Patient case: 73-year-old female with breast cancer; genetic feature: CDKN2A

Clinical trial: Neoadjuvant Lenvatinib Combined With Letrozole in Hormone Receptor Positive Breast Cancer

Summary: Background: Endocrine therapy is the standard treatment for hormone receptor positive breast cancer. However, both primary and acquired resistance occurs, and better strategies to improve treatment outcome and overcome resistance are urgently needed. There is known cross talk between RET and ER, and preclinical studies have suggested that combining a RET inhibitor with endocrine therapy may improve cell kill in breast cancer cell lines.
  Aim: To determine the safe dose of lenvatinib that can be co-administered with letrozole in a phase Ib study, followed by a phase II study to determine the efficacy of lenvatinib + letrozole in post-menopausal patients newly diagnosed with hormone receptor positive breast cancer in the neoadjuvant setting.
  Methods: Eligible patients will be treated with 2 weeks of single agent lenvatinib, followed by 12 weeks of lenvatinib + letrozole. Blood and tumor samples will be obtained from the patient serially to study tumor and host factors that may influence drug efficacy and toxicity.
  Importance of the proposed research: The combination of lenvatinib + letrozole may improve the treatment response in some ER+ breast cancers. The study will seek to identify biomarkers (eg tumor RET expression) that may select patients most likely to benefit from the combination therapy.
  Potential benefits and risks: The combination may improve treatment response. Adding lenvatinib may increase treatment risks, but these will be monitored closely. Pharmacokinetic analyses will also be performed to determine the drug levels achieved in the patients, and correlate that with treatment toxicity and efficacy.

Detailed description: Breast cancer is the commonest cancer among females in Singapore and worldwide. Approximately 60-70% of breast cancers are hormone receptor positive and thus potentially sensitive to endocrine therapy. However, both primary and acquired resistance to endocrine therapy exists, and better combinations are constantly being explored to delay endocrine resistance and improve treatment outcome. Several known mechanisms of endocrine resistance have been proposed, and include deregulation of various components of the ER pathway itself, alterations in cell cycle and cell survival signaling molecules, and the activation of escape pathways that can provide tumors with alternative proliferative and survival stimuli.
  Endocrine blockade in breast cancer can be achieved by reducing the levels of estrogens through ovarian ablation (medical, surgical, or through radiation) in pre-menopausal women or with the administration of aromatase inhibitors in post-menopausal women. Direct inhibition of estrogen receptors can be achieved by administering selective estrogen receptor modulators, such as tamoxifen, or a pure estrogen receptor antagonist such as fulvestrant. In post-menopausal women with advanced breast cancer, current standard first-line endocrine therapy comprises of a reversible aromatase inhibitor such as letrozole or anastrozole. Other endocrine therapy options in advanced breast cancers include a irreversible aromatase inhibitor (exemestane), tamoxifen, megestrol acetate, and more novel combinations of an aromatase inhibitor with fulvestrant (combined estrogen blockade), exemestane combined with an mTOR inhibitor (everolimus), or letrozole combined with a CDK4/6 inhibitor (palbociclib).
  RET is an estrogen response gene, and preclinical studies have demonstrated cross talk between RET and ER. Significant interactions between RET and ERa pathways have been described, with increased response to estrogen stimulation observed in the presence of functional RET. RET is associated with resistance to tamoxifen and aromatase inhibitors, and increased RET expression has been demonstrated in hormone resistant cell lines and primary tumors. Combined anti-estrogen and anti-RET therapy in luminal breast cancer had a greater effect on cell growth than either therapy alone. The two classes of drugs have different mechanisms of action; a RET TKI reduced growth through induction of apoptosis, while anti-ERa reduced cell proliferation, forming the biologic basis for dual treatment. Dual therapy with tamoxifen and vandetinib, a RET inhibitor, resulted in greater reduction in tumor growth rate in MCF7 xenografts in mice. RET has been reported to be over-expressed in up to 75% of ER+ breast cancers (n=20), compared to only 10% of ER-negative breast cancers (n=10) in a small study.

Eligibility: Inclusion Criteria:
  -  Female, age ≥18 years.
  -  Histologic or cytologic diagnosis of breast carcinoma.
  -  T1-4 breast cancer with measurable primary breast tumor, defined as palpable tumor with both diameters 2.0cm or greater as measured by caliper. Newly diagnosed metastatic patients with measurable primary breast tumor ≥2cm are eligible provided that there are plans for toilet mastectomy after completing 14 weeks of pre-operative drug therapy.
  -  Patients must not have received prior chemotherapy or hormonal therapy for the treatment of the current breast cancer.
  -  ECOG 0-1.
  -  Estimated life expectancy of at least 12 weeks.
  -  Adequate organ function including the following:
  -  Bone marrow:
  Absolute neutrophil (segmented and bands) count (ANC) ≥ 1.5 x 10^9/L Platelets ≥ 100 x 10^9/L
  Hepatic:
  -  Bilirubin <= 1.5 x upper limit of normal (ULN),
  -  ALT or AST <= 2.5x ULN, (or <=5 X with liver metastases)
  -  Renal:
  Creatinine <= 1.5x ULN
  -  Post-menopausal women. Post-menopausal status is defined either by
  -  Age ≥ 60 years and one year or more of amenorrhea
  -  Age < 60 years and one year or more of amenorrhea (in the absence of ovarian suppression) and with estradiol and FSH levels consistent with menopause, *Treatment with a luteinizing hormone-releasing hormone (LHRH) agonist (goserelin acetate or leuprolide acetate) is not permitted for induction of ovarian suppression.
  -  Signed informed consent from patient or legal representative.
  Exclusion Criteria:
  -  Prior treatment for locally advanced or metastatic breast cancer.
  -  Treatment within the last 30 days with any investigational drug.
  -  Concurrent administration of any other tumor therapy, including cytotoxic chemotherapy, hormonal therapy, and immunotherapy.
  -  Major surgery within 28 days of study drug administration.
  -  Active infection that in the opinion of the investigator would compromise the patient's ability to tolerate therapy.
  -  Pregnancy.
  -  Breast feeding.
  -  Serious concomitant disorders that would compromise the safety of the patient or compromise the patient's ability to complete the study, at the discretion of the investigator.
  -  Active bleeding disorder or bleeding site.
  -  Non-healing wound.
  -  Poorly controlled diabetes mellitus.
  -  Second primary malignancy that is clinically detectable at the time of consideration for study enrollment.
  -  Symptomatic brain metastasis.
  -  History of significant neurological or mental disorder, including seizures or dementia.

Relevance to patient case: not relevant