A Phase II Study of Fulvestrant plus Abemaciclib in Hormone Receptor–Positive Advanced or Recurrent Endometrial Cancer Available to Purchase

Endometrial cancer is the most common gynecologic malignancy in the United States. Its incidence is increasing by 1% per year, and approximately 67,880 new diagnoses were predicted in 2023 (1). Although cancer-specific mortality is decreasing overall, endometrial cancer mortality has increased by approximately 1.8% annually since 2000 (2). Most patients with endometrial cancer are diagnosed at an early stage and have a favorable prognosis; however, patients with advanced or recurrent endometrial cancer have poor outcomes, and treatment options are limited (3).

Endocrine therapy is an established therapeutic option for patients with advanced or recurrent endometrial cancer, with response rates ranging from 10% to 30% in prior studies, which included endometrial cancer populations mostly unselected for predictive biomarkers (4–7). Commonly prescribed endocrine therapies include progesterones, the selective estrogen receptor (ER) modulator tamoxifen, aromatase inhibitors, and fulvestrant, a selective ER downregulator (SERD). The highest response rates are observed in patients with grade 1 or grade 2 endometrioid histology; however, the extent and duration of responses with endocrine monotherapy are limited, and no validated threshold for ER positivity has been established in endometrial cancer. Although well tolerated with minimal toxicity, aromatase inhibitors are associated with an objective response rate (ORR) of only 10% in advanced endometrial cancer and a median progression-free survival (PFS) of 1 to 3.9 months, even in ER-positive disease (8–10).

Two single-arm phase II studies of 250 mg of fulvestrant, a single-agent SERD, given intramuscularly every 4 weeks in patients with recurrent or advanced endometrial cancer were published in 2011 and 2013, respectively. In the 2011 study by Gynecologic Oncology Group, among the 31 patients enrolled with ER-positive disease and treated with fulvestrant, 1 (3%), 4 (13%), and 9 patients (29%) showed a complete response, partial response, and stable disease, respectively (11). Within the German working group Gynecological Oncology trial, 28 patients with ER-positive or progesterone receptor (PgR)–positive disease were treated with 250 mg of fulvestrant intramuscularly every 4 weeks, of whom four (14%) had a partial response (12).

Inhibition of the cyclin D–cyclin-dependent kinase (CDK)4/6–INK4–retinoblastoma (Rb) pathway has demonstrated the ability to overcome acquired or de novo treatment resistance to endocrine monotherapy in advanced ER-positive breast cancer, leading to the regulatory approval of multiple CDK4/6 inhibitors in combination with endocrine therapy in this disease (13, 14). In contrast to palbociclib and ribociclib, which solely inhibit CDK4 and CDK6, abemaciclib also inhibits CDK9 (15). CDK4 and CDK6 activation is required for cell-cycle progression by regulating the G₁–S phase transition via phosphorylation of Rb, and dysregulation promotes oncogenesis. The cyclin D–CDK4/6–INK4–Rb pathway is aberrantly activated in cancer cells through gene amplification or rearrangement, loss of negative regulators, epigenetic alterations, and point mutations in key pathway components, though CDK2NA loss has not predicted sensitivity to CDK4/6 inhibition in clinical studies (16, 17). Elevated CDK4 expression is observed in 34% to 77% of endometrioid endometrial cancer and is considered an early event of neoplastic transformation (18, 19).

Given the CDK4/6 activity observed in endometrial cancer cells and the potential to leverage this pathway to overcome resistance to endocrine therapy in endometrial cancer, we hypothesized that CDK4/6 inhibition with abemaciclib plus fulvestrant is a promising therapeutic strategy to improve outcomes among patients with ER- or PgR-positive endometrial cancer. To test this hypothesis, we designed a phase II trial to evaluate efficacy in terms of the ORR of abemaciclib with fulvestrant for the treatment of recurrent or advanced hormone receptor (HR)–positive endometrial cancer. Molecular classification is increasingly used for prognostication and the prediction of therapeutic response in the management of endometrial cancer (20–23); thus, we also examined associations between tumor molecular subtypes and response to combined abemaciclib and fulvestrant.

This was an investigator-initiated, open-label, single-arm phase II study at Memorial Sloan Kettering Cancer Center (MSKCC). Patients were scheduled to receive 500 mg of fulvestrant monthly with an initial 2-week loading dose and 150 mg of abemaciclib orally twice daily until disease progression or prohibitive toxicity. The study was approved by the MSKCC Institutional Review Board and conducted in accordance with the precepts set forth by the Declaration of Helsinki. Abemaciclib was supplied by Eli Lilly and Company. This study was registered with the NIH (ClinicalTrials.gov identifier: NCT03643510). Written informed consent was obtained from all patients or their guardians before enrollment in the study.

The trial was designed to evaluate the activity of abemaciclib plus fulvestrant as measured by the primary endpoint, ORR, defined as the percentage of patients with a complete response or partial response by RECIST v1.1. Secondary endpoints included clinical benefit rate (defined as the percentage of patients with a complete or partial response or stable disease ≥16 weeks), PFS, overall survival (OS), duration of response, and the safety and tolerability of the combination. Exploratory analyses examined the association with response across specific biomarkers and molecular subgroups.

All patients were at least 18 years of age and had recurrent or persistent endometrial cancer refractory to curative therapy that was HR-positive by IHC. HR positivity was confirmed at MSKCC and defined as expressing at least one of the HRs (ER or PgR as defined in the relevant American Society of Clinical Oncology/College of American Pathologists guidelines in breast cancer) on either the primary or recurrence tissue (24). ER or PgR assays were considered positive if there were at least 1% positive tumor nuclei. Patients with the following histologic epithelial cell types were eligible: endometrioid adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma, dedifferentiated carcinoma, clear-cell adenocarcinoma, mixed epithelial carcinoma, adenocarcinoma not otherwise specified, mucinous adenocarcinoma, squamous cell carcinoma, and transitional cell carcinoma. For mixed epithelial cell type endometrial carcinomas, the endometrioid component was required to comprise at least 95% of the total tumor, with the nonendometrioid component comprising <5% of the total tumor.

Patients were required to exhibit an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate bone marrow function, renal function, and hepatic function. All patients were required to have measurable disease, defined as one or more target lesions per RECIST v1.1. Tumors within a previously irradiated field were designated as “nontarget” lesions unless progression was documented, or a biopsy was obtained to confirm the persistence of the tumor ≥90 days following completion of radiation therapy.

Patients were not required to but may have received no more than two prior chemotherapeutic regimens, including chemotherapy, small-molecule inhibitors, and/or immunotherapy, for the management of endometrial cancer. Adjuvant chemotherapy and chemotherapy administered in conjunction with primary radiation therapy as a radiosensitizer were counted as systemic chemotherapy regimens. Patients were not required to but may have received a single line of prior hormonal therapy with either an antiestrogen, antiprogesterone (or combination), or an aromatase inhibitor; these treatments did not count toward total prior therapy.

Archival formalin-fixed, paraffin-embedded specimens were obtained from enrolled patients to perform clinical tumor-normal panel sequencing to assess somatic mutations and copy number alterations in >500 cancer-related genes. Matched tumor and blood samples from patients were analyzed using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay (25). Molecular subtype classification, including the DNA mismatch repair–deficient/microsatellite instability–high (MSI-H), POLE, copy number–high (CN-H)/TP53abnormal (abn), and copy number–low (CN-L)/no specific molecular profile (NSMP) subtypes, was performed using an integrated molecular and IHC-based approach, as recently described (26).

For the primary endpoint analysis (ORR), the null hypothesis was based on historical data from studies with ineffective agents in a similar patient population, which have an ORR <10% and a PFS rate at 6 months of <20% (11, 27–30). Using an exact, one-sample test for binomial proportion with a one-sided type 1 error of 10%, a sample size of 25 patients provided 90% power to test the hypothesis that the response rate was promising (defined as 30% or higher) against the null hypothesis of 10%. At the end of the study, if at least five responses among 25 patients were observed, then we would reject the null hypothesis and deem the ORR promising.

PFS was defined as the time from the date of treatment start until the first date of progression or death due to any cause. The duration of response was defined as the time from which criteria were met for complete or partial response (whichever was recorded first) until the date of progression or death due to any cause. OS was defined as the time from treatment start to the date of death due to any cause. Participants alive without disease progression were censored at the date of the last follow-up. Patients with any post-baseline assessment of efficacy response were considered evaluable for efficacy.

Fisher exact tests were used for exploratory analyses examining the association between objective response outcomes and biomarkers and molecular alterations, respectively. The Kaplan–Meier method was applied to obtain the median survival time and survival rate at a certain time; the 90% confidence interval (CI) was reported to reflect the power of the design. The first participant was enrolled in October 2018. On July 6, 2023, after enrolling 25 evaluable patients, the study was closed to further enrollment. All analyses were conducted using R 4.3.1 (https://ww.R-project.org).

The raw sequencing data for the MSK-IMPACT cohort are protected and are not broadly available due to privacy laws. Raw data may be requested from the corresponding author ([email protected]) with appropriate institutional approvals. Targeted sequencing data that support the findings of this study are available at cBioPortal [https://www.cbioportal.org/study/summary?id=uec_msk_2024, “Endometrial cancer HR-positive (MSK, Clin Cancer Res 2024)”]

A total of 27 patients enrolled and initiated protocol therapy (Table 1; Supplementary Fig. S1; Supplementary Table S1). Twenty-five patients were considered evaluable for efficacy. Two patients enrolled, initiated therapy, and subsequently withdrew consent (due to COVID-19 and grade 1 diarrhea, respectively) prior to completing one cycle of therapy. Patient characteristics are included in Table 1. The median age of patients at enrollment was 66 years. Twenty-four patients (89%) had tumors with endometrioid histology, 20 (83%) of whom had grade 1 or 2 histology and 4 (17%) of whom had grade 3 histology. Eleven patients (41%) received a prior line of hormonal therapy (including two patients who withdrew consent), and all patients had received at least one prior line of systemic therapy. The median follow-up time was 16.8 months (range, 0.9–43.8).

Among the 25 evaluable patients at data cutoff (October 7, 2023), 11 patients achieved a partial response per independent central review; the ORR of 44% (90% CI, 27.0%–62.1%) met the predefined criteria that the response rate is promising and warrants further evaluation. All responses were in patients with grade 1 or 2 endometrioid tumors, seven with grade 1 endometrioid tumors, and four with grade 2 endometrioid tumors. Ten (91%) of the 11 responses were observed in patients with CN-L/NSMP tumors, whereas one response (9%) was observed in a patient with an MSI-H tumor. A waterfall plot of the best responses is shown in Fig. 1. The median duration of response among patients who experienced a response was 15.6 months (90% CI, 7.2–nonestimable). Eight responses (50%) were observed among 16 patients who did not receive prior hormonal therapy, whereas 3 responses (33%) were observed among 9 patients who did receive prior hormonal therapy. Six patients (24%) had a best response of stable disease (Fig. 1). One patient with stable disease and a grade 3 endometrioid tumor that was CN-L/NSMP developed a partial response shortly after data cutoff and remains on study with a partial response for over 22 weeks. The clinical benefit rate was 44% (90% CI, 28.0%–61.8%). The median PFS was 9.0 months (90% CI, 1.8–20.4), and the median OS was 37.8 months (90% CI, 16.3–nonestimable; Fig. 2).

Eight patients (32%) had disease progression at their first evaluation. None of these patients discontinued therapy early. Two patients with endometrioid endometrial cancer, grades 1 and 3, respectively, were nonevaluable for efficacy. One patient experienced grade 1 diarrhea related to abemaciclib and withdrew consent before restaging imaging could be performed, and the other patient had a clinical decline unrelated to protocol therapy and due to COVID-19 and withdrew consent before restaging imaging could be performed. A swimmer plot for all patients with evaluable disease is presented in Fig. 3.

There were no grade 5 toxicities. The most common grade ≥3 treatment-related adverse events (TRAE) were neutropenia (seven patients, 26%) and anemia (five patients, 19%). All grade 3 TRAEs and any TRAEs that occurred in at least 20% of patients are presented in Table 2. Diarrhea, a known toxicity of abemaciclib, was observed in 24 patients (89%), all of which were grade 1 or 2. Consistent with prior research, reversible grade 1 or 2 increases in creatinine were observed in six patients (22%). Ten patients (37%) required a dose reduction of abemaciclib. Three patients (11%) discontinued therapy because of toxicity. One patient experienced grade 4 neutropenia, and another experienced grade 4 elevation in aspartate aminotransferase, both deemed related to abemaciclib. The patient with grade 4 neutropenia developed enterocolitis necessitating hospitalization with subsequent recovery. The grade 4 aminotransferase elevation resolved with dose hold, and abemaciclib was restarted at the first dose reduction. The patient received another dose reduction due to the recurrence of grade 2 transaminitis with no subsequent issues. This patient remains on study for over 20 months and continues to derive treatment benefits.

All 27 patients who initiated therapy received targeted panel sequencing, 26 patients by MSK-IMPACT and one patient by FoundationOne CDx. For the 25 evaluable patients, the molecular subtype distribution was as follows: 17 patients (68%) had CN-L/NSMP tumors, 4 patients (16%) had MSI-H tumors, four patients (16%) had CN-H/TP53abn tumors, and none had a POLE hotspot mutation (Fig. 4; Supplementary Table S2). One endometrial cancer was p53 aberrant by IHC and had high levels of chromosomal instability (fraction of the genome altered of 50.2%), and thus was classified as CN-H/TP53abn despite not harboring a somatic TP53 mutation (Supplementary Table S3). Ten (59%) of the 17 patients with CN-L/NSMP tumors had a partial response. Among the four patients with MSI-H tumors, one had a partial response, and three derived no clinical benefit. Among four patients with CN-H/TP53abn tumors, none demonstrated an objective response or derived clinical benefit. Patients with CN-L/NSMP tumors were significantly more likely to have a response to treatment than patients with other molecular subtypes (ORR, 59% vs. 13%; P = 0.042). Ten patients had CTNNB1 hotspot mutations, six (60%) of whom had a partial response, all with CN-L/NSMP subtype. Seven patients had KRAS hotspot mutations, two (29%) of whom had a partial response and CN-L/NSMP subtype. Alterations in PI3K pathway genes, including PTEN, PIK3CA, and PIK3R1, were found in 20 patients, of whom 9 (45%) had a partial response. One patient (3.7%) had an ESR1 p.Y537S hotspot mutation in the primary tumor; she had a partial response to treatment and remains on study with a duration of response of over 18 months at the data cutoff. She received no prior endocrine therapy but was pretreated with paclitaxel and carboplatin and lenvatinib plus pembrolizumab.

In this study, treatment with abemaciclib plus fulvestrant resulted in durable antitumor activity for patients with HR–positive endometrial cancer, with an acceptable safety profile. TRAEs were comparable with those in prior studies of patients with endometrial or breast cancer who received endocrine therapy combinations with CDK4/6 inhibitors (31). No new safety signals were identified.

In the present study, abemaciclib and fulvestrant demonstrated an ORR of 44% and a median PFS of 9.0 months, further supporting the promising activity of CDK4/6 endocrine combinations observed in three prior studies in patients with advanced endometrial cancer. Konstantinopoulos and colleagues (32), who examined the efficacy of abemaciclib and letrozole in a single-arm phase II trial among 35 patients with ER-positive endometrial cancer, demonstrated an ORR of 30% and a median PFS of 9.1 months (95% CI, 3.5–16.5). NSGO-PALEO/ENGOT-EN3, a randomized study examining the efficacy of palbociclib plus letrozole versus letrozole alone in patients with advanced ER-positive endometrioid endometrial cancer, also showed improved PFS in patients treated with the combination compared with letrozole alone (median PFS, 8.3 vs. 3.0 months; HR, 0.56; 95% CI, 0.32–0.98; P = 0.041; ref. 33). A study by Colon-Otero and colleagues (34) also examined the efficacy of ribociclib plus letrozole in a single-arm study in ER-positive ovarian and endometrial cancers, which demonstrated a median PFS of 5.4 months (95% CI, 3.1–11.8) among the 20 patients included in the endometrial cancer cohort.

Endometrial cancers are genetically heterogeneous, and molecular classification is increasingly used to predict therapeutic responses and to identify patients who may benefit from novel therapeutics (18, 20). Almost all responses (91%) in this study were in patients with CN-L/NSMP tumors, and the ORR was higher among patients with CN-L/NSMP tumors compared with the overall population (59% vs. 44%). Four patients with CN-H/TP53abn tumors were enrolled in the study, and none derived clinical benefit. These results suggest that CN-L/NSMP molecular subtype or alternatively, p53 wild-type status by IHC based on the more pragmatic Proactive Molecular Risk Classifier for Endometrial Cancer (35), may serve as a positive predictive biomarker for response to endocrine therapy combinations and could inform the design of future phase III clinical trials. Agreement between p53 IHC and TP53 next-generation sequencing was observed in 90.7% of endometrial cancers included in a retrospective cohort from the PORTEC-3 trial, resulting in a sensitivity and specificity of 83.6% and 94.3%, respectively. Thus, p53 wild-type status by IHC is an acceptable biomarker when comprehensive molecular profiling is unavailable (36). Notably, the presence of TP53 mutation is associated with decreased response among patients with ER-positive breast cancer treated with CDK4/6 inhibitors as well (17, 37).

The role of endocrine therapy was less clear for patients with MSI-H/hypermutated tumors. One of 4 patients with an MSI-H tumor in this study had a durable response to abemaciclib plus fulvestrant, and a second patient-derived clinical benefit with stable disease for 19 weeks. The patient with a response was previously treated with platinum-based chemotherapy, Lupron, and pembrolizumab and was treated on trial with abemaciclib and fulvestrant for 21.2 months; ER showed 100% nuclear staining with strong intensity. Thus, a subset of MSI-H tumors may be hormonally dependent, warranting further exploration of combined endocrine therapy plus CDK4/6 inhibitor treatment in this subgroup. Three of nine patients who received prior endocrine therapy (with Lupron, letrozole, and tamoxifen plus Megace, respectively) had a response to abemaciclib and fulvestrant, indicating that combination endocrine therapy can still be effective despite prior treatment, and CDK4/6 inhibition may overcome secondary hormonal resistance arising in endometrial tumors.

We conducted exploratory analyses of molecular data regarding the presence of mutations involved in the PI3K and Wnt/β-catenin pathway genes, which are commonly altered in endometrioid endometrial cancer (38). These pathways have been associated with the development of endocrine resistance in breast malignancies and have been shown to upregulate cyclin D1 with the subsequent activation of CDK4/6 (39–41). We found no apparent association between the presence of PI3K pathway gene, KRAS, or CTNNB1 mutations, respectively, and response to abemaciclib and fulvestrant.

Treatment with combined endocrine therapy plus CDK4/6 inhibitor for eligible subgroups offers a favorable toxicity profile for patients with advanced endometrial cancer compared with standard options such as lenvatinib and pembrolizumab or chemotherapy. Everolimus plus letrozole is the only other guideline-concordant endocrine combination therapy recommended in advanced endometrial cancer. In a randomized phase II trial among patients with advanced or recurrent endometrial cancer treated with zero or one prior line of chemotherapy, everolimus plus letrozole demonstrated an ORR of 22% (95% CI, 11%–37%) and a median PFS of 6 months (95% CI, 4–18), compared with 4 months (95% CI, 3–6) in patients treated with medroxyprogesterone acetate alternating with tamoxifen (42).

As hypothesized, CDK4/6 inhibition in endometrial cancer can overcome resistance to endocrine therapy in advanced disease, significantly improving on the limited responses historically observed with single-agent aromatase inhibitors or SERDs. Compared with ribociclib and palbociclib, abemaciclib has more gastrointestinal toxicity but has demonstrated less neutropenia, higher single-agent activity in breast cancer possibly due to its CDK9 inhibition, and can be dosed continuously (15). Ribociclib, palbociclib, and abemaciclib have demonstrated similar PFS benefits in combination with endocrine therapy among patients with advanced breast cancer (43); however, direct comparative evaluation has been limited, and it is uncertain, based on studies so far, which agent would be optimal in the treatment of endometrial cancer.

Our study suggests that CDK4/6 inhibition combined with a SERD, as opposed to an aromatase inhibitor, may result in better treatment responses, given the ORR of 44% observed in the present study versus 30% in the study by Konstantinopoulos and colleagues (32). Patients may have been more heavily pretreated in Konstantinopoulos and colleagues’s (32) study, however, given no exclusions on prior lines of therapy.

Resistance to endocrine therapy in breast cancer can develop through ESR1 (ER alpha) mutations resulting in estrogen-independent activation of the ER, thus rendering aromatase inhibitors ineffective but not SERDs (44). ESR1 mutations are relatively uncommon in newly diagnosed breast cancer but are acquired frequently in metastatic or recurrent disease after treatment with aromatase inhibitors (45, 46). Estrogen signaling in endometrial cancer, however, is less clear. In a large cohort of patients with gynecologic malignancies and no information on prior treatment, ESR1 mutations were found in 4.4% of endometrioid endometrial cancers (47). Further research is needed to elucidate the frequency of ESR1 mutations in advanced or recurrent endometrial cancer previously treated with endocrine therapy. Other factors, such as PI3K pathway hyperactivation and amplification of cyclin D1, may play a role in the development of estrogen-independent activation of ER alpha, which could further support the use of SERDs over aromatase inhibition in endometrial tumors (48, 49).

Despite the possibility that CDK4/6 and SERD combinations may be more effective than CDK4/6 and aromatase inhibitor combinations, the clinical practicality of fulvestrant is limited due to its lack of oral bioavailability and need for administration through intramuscular injection. Furthermore, some data suggest that suboptimal occupancy of the ER still occurs with fulvestrant at the 500 mg dose (50, 51). Novel oral SERDs, such as elacestrant, have recently been developed that degrade ER α in a dose-dependent manner, inhibit estrogen-dependent ER-directed gene transcription and tumor growth in in vitro and in vivo preclinical models, and have improved pharmacokinetic properties compared with fulvestrant (52). These novel endocrine therapies may offer superior efficacy when combined with CDK4/6 inhibitors for the treatment of advanced ER-positive endometrial cancer and are worthy of further exploration.

In conclusion, our study demonstrated that the combination of abemaciclib and fulvestrant has promising activity in patients with recurrent or advanced endometrial cancer, with a greater benefit observed in patients with CN-L/NSMP molecular subtypes. A randomized phase III trial examining the efficacy of CDK4/6 inhibition in combination with endocrine therapy in patients with p53 wild-type by IHC advanced or recurrent endometrial cancer is planned.

A.K. Green reports other support from Eli Lilly and Company and grants from NIH/NCI Cancer Center Support Grant during the conduct of the study, as well as personal fees from Merck and Stemline Menarini and other support from Aadi Bioscience, Mereo BioPharma, DualityBio, and Cullinan Therapeutics outside the submitted work. Q. Zhou reports grants from NIH during the conduct of the study. B. Weigelt reports grants from Repare Therapeutics and SAGA Diagnostics outside the submitted work. J. Erinjeri reports other support from AstraZeneca outside the submitted work. S. Chandarlapaty reports other support from Eli Lilly and Company and Totus; grants and personal fees from Daiichi Sankyo and AstraZeneca; and personal fees from Casdin Capital, Nuvalent, Blueprint Medicines, eFFECTOR Therapeutics, SAGA Diagnostics, and Novartis outside the submitted work. S. Cohen reports grants from Eli Lilly and Company during the conduct of the study. R. Grisham reports other support from Gynecologic Oncology Group Partners, AstraZeneca, GSK, Myriad, Incyte, and Genmab outside the submitted work, as well as consulting for OncLive, MJH Health, and Cardinal Health. J. Konner reports consultant fee from AstraZeneca, unrelated to this study. M.M. Rubinstein reports grants from AstraZeneca, Merck, Faeth Therapeutics, Duality Biologics, Debiopharm, and Summit Therapeutics outside the submitted work. C. Aghajanian reports personal fees from WCG, AstraZeneca, and Merck; other support from Gynecologic Oncology Group Foundation (board of directors) and NRG Oncology (board of directors); and clinical trial funding to MSKCC outside the submitted work. V. Makker reports grants from Eli Lilly and Company during the conduct of the study, as well as grants from AstraZeneca, Bristol Myers Squibb, Cullinan, Duality Biologics, Eisai, Merck, Mereo, Karyopharm, Zymeworks, and Takeda and personal fees from AstraZeneca, Merck, Eisai, and Karyopharm outside the submitted work. No disclosures were reported by the other authors.

A.K. Green: Conceptualization, data curation, formal analysis, funding acquisition, investigation, methodology, writing–original draft, writing–review and editing. Q. Zhou: Data curation, formal analysis, investigation, methodology. A. Iasonos: Data curation, formal analysis, investigation, methodology. W.A. Zammarrelli III: Data curation, investigation. B. Weigelt: Formal analysis, investigation, visualization, writing–review and editing. L.H. Ellenson: Investigation. R. Chhetri-Long: Data curation, project administration. P. Shah: Data curation, project administration. J. Loh: Data curation, project administration. V. Hom: Investigation. P. Selenica: Investigation. J. Erinjeri: Investigation, writing–review and editing. I. Petkovska: Investigation, writing–review and editing. S. Chandarlapaty: Writing–review and editing. S. Cohen: Investigation. R. Grisham: Investigation. J. Konner: Investigation. M.M. Rubinstein: Investigation. W. Tew: Investigation. T. Troso-Sandoval: Investigation. C. Aghajanian: Conceptualization, supervision, investigation, visualization, writing–review and editing. V. Makker: Conceptualization, supervision, funding acquisition, investigation, visualization, writing–review and editing.

This work was supported in part by an NIH/NCI Cancer Center Support Grant (P30 CA008748). Research reported in this publication was supported in part by a Cancer Center Support Grant of the NIH/NCI (grant number P30CA008748) and by funding from Eli Lilly and Company. B. Weigelt is supported in part by Cycle for Survival, Breast Cancer Research Foundation grants, and NIH 1P50CA247749-01 grants.