Recent data show a significant benefit from combining an anti-HER-2 agent with endocrine therapy in HER2-positive and hormone receptor (HR)-positive metastatic breast cancer. However, as the clinical ...outcomes achieved by these combinations do not favourably match those with chemotherapy, clinicians still perceive HER2-positive breast cancer as an homogeneous group and consider chemotherapy with anti-HER2 agents as the preferred treatment option, regardless of the HR status. Indeed, in HR-positive HER2-positive tumours, chemotherapy with anti-HER2 agents is the backbone of treatment, while endocrine therapy is commonly used in sequence when HR and HER2 are co-expressed rather than as a real alternative. Emerging biological and clinical data challenge this paradigm, suggesting that HER2-positive tumours are rather heterogeneous that HRs co-expression may account for part of this heterogeneity and, finally, that chemotherapy may represent an overtreatment in selected cases. The present review aims to summarise the biological features of HER2-positive breast cancer according to HR status, the role of the bi-directional cross-talk between HER2 and HR pathways on resistance development to anti-HER2 and endocrine therapy, and finally, the novel therapeutic strategies, including but not limited to chemotherapy, targeting these two pathways.
•The AR positive subtype has better prognosis and less chemotherapy responsiveness.•AR is involved in cell cycle regulation and Epithelial-to-Mesenchymal Transition.•Clinical data demonstrate the ...efficacy of antiandrogen therapies for AR positive TNBC.
Triple negative breast cancer (TNBC) represents the 15–20% of all breast cancers (BC) and is characterized by a very aggressive behavior. Recent data suggest that TNBC is not a single disease, but it is rather an umbrella for different ontology-profiles such as basal like 1 and 2, mesenchymal, and the luminal androgen receptor (LAR). The LAR subtype is characterized by the expression of the Androgen Receptor (AR) and its downstream effects. Notwithstanding the role of the AR in several signaling pathways, its impact on a biological and clinical standpoint is still controversial. The LAR subtype has been associated with better prognosis, less chemotherapy responsiveness and lower pathologic complete response after neoadjuvant treatment. Clinical evidence suggests a role for anti-androgen therapies such as bicalutamide, enzalutamide and abiraterone, offering an interesting chemo-free alternative for chemo-unresponsive patients, and therefore potentially shifting current treatment strategies.
SUMMARY Breast cancer is not considered anymore a unique disease. Microarray gene expression analysis led to the identification of 4 major breast cancer “intrinsic” subtypes, including hormone ...receptor (HR)-positive luminal A and B, human epidermal growth receptor 2 (HER2)-positive and basal-like breast cancer (BLBC). These subtypes have distinct phenotypes, molecular profiles, clinical behaviour and response to therapy, with the BLBC carrying the worst outcome. Microarray analysis is not feasible in routine practice and therefore oncologists rely on a simpler immunohistochemical (IHC) classification to identify relevant breast cancer subtypes. Triple negative breast cancer (TNBC) is defined by the absence of oestrogen receptor, progesterone receptor and HER2 expression at IHC analysis. TNBC is strictly related to BLBC and, given the lack of common therapeutic targets, represent a major challenge for breast oncologist. In this review we will summarize the updated knowledge on TNBC, with emphasis on its current treatment and on the new therapeutic options under development.
The activity of palbociclib as a single agent in advanced breast cancer has not been extensively studied, with the only available clinical data limited to heavily pretreated patients. Preclinical ...data suggests palbociclib may partially reverse endocrine resistance, though this hypothesis has not been evaluated in previous clinical studies. This phase II, open-label, multicenter study examined the activity of palbociclib monotherapy, as well as palbociclib given in combination with the same endocrine therapy (ET) that was received prior to disease progression, in postmenopausal women with moderately pretreated, estrogen receptor-positive, HER2 negative advanced breast cancer.
Eligible women with advanced disease which had progressed on one or two prior ETs were randomized 1 : 1 to receive either palbociclib alone, or palbociclib in combination with the ET as previously received. Primary end point was clinical benefit rate (CBR); secondary end points included progression-free survival (PFS).
Between October 2012 and July 2016, a total of 115 patients were randomized. The CBR was 54% 95% confidence interval (CI): 41.5–63.7 for combination therapy, and 60% (95% CI: 47.8–72.9) for monotherapy. Median PFS was 10.8months (95% CI: 5.6–12.7) for combination therapy, and 6.5months (95% CI: 5.4–8.5) for monotherapy hazard ratio (HR) 0.69; 95% CI: 0.4–1.1, exploratory P-value=0.12. Exploratory analyses revealed the PFS advantage for combination therapy was seen in the subgroup of patients who received prior ET for >6months (HR 0.53; 95% CI: 0.3–0.9, exploratory P-value=0.02), but not in those who received prior ET for ≤6months.
Palbociclib has clinical activity as a single agent in women with moderately pretreated, oestrogen receptor-positive, HER2-negative advanced breast cancer. Palbociclib may have potential to reverse endocrine resistance in patients with a history of previous durable response to ET.
NCT02549430
Studies on well characterized, large populations of estrogen receptor (ER)/progesterone receptor (PgR)/HER2-negative triple-negative (TN) breast cancer (BC) patients with long-term follow-up are ...lacking. In this study, we analyze clinical outcomes of TN BC and implications of epidermal growth factor receptor (EGFR) expression. Clinical and biologic features, time to first recurrence (TTFR), and overall survival (OS) were compared in 253 TN versus 1,036 ER positive, PgR positive, HER2-negative estrogen-driven (ED) BC. Compared to ED, TN tumors were larger (
p
= 0.02), more proliferative (high S-phase 54 vs. 17 %,
p
< 0.0001), more aneuploid (64 vs. 43 %,
p
< 0.0001) and more likely EGFR positive (≥10 fmol/mg by radioligand-binding assay, 49 vs. 7 %,
p
< 0.0001). Among TN, EGFR-positive BC were larger (
p
= 0.0018), more proliferative (
p
< 0.0001), and more aneuploid, (
p
< 0.0001) than EGFR-negative BC. Adjuvant-treated TN patients had shorter TTFR (
p
= 0.0003), and OS (
p
= 0.0017), than ED patients. However, in untreated patients, no differences in TTFR and OS were observed at 8 years median follow-up. Among TN patients, EGFR expression was not associated with worse outcome. TN tumors have a worse outcome in systemically treated patients but not in untreated patients. EGFR expression, does not predict for worse long-term survival.
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•Triple-negative metastatic breast cancer represents a challenging scenario.•Besides chemotherapy, several novel agents are now available in clinical practice.•A modified Delphi ...approach was adopted to address high-priority statements.•A set of prioritized consensus statements was provided.•Relevant/unexpected results and divisive statements were discussed by the Panel.
Triple-negative (TN) metastatic breast cancer (mBC) represents the most challenging scenario withing mBC framework, and it has been only slightly affected by the tremendous advancements in terms of drug availability and survival prolongation we have witnessed in the last years for advanced disease. However, although chemotherapy still represents the mainstay of TN mBC management, in the past years, several novel effective agents have been developed and made available in the clinical practice setting. Within this framework, a panel composed of a scientific board of 17 internationally recognized breast oncologists and 42 oncologists working within local spoke centers, addressed 26 high-priority statements, including grey areas, regarding the management of TN mBC. A structured methodology based on a modified Delphi approach to administer the survey and the Nominal Group Technique to capture perceptions and preferences on the management of TN mBC within the Italian Oncology community were adopted. The Panel produced a set of prioritized considerations/consensus statements reflecting the Panel position on diagnostic and staging approach, first-line and second-line treatments of PD-L1-positive/germline BRCA (gBRCA) wild-type, PD-L1-positive/gBRCA mutated, PD-L1-negative/gBRCA wild-type and PD-L1-negative/gBRCA mutated TN mBC. The Panel critically and comprehensively discussed the most relevant and/or unexpected results and put forward possible interpretations for statements not reaching the consensus threshold.
Circulating tumor cells (CTCs) are associated with inferior prognosis in metastatic breast cancer (MBC). We hypothesized that the relationship between CTCs and disease subtype would provide a better ...understanding of the clinical and biologic behavior of MBC.
We retrospectively analyzed 517 MBC patients treated at a single institution. Subtypes of primary tumors were analyzed by immunohistochemical (IHC) or fluorescent in situ hybridization analyses and CTCs were enumerated by CellSearch® at starting a new therapy. Overall survival (OS) and progression-free survival durations for each IHC subtype were determined.
At a median follow-up of 24.6 months, 276 of 517 (53%) patients had died. The median OS for patients with <5 and ≥5 CTCs were 32.4 and 18.3 months, respectively (P < 0.001). Except in HER2+ patients, the prognostic value of CTCs was independent of disease subtype and disease site.
In this large retrospective study, CTCs were strongly predictive of survival in all MBC subtypes except HER2+ patients who had been treated with targeted therapy. Our results clearly demonstrate the value of enumerating CTCs in MBC and strongly suggest an interesting biological implication in the HER2+ subset of patients that need to be further explored.
Abstract Approximately five percent of all breast cancer patients in developed countries present with distant metastases at initial diagnosis. Due to its incurability, metastatic breast cancer is ...generally treated with systemic therapies to achieve disease control and reduce tumor-related symptoms. Primary treatments for metastatic breast cancer are chemotherapy, endocrine- and biologic therapy, whereas surgery with or without radiotherapy is usually performed to treat impending wound issues. Since 2002, several retrospective non-randomized clinical studies have shown that extirpation of the primary tumor correlates with a significantly improved survival in patients with primary metastatic breast cancer. Others have argued that this survival benefit associated with surgery may be due to selection biases. Therefore, in the absence of published results from randomized controlled trials carried out in India and Turkey and completion of a trial in the United States, there is no clear conclusion on whether surgical excision of the primary breast cancer translates into a survival benefit for patients with de novo metastatic disease. Furthermore, timing and type of surgical procedure, as well as selection of patients who could benefit the most from this approach, represent additional points of uncertainty. Despite the epidemiological burden of this condition, there are no guidelines on how to manage breast cancer patients presenting with de novo metastatic breast cancer; and decisions are often left to provider and patient preferences. Here, we present a critical overview of the literature focusing on the rationale and potential role of primary tumour excision in patients with de novo metastatic breast cancer.
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