The effects of anticancer therapies on bone metastases in breast cancer

HR-positive advanced breast cancer

Estrogen deprivation is the mainstay of the treatment of ER-positive advanced breast cancer and it is achieved either by targeting the ER with the use of selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs), or by blocking estrogen production using aromatase inhibitors (AIs) in postmenopausal women, or ovarian function suppression (OFS) in premenopausal women [ ]. In premenopausal women, OFS is achieved by the use of LHRH (luteinizing hormone–releasing hormone) agonists (e.g., goserelin q4w, commenced at least 4 weeks before the start of endocrine treatment), bilateral oophorectomy, or pelvic RT, the former (LHRH agonists) being preferable if preserving fertility is desired [ ].

Endocrine therapy is the preferred treatment option in patients with ER-positive, HER-2-negative advanced breast cancer (even in the presence of concurrent visceral disease), except in the event of life-threatening disease, significant organ involvement that requires early symptomatic relief or visceral crisis, where chemotherapy should be offered first line [ ].

Historically, tamoxifen had been the first-line endocrine therapy of choice for many years in patients with HR-positive breast cancer. However, more recent studies demonstrated an improvement in progression-free survival (PFS) for AIs compared to tamoxifen and are now the preferred treatment option [ ]. Currently, nonsteroidal AIs (letrozole and anastrozole) are considered first-line treatment in postmenopausal women with HR-positive advanced breast cancer, while steroidal AIs such as exemestane or the SERD fulvestrant are most commonly used as second-line [ ]. Interestingly, fulvestrant demonstrated an improvement in OS compared to anastrozole in the FALCON phase III study, with the greater improvement in PFS in patients with nonvisceral disease [ ].

Recent studies have led to the approval of oral CDK4/6 inhibitors (ribociclib, palbociclib, and abemaciclib) in combination with endocrine therapy (either an AI or fulvestrant) and this has become the standard of care in this setting. The MONALEESA-2 phase III trial showed that the combination of ribociclib plus letrozole extended median PFS compared to letrozole alone (25.3 vs. 16.0 months) in postmenopausal women who had not received prior systemic treatment [ ]. Similarly, the MONALEESA-3 phase III trial evaluating ribociclib plus fulvestrant compared to fulvestrant alone showed median PFS of 20.5 versus 12.8 months in favor of combination therapy in postmenopausal women who were treatment-naïve or had received up to one line of endocrine therapy [ ], and the MONALEESA-7 phase III trial demonstrated that ribociclib in combination with endocrine therapy (either tamoxifen or a nonsteroidal AI) was superior to endocrine therapy alone with a median PFS of 23.8 versus 13.0 months, respectively, in premenopausal patients [ ]. On the other hand, the PALOMA-2 phase III trial compared the efficacy of palbociclib plus letrozole versus letrozole alone and demonstrated a significant improvement in median PFS in favor of the combination arm (27.6 vs. 14.5 months) in postmenopausal women who had no prior therapy [ , ], while the PALOMA-3 phase III trial demonstrated that the combination of palbociclib and fulvestrant compared to fulvestrant alone significantly extended PFS (11.2 vs. 4.6 months, respectively) in women who had progressed on previous endocrine therapy [ , ]. Furthermore, the MONARCH 2 study showed extended PFS when evaluating the combination of abemaciclib plus fulvestrant compared to fulvestrant alone (16.4 vs. 9.3 months, respectively) in women who progressed while receiving endocrine therapy [ ], and the MONARCH 3 phase III trial demonstrated median PFS of 28.2 versus 14.8 months in favor of the combination of abemaciclib plus nonsteroidal AI compared to nonsteroidal AI alone in postmenopausal women with no prior systemic therapy [ ]. In addition, the phase III trial MONARCH plus showed that abemaciclib in combination with either a nonsteroidal AI (cohort A) or fulvestrant (cohort B) improves median PFS compared to nonsteroidal AI or fulvestrant alone, in postmenopausal patients with no previous systemic therapy (cohort A) or who progressed on endocrine therapy (cohort B) [ ]. Table 67.1 displays a summary of clinical trials with CDK4/6 inhibitors, their median PFS, ORR, and hazard ratio PFS for bone-only and visceral disease with the different drug combinations.

To date, these CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) have not been compared head-to-head in clinical trials. However, an adjusted indirect meta-analysis of RCTs showed that these agents have similar efficacy in first- or second-line therapy, although they have different toxicity profiles [ ]. However, the optimum treatment sequence strategy is still unclear (first-line CDK4/6 inhibitor plus AI followed by fulvestrant vs. first-line endocrine therapy alone followed by CDK4/6 inhibitor plus fulvestrant upon progression) and an ongoing trial (the SONIA study) aims to address this (NCT03425838). Interestingly, the results of a network meta-analysis showed that CDK4/6 inhibitors significantly improve PFS in patients with bone-only disease and nonvisceral disease in comparison with fulvestrant-based therapies alone [ ].

With regard to second-line therapy, the combination of everolimus and exemestane is an alternative based on the findings of the BOLERO-2 phase III trial which demonstrated a significant improvement in median PFS of 7.8 versus 3.2 months compared to exemestane alone in postmenopausal women with HR-positive breast cancer who progressed during or after nonsteroidal AIs [ ]. However, the combination of CDK4/6 inhibitors and fulvestrant is generally better tolerated, and without the increased incidence of stomatitis and occasional severe pneumonitis [ ].

Upstream targeting of the PI3K/Akt/mTOR signaling pathway with drugs such as the PI3K inhibitor alpelisib has shown promising results. The SOLAR-1 phase III trial demonstrated an improvement in median PFS for the combination of alpelisib and fulvestrant compared to fulvestrant alone (11.0 vs. 5.7 months, respectively) in patients with PIK3CA mutated, HR + HER-2- breast tumors, although with a higher incidence of rash, diarrhea, and hyperglycemia [ ].

HER-2-positive advanced breast cancer

In patients with HER-2-positive advanced breast cancer, anti-HER2 therapy should be offered first line, along with endocrine therapy in the case of ER-positive tumors. Standard first-line treatment for untreated patients with HER-2-positive metastatic breast cancer is combination of chemotherapy plus trastuzumab and pertuzumab, based on the results of the CLEOPATRA phase III trial which demonstrated that the combination of pertuzumab, trastuzumab, and docetaxel compared to trastuzumab and docetaxel alone improved significantly median overall survival (56.5 vs. 40.8 months) [ ]. According to international guidelines, first-line regimens with cytotoxic agents can include docetaxel or paclitaxel if using dual blockade, and trastuzumab plus vinorelbine or a taxane (if pertuzumab is not given) [ ].

T-DM1 (trastuzumab emtansine) is used for second-line treatment based on the EMILIA phase III trial that evaluated T-DM1 versus lapatinib plus capecitabine, and demonstrated an improvement in median PFS (9.6 vs. 6.4 months) and median overall survival (30.9 vs. 25.1 months, respectively) in patients with HER-2-positive metastatic breast cancer who previously received trastuzumab and a taxane [ ]. Further lines of treatment include trastuzumab plus lapatinib [ ], capecitabine plus lapatinib [ ], capecitabine plus trastuzumab beyond progression [ ], or trastuzumab plus pertuzumab [ ].

Fam-trastuzumab deruxtecan-nxki (an anti-HER-2 antibody-drug conjugate linked to a topoisomerase 1 inhibitor) and neratinib (an irreversible inhibitor of the HER-2 tyrosine kinase) have also been recently approved by the FDA for patients with advanced or metastatic HER-2-positive breast cancer who have had two or more regimens for metastatic disease as they have shown improved response rates and survival benefit [ , ], although are still being evaluated by the EMA.

Triple-negative breast cancer

TNBC is characterized by the lack of overexpression of hormone receptors and HER-2. Due to a lack of therapeutic targets, endocrine therapy or targeted therapy is not effective in this setting. TNBC is associated with younger age, aggressive behavior, high risk of recurrence, and poor prognosis, with more than one-third of patients presenting with metastatic lesions during the course of their disease [ ].

Historically, treatment of patients with TNBC has relied on systemic chemotherapy with combinations based on anthracycline, taxane, cyclophosphamide, fluorouracil, and cisplatin [ ]. Single-agent taxanes such as paclitaxel and docetaxel are reasonable alternatives in the first-line setting, followed by chemotherapy with anthracyclines upon progression, or vice versa. In patients who are very symptomatic or have high disease burden, the combination of cyclophosphamide and anthracyclines, or taxanes plus platinum are alternatives. In addition, in the event of contraindication to or progression after taxanes and/or anthracyclines, other alternatives include capecitabine, eribulin, platinum, gemcitabine, vinorelbine, or ixabepilone [ ].

Recent advances have widened the therapeutic alternatives and currently, treatment of TNBC patients also takes into consideration PD-L1 expression and BRCA mutation status. Recent clinical trials have shown that patients with BRCA mutations benefit from treatment with platinum or PARP (poly (ADP-ribose) polymerase) inhibitors. The TNT phase III trial evaluated carboplatin compared to docetaxel, and demonstrated an improvement in ORR (68% vs. 33%) and median PFS (6.8 vs. 4.4 months) in favor of carboplatin in the subgroup of patients with a deleterious BRCA1/2 germline mutation [ ]. On the other hand, the EMBRACA phase III trial evaluated single-agent talazoparib compared to standard chemotherapy (capecitabine, gemcitabine, eribulin, or vinorelbine) in patients with a BRCA1/2 germline mutation, and showed a significant improvement in PFS (8.6 vs. 5.6 months) and ORR (62.6% vs. 27.2%, respectively) [ ]. Similarly, the OlympiAD phase III trial compared the PARP inhibitor olaparib versus chemotherapy of choice, and found a significant improvement in median PFS (7.0 vs. 4.2 months) and response rate (59.9% vs. 28.8%) [ ].

In recent years, immunotherapy has shown remarkable and long-lasting responses in various tumors such as melanoma [ ], non–small cell lung cancer [ ], and renal carcinoma [ ]. Although breast cancer is not considered an immunogenic malignancy, a subset of tumors might be more susceptible to the immune response. PD-L1 expression has been found to be higher in TNBC than in other breast cancer subtypes, and elevated levels of tumor-infiltrating lymphocytes have been associated with good prognosis and increased sensitivity to chemotherapy in patients with TNBC [ , ]. These observations and subsequent studies led to the recent approval of atezolizumab plus nab-paclitaxel as the first-line therapy of choice in patients with PD-L1-positive triple-negative advanced breast cancer (defined as ≥1% positive staining on immune cells determined by the companion test SP142 antibody), based on the results of the IMpassion130 phase III trial, which demonstrated a clinical meaningful overall survival benefit in comparison to placebo/nab-paclitaxel (median OS 25.0 vs. 18.0 months) [ ].