Introduction
Breast cancer (BC) is the most commonly diagnosed cancer type in the US and worldwide according to estimates by ACS [
1] and GLOBOCAN [
2], respectively. HR-positive patients constitute 75-80% of all BC cases. The standard-of-care (SOC) in the HR+/HER2- metastatic patients is endocrine therapy (ET) in combination with CDK4/6 inhibitors [
3,
4]. However, targeted treatment options after progression on the SOC is quite limited, and their sequencing for the optimum response is not clearly defined [
5,
6].
ESR1 mutations can lead to acquired resistance to ETs, but especially prevalent after progression on prior aromatase inhibitor (AI) treatment, even more prevalent after AI plus CDK4/6i and in the metastatic setting (de novo: 3.9% vs. up to 55% posttreatment) [
7,
8,
9,
10]. As these mutations could be also associated with worse survival, new treatment strategies need to be explored. Recent approval of elacestrant, an orally available selective estrogen receptor degrader (SERD), for ER+/HER2-,
ESR1-mutated advanced or metastatic breast cancer (A/MBC) patients exemplifies the success of such a strategy.
PIK3CA is also frequently altered and is an actionable target in breast cancer. Although some studies discovered
PIK3CA mutation as a negative prognostic marker following the SOC, PI3K-alpha specific inhibitor alpelisib together with fulvestrant was not approved in the first line but following progression on or after an endocrine-based regimen in HR+/HER2-,
PIK3CA-mutated, A/MBC patients. These alterations could limit the efficacy of endocrine and targeted therapies. However, there are currently no data (ongoing, NCT05563220) regarding the safety and clinical activity for combination of elacestrant and inhibitors against PI3K/AKT/mTOR pathway and/or CDK4/6 in the ER-positive,
ESR1 and
PIK3CA co-mutated BC patients.
Here, to our knowledge, we report the first case of safety and efficacy of all-oral elacestrant and alpelisib combination in a heavily pretreated, ESR1 and PIK3CA co-mutated HR+/HER2- MBC patient. There was a partial response following this combination with minor adverse events.
Discussion
BC, as the most diagnosed cancer, is a global health problem with a 5-year survival rate less than 30% in the distant metastatic cases [
12]. The first-line treatment in the HR+/HER2- MBC without visceral metastasis and without germline
BRCA1/2 mutation is endocrine therapy (a nonsteroidal AI or fulvestrant) plus a CDK4/6 inhibitor [
3,
4]. However, de novo or especially acquired resistance to hormone therapy is observed in many patients, rendering current approaches ineffective. Some resistance mechanisms include acquisition of
ESR1 mutations, loss of ER and high cyclin E1 expression, dysregulation in ER co-regulatory proteins, amplifications in
MYC and
FGFR1 as well as
TP53 mutations [
13,
14,
15,
16].
ESR1 mutations are frequently detected in metastatic tumors as compared to the primary tumors [
17]. Many of these mutations are activating and can drive ligand-independent ER activity but may differentially affect the response to endocrine therapies (Y537S vs. D538G, E380Q, S463P) [
18]. They are mostly found after aromatase inhibitor treatment (or AI plus CDK4/6i), and are associated with worse patient outcomes [
9,
19]. Unlike AIs, some clinical studies showed that fulvestrant-based treatment could be efficacious in the
ESR1-mutant patients similar to the
ESR1 WT patients [
7]. However,
ESR1 Y537S mutation was found to be statistically enriched in the posttreatment (fulvestrant plus palbociclib) samples through the genomic landscape and clonal evolution analysis in the PALOMA-3 trial [
20]. Similarly, patients harboring baseline Y537S mutation had a shorter progression-free survival (PFS – 1.8 vs. 3.5 months) than those WT for this residue following fulvestrant treatment (cohort A) in the plasmaMATCH phase 2 trial [
21]. One strategy to overcome the resistance could be chemotherapy and fulvestrant combination; however, a study demonstrated that the combination was synergistic in the Y537S-mutant models but dependent on p53 activity [
22]. Considering the previous failures with multiple lines of chemotherapy and the patient’s
TP53 mutation, this approach was not prioritized in our case. Moreover,
PIK3CA mutations or activation have been previously associated with resistance to chemotherapy in many cancer types [
23,
24,
25]. As next generation of anti-estrogen therapies active against
ESR1 mutations have been developed, they could form the backbone for the treatment of the endocrine-refractory patients. Following the phase III EMERALD trial, elacestrant has received regulatory approval as monotherapy for postmenopausal women or adult men with ER+/HER2-,
ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy [
26]. Patients with concurrent
ESR1 and
TP53 mutations (8.61 vs. 1.87 months), or
ESR1 mutations with liver and/or lung metastases (7.26 vs. 1.87 months) exhibited remarkably longer PFS upon elacestrant vs. placebo [
27]. There are also ELAINE 2 phase II trial [
28] (with abemaciclib) and a case report (monotherapy) [
29] showing the clinical efficacy of lasofoxifene (LAS), a nonsteroidal selective estrogen receptor modulator (SERM), in a similar group of patients after disease progression on prior therapies. Lastly, early results from a randomized phase II trial (SERENA-2) demonstrated improved and promising clinical outcomes with a next-generation oral SERD, camizestrant versus fulvestrant in postmenopausal women with advanced ER+/HER2˗ breast cancer with disease recurrence or progression after ≤1 endocrine therapy and a baseline
ESR1 mutation, including Y537S [
30,
31]. Since our patient did not obtain clinical benefit from the ET-containing regimens and potential resistance to fulvestrant through Y537S mutation, we switched to elacestrant to enhance therapeutic efficacy.
PIK3CA is the most commonly mutated gene in TCGA PanCancer Atlas [
32] and METABRIC breast cancer cohorts [
33]. A meta-analysis in advanced HR+, HER2- breast cancer patients not receiving PI3K-targeted drugs revealed that
PIK3CA mutation was a negative prognostic factor for both progression-free and overall survival (OS) [
34]. For example, PFS was shorter in patients concomitant
ESR1 and
PIK3CA mutations compared to all
ESR1-mutated patients (5.45 vs. 8.61 months) although elacestrant still led to significantly higher PFS compared to placebo (5.45 vs. 1.94 months) [
27]. In line, LAS plus abemaciclib yielded a 73% CBR and 12.9 months PFS in the ESR1-mutant patients whereas they were 63% and 7.8 months in the
ESR1 and
PIK3CA co-mutant patients [
35]. Just 5 hotspot mutations cover approximately 75% of all
PIK3CA mutations in breast cancer, where E545K accounts for more than 15% [
36]. These alterations could be currently targeted by alpelisib, capivasertib or mTOR inhibitor, everolimus [
37,
38]. While alpelisib with fulvestrant is indicated for postmenopausal women and men with HR+/HER2-,
PIK3CA-mutated, advanced or metastatic breast cancer as following progression on or after an endocrine-based regimen, the everolimus with exemestane is for patients with metastatic HR-positive breast cancer who progressed on nonsteroidal aromatase inhibitor (NSAI) therapy [
39]. Prior exposure to CDK4/6 inhibitors did not lead to differential survival outcomes with this combination. More recently, pan-AKT inhibitor capivasertib in combination with fulvestrant has been approved in HR+/HER2- locally advanced or metastatic breast cancer harboring one or more
AKT1,
PIK3CA, or
PTEN alterations following the positive results from the phase 3 CAPItello-291 trial [
38]. However, the currently available data regarding the tolerability and efficacy of elacestrant with these agents is limited even though there are ongoing early-phase clinical trials (NCT05563220 and NCT05386108, n=3 for elacestrant 300 mg/day plus alpelisib 250 mg/day) evaluating the combinations of elacestrant with alpelisib, capivasertib, everolimus or CDK4/6 inhibitors [
40]. Here our precision oncology center, for the first time, showed that elacestrant and alpelisib at doses selected through molecular tumor board discussions was well-tolerated with minor toxicities such as grade 1 asthenia. The ketogenic diet was reported to potentially improve tolerability and efficacy of PI3K inhibitors. Similarly, prophylactic metformin could diminish incidence and severity of hyperglycemia [
41]. Overall, we achieved a partial response in the liver and bone metastatic lesions upon combinatorial treatment (
Figure 2).
Gene fusions are strong oncogenic drivers that can drive tumorigenesis, cancer progression and therapeutic failure. However,
FGFR2-TACC2 rearrangement reported in the FoundationOne Liquid CDx was later predicted to be “not in-frame” upon additional information request from the test provider. It was a result of chromosome 10 duplication fragment with breakpoints at chr10:123241583 and chr10:123788371 [5′- FGFR2 (x1-17) -3′:3′-
TACC2 (x2-1) -5′]. Consistently, Tempus test from the liver biopsy did not report any
FGFR2-TACC2 rearrangement although the alteration was detected at DNA level, it was absent at RNA level. Besides, out-of-frame fusions are often assumed to be inactivating mutations and labeled as passenger mutations [
42,
43,
44]. Considering that RNA-based approach is the gold standard for the detection of structural variants, we initially did not include any FGFR inhibitor in the combination therapy. Similarly, the specimen harbors
CCND1 and
FGF amplifications (albeit equivocal in the F1 Liquid CDx) that can undermine therapeutic benefit. Pan-FGFR inhibitors such as pemigatinib have limited activity against these amplifications [
45]. Multikinase FGFR inhibitors, unlike specific FGFR inhibitors, have also activity against other receptor tyrosine kinases (RTKs), such as VEGFR, which could be upregulated due to the presence of the
TP53 mutation [
46,
47]. For example, lenvatinib in combination with palbociclib was highly active (50% PR) in the FGF/FGFR and accompanying alterations [
48]. Therefore, these alterations should be monitored carefully during the course of treatment.
Overall, HR+/HER2- MBC is a challenging clinical entity to treat, especially after the failure of the SOC and in the heavily pretreated patients. Fortunately, we demonstrated for the first time that all-oral combination of elacestrant plus alpelisib with dose modifications and ketogenic diet was feasible and clinically active in an ESR1 and PIK3CA co-mutated patient. This case underlines the importance of utilizing up-to-date therapeutic agents and reactive decision-making (such as addition of lenvatinib) during personalized cancer treatment. It is also important to note that we should strive to make precision oncology the standard-of-care, not the currently organ-based therapeutic approaches. The timely evaluation and approval of such off-label drug combinations by health authorities could speed up paradigm shift towards precision oncology.