessy, and Gullo (2012) and Joensuu and Gligorov (2012), PARP inhibitors that are showing promise in clinical trials against TNBC include olaparib, veliparib, MK-4827, and PF-01367338. The phase III trials of the once-classified PARP iniparib demonstrated no difference in overall survival or progression-free survival in patients with TNBC (Crown et al., 2012). However, Liedtke and Kiesel (2012) reported that iniparib may have a role in second- or third-line treatment for metastatic breast cancer.
Cisplatin appears to have superior disease-free and overall survival rates as compared to carboplatin in the platinum salts class of chemotherapeutic drugs (Gelmon et al., 2012). Telli and Ford (2010) noted that five clinical trials testing platinum salts in neoadjuvant regimens reported increased pathologic complete response over the regimens without the platinum salts.
Potential for the EGFR inhibitors cetuximab, erlotinib, lapatinib, and panitumumab in combination with taxanes or platinum salts also has been noted in trials (Crown et al., 2012; Gelmon et al., 2012; Joensuu & Gligorov, 2012; Telli & Ford, 2010).
Vascular endothelial growth factor receptor (VEGFR) or angiogenesis inhibitors like bevacizumab have been reported by many to show promise in progression-free survival in metastatic TNBC and increasing pathologic complete response in early TNBC neoadjuvant therapy (Gelmon et al., 2012; Joensuu & Gligorov, 2012; Liedtke & Kiesel, 2012). Crown et al. (2012) mentioned that a newer VEGFR, ramucirumab, is in phase III clinical trials with docetaxel for metastatic HER2-negative breast cancer, and Hudis and Gianni (2011) reported the initial outcome of trials testing sunitinib had an overall response rate of 15%.
Everolimus, an mTOR inhibitor, has demonstrated mixed results according to Gelmon et al. (2012). In one study conducted by Andre et al. (2010), combining it with paclitaxel revealed encouraging results; however, another randomized trial did not display significant increase in pathologic complete response (Gelmon et al., 2012). Crown et al. (2012) indicated that among the many clinical trials occurring with mTOR inhibitors, no preliminary data revealed their efficacy in breast cancer treatment.
Some interventions are too new for data reporting, such as notch or secretase inhibitors, marine natural product DNA-damaging agents, and HDAC-I. HSP90 inhibitors have demonstrated anticancer properties in preliminary testing, as well. In addition, JAK1 and JAK2 inhibitors have been identified as possibly having therapeutic benefits in breast cancer and are being trialed in solid malignancies (Crown et al., 2012).
