DNA-Guided Second Line Adjuvant Therapy For High Residual Risk, Stage II-III, Hormone Receptor Positive, HER2 Negative Breast Cancer
DNA-Guided Second Line Adjuvant Therapy For High Residual Risk, Stage II-III, Hormone Receptor Positive, HER2 Negative Breast Cancer
A randomized, Phase II trial of circulating tumor DNA-guided second line Adjuvant therapy for
 high Residual risk, stage II-III, Estrogen Receptor positive, HER-2 negative breast cancer
 (DARE)
Surveillance population and ctDNA screening (up to 1000 patients): Clinically high risk,
 stage II-III, ER positive, HER2-, breast cancer patients who are currently receiving adjuvant
 endocrine therapy with an aromatase inhibitor or tamoxifen are eligible for ctDNA screening
 if they meet any one of the following criteria for high risk for recurrence: (i) predicted
 risk of distant recurrence or death equal to or greater than 15% calculated by PREDICT, RSPC,
 or CTS5 (for late recurrence), (ii) four or more positive axillary lymph nodes or ipsilateral
 supraclavicular involvement regardless of tumor size, (iii) primary tumor equal to or greater
 than 5 centimeters regardless of nodal status, (iv) patients with 1-3 positive nodes,
 regardless of tumor size are eligible if at least one of the following is also true: grade 3
 histology, greater than or equal to 3 cm tumor size, high molecular risk score (i.e. Oncotype
 Dx Recurrence score(RS) > 26, MammaPrint high risk, EndoPredict > 4, Prosigna score > 60).

 In order to start ctDNA surveillance, patients must be currently receiving endocrine therapy
 and have completed at least 6 months, but no more than 7 years and with at least 3 more years
 of planned adjuvant endocrine therapy of treatment without distant recurrence. Prior adjuvant
 CDK4/6 therapy is allowed, but at least 12 months must have elapsed since completing CDK4/6
 therapy and enrolling into ctDNA surveillance on this study. However, participants in the
 PENELOPE and PALLAS clinical trials are not eligible.

 For screening, patients will undergo Signatera testing during routine follow up clinic
 visits. The current ASCO/NCCN breast cancer practice guidelines recommend follow up visits
 every 4 to 6 months at the treating physician's discretion. The investigators anticipate that
 screening positivity rates will be the highest in patients between years 1-5 after initial
 diagnosis, based on the annual hazard rates of recurrence in ER positive breast cancer.
 However, since up to 50% of all recurrences occur after 5 years of follow-up, the
 investigators allow starting ctDNA screening up to 7 years after starting adjuvant endocrine
 therapy if a patient meets criteria for high risk.
Inclusion Criteria:

 - 4.1.1. Stage II or III, HER2 negative, ER positive invasive breast cancer in male or
 female patients. For this study, ER positivity is defined as equal to or greater than 10%
 ER positivity by immunohistochemistry, regardless of progesterone receptor (PR) status.
 Patients with PR positive but ER negative cancer are not eligible. HER2 negative status is
 defined as per the ASCO/CAP 2018 practice guidelines.

 (i) if patients have synchronous bilateral ER+ breast cancer tissue from both sites should
 be submitted to Natera to perform ctDNA testing.

 (ii) patients with multifocal/multicentric tumors are eligible and the largest focus of
 cancer should be submitted for testing. All tumors must meet pathological criteria for
 HER2-and ER+ status.

 (iii) For. patients who received neoadjuvant therapy and have discordant ER and HER2
 results between the diagnostic biopsy (pre-treatment) and surgical pathology (post
 neoadjuvant therapy), the ER+ and HER2- status of the post-treatment specimen determine
 eligibility.

 4.1.2. Currently taking an aromatase inhibitor, or tamoxifen, as adjuvant endocrine therapy
 and have completed at least 6 months (i.e. 24 weeks), but no more than 7 years with 3 more
 years planned, of endocrine therapy. Patients may register for the screening phase of the
 study within the first 6 months of adjuvant endocrine therapy but the first ctDNA testing
 must occur at, or after, 6 months of endocrine therapy.

 (i) Adjuvant bisphosphonate therapy is allowed. (ii) LHRH analogues are required for
 premenopausal patients randomized to receive fulvestrant.

 4.1.3. Clinical and pathological high risk for recurrence defined as any one of the
 following: (i) At least a 15% predicted risk of death within 10 years using ePREDICT V2.1
 (https://breast.predict.nhs.uk/tool), or (ii) At least 15% or greater risk of distant
 metastasis within 10 years using RSPC,
 (https://tools.genomichealth.com/Tools/RSPCTool.aspx), or (iii) At least 15% or greater
 risk of distant metastasis within 10 years CTS5 (https://www.cts5-calculator.com) for
 patients who have completed a minimum of 4 years of adjuvant endocrine therapy, or (iv)
 Tumor size > 5 cm, regardless of lymph node status, or (v) 1-3 involved axillary lymph
 nodes and at least one of the following;

 -  Tumor size > 3 cm,

 -  High histological grade (e.g. grade 3).

 -  High genomic risk defined as Oncotype Dx Recurrence Score >26, EndoPredict score >4,
 Prosigna risk of recurrence score ≥ 60, or Mammaprint high risk.

 (vi) Patients who have received pre-operative (neoadjuvant) chemotherapy must have either:

 -  greater than or equal to 3 cm invasive residual cancer regardless of nodal status AND
 grade 3 disease or RS>26/MammPrint High/Prosigna high/Endopredict high status, or

 -  greater than or equal to 1 cm invasive residual cancer (ypT1c) and at least 1 positive
 lymph node (ypN+) AND grade 3 disease, or RS>26, or MammPrint High, or Endopredict
 high or Prosigna high status.

 4.1.4. Patients must have FFPE tissue from the primary tumor available for submission to
 Natera to perform ctDNA assay (see Appendix B for tissue submission instructions).

 4.1.5. Signed and dated informed consent, including willingness to be randomized to
 standard of care versus fulvestrant + palbociclib.

 4.2 Inclusion and exclusion criteria for treatment randomization

 Inclusion criteria for randomization

 4.2.1. ctDNA positivity by the Signatera assay, defined as 2 of the 16 cancer specific
 markers positive in plasma.

 4.2.2. Patients with positive Signatera results obtained in the context of commercial
 testing, outside of the screening phase of this trial, are also eligible for randomization
 if they meet other eligibility criteria.

 4.2.3. No evidence of metastatic disease on CT scan of the chest, abdomen and pelvis.

 -  If imaging, after review with a radiologist, is low probability for metastatic
 disease, patients may proceed to randomization.

 -  Patients with suspicious but inconclusive imaging results should undergo a diagnostic
 biopsy, if biopsy is negative patients are eligible for randomization.

 -  Patients with positive imaging that is conclusive of metastatic disease, or with
 biopsy proven metastatic disease, are not eligible for randomization.

 4.2.4. Pre-menopausal women and male patients must be willing to use an adequate method of
 contraception for the duration of trial treatment and for 4 additional weeks after
 completion of treatment in the control arm, and for 2 years after the last dose of
 fulvestrant, if randomized into the experimental arm.

 Post-menopausal status is defined as:

 -  Documented bilateral oophorectomy.

 -  Age ≥ 60 years.

 -  Age < 60 years and amenorrhoeic for ≥ 12 consecutive months and FSH and estradiol
 levels in the post-menopausal range according to the institutional reference range for
 post-menopausal.

 Adequate contraception is defined as ONE highly effective form (i.e. abstinence, surgical
 sterilization through bilateral tubal ligation, vasectomy), or TWO effective forms (e.g.
 non-hormonal IUD and condom / occlusive cap with spermicidal foam / gel / film / cream /
 suppository).

 - Abstinence is to be interpreted as "true abstinence" for heterosexual intercourse and
 therefore, "periodic abstinence" (e.g. calendar, symptothermal, post-ovulation methods) and
 withdrawal (coitus interruptus) are not considered highly effective.

 Exclusion Criteria

 4.1.5. Prior or current treatment with fulvestrant, or current treatment with a CDK4/6
 inhibitor, or treatment in the prior 12 months, or participants in the PENELOPE and PALLAS
 clinical trials.

 4.1.6. Patients cannot start participation in another therapeutic clinical trial for breast
 cancer after enrollment in this trial.

 4.1.7. Patients with current or past invasive cancer, other than breast cancer are not
 eligible, except:

 -  Adequately treated basal or squamous cell carcinoma of the skin are eligible.

 -  Cancer survivors of previously diagnosed invasive cancer, who were treated with a
 curative intent, have no evidence of disease recurrence for 5 years or more, and are
 considered low risk for future recurrence by the treating physician are also eligible.

 4.1.8. Patients with a second HER2 positive or triple negative synchronous breast cancer
 are not eligible.

 Exclusion criteria for randomization

 4.2.5. Patients with known contraindications to receive fulvestrant and palbociclib or
 those who are unable to tolerate these drugs are not eligible.

 -  Absolute neutrophil count less than <1000/mm3;

 4.2.6. Any concurrent severe and uncontrolled medical condition that would, in the
 Investigator' opinion cause unacceptable safety risks or compromise compliance with the
 protocol including but not limited to:

 -  Impairment of gastrointestinal (GI) function or GI disease that may significantly
 alter the absorption of oral medication (e.g. Crohn's disease, ulcerative diseases,
 uncontrolled chronic nausea, vomiting, diarrhea, malabsorption syndrome, or small
 bowel resection).

 -  History of pneumonitis, interstitial lung disease or pulmonary fibrosis.

 -  Known history of Human Immunodeficiency Virus (HIV) (testing is not mandatory).

 -  Known active Hepatitis B or Hepatitis C (testing is not mandatory).

 -  Females who are pregnant or breastfeeding.

 -  History of bleeding diathesis (i.e. disseminated intravascular coagulation, clotting
 factor deficiency) that preclude the IM injections of fulvestrant or LHRH agonist as
 applicable.

 4.2.7 Patients taking any CYPC3A4 strong inducers and inhibitors, that cannot be changed.