• Incidence of adverse events [ Time Frame: Up to 60 days ]
  Adverse events will be monitored and graded with attribution assigned using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. For each type of adverse event (AE) reported, the proportion of patients experiencing a grade 2 or worse level of that AE will be determined.
• Changes in vimentin expression [ Time Frame: Up to 60 days ]
  Vimentin expression will be evaluated by immunohistochemistry (IHC) with using 0, 1+, 2+ or 3+ scoring scheme. A point estimate of the proportion of eligible patients whose post-NAC residual tumor Vimentin expression levels were 2+ or 3+ and then fell to 0 or 1+ after abemaciclib among the eligible patients whose began abemaciclib treatment after a post NAC residual tumor Vimentin expression level finding of 2+ or 3+ will be calculated. A 90% confidence interval for this proportion will be constructed using one-sample binomial confidence for proportions.
• Impact of length of treatment [ Time Frame: Up to 60 days ]
  Association between amount of abemaciclib received and the change in CD8/FOXP3 ratio after abemaciclib will be explored graphically. A plot of the change in change in CD8/FOXP3 ratio after abemaciclib and days of treatment will be constructed to visually assess for trends. Also, the a 90% confidence interval for the difference in binomial proportions will be constructed to assess whether the proportion of patients whose post abemaciclib CD8/FOXP3 ratio >= 1.6 after completing 14-21 days of abemaciclib differs between those who discontinued abemaciclib the day prior to surgery and who discontinued abemaciclib 2 or more days prior to surgery. A 90% binomial confidence interval for the proportion of women who failed to complete 14-21 days of abemaciclib or underwent surgery or breast biopsy 2 or more days after last dose of abemaciclib among the eligible women who began abemaciclib treatment.

• Incidence of adverse events [ Time Frame: Up to 60 days ]
  Adverse events will be monitored and graded with attribution assigned using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. For each type of adverse event (AE) reported, the proportion of patients experiencing a grade 2 or worse level of that AE will be determined.
• Changes in vimentin expression [ Time Frame: Up to 60 days ]
  Vimentin expression will be evaluated by immunohistochemistry (IHC) with using 0, 1+, 2+ or 3+ scoring scheme. A point estimate of the proportion of eligible patients whose post-NAC residual tumor Vimentin expression levels were 2+ or 3+ and then fell to 0 or 1+ after abemaciclib among the eligible patients whose began abemaciclib treatment after a post NAC residual tumor Vimentin expression level finding of 2+ or 3+ will be calculated. A 90% confidence interval for this proportion will be constructed using one-sample binomial confidence for proportions.

• Changes in mitoses [ Time Frame: Up to 60 days ]
  Examined graphically overall and by triple negative breast cancer (TNBC) subtypes.
• Changes in nuclear pleomorphism [ Time Frame: Up to 60 days ]
  Examined graphically overall and by TNBC subtypes.
• Changes in tubule formation [ Time Frame: Up to 60 days ]
  Examined graphically overall and by TNBC subtypes.
• Changes in tumor Ki-67 [ Time Frame: Up to 60 days ]
  Examined graphically overall and by TNBC subtypes.
• Changes in serum tyrosine kinase inhibitor (TKI) [ Time Frame: Up to 60 days ]
  Examined graphically overall and by TNBC subtypes.
• Changes in SNAIL [ Time Frame: Up to 60 days ]
  Examined graphically overall and by TNBC subtypes.
• Changes in SLUG [ Time Frame: Up to 60 days ]
  Examined graphically overall and by TNBC subtypes.
• Changes in E-Cadherin [ Time Frame: Up to 60 days ]
  Examined graphically overall and by TNBC subtypes.
• Changes in tumor-infiltrating lymphocytes [ Time Frame: Up to 60 days ]
  Examined graphically overall and by TNBC subtypes.
• Effect of abemaciclib on tumor ribonucleic acid (RNA)-sequencing (seq) data [ Time Frame: Up to 60 days ]
  Effect of abemaciclib on tumor RNA sequencing followed by standard and customized pathway and enrichment analysis (e.g., Gene set enrichment analysis (GSEA) and CIBERSORT methods). The GSEA method determines whether an a priori set of genes are over-represented in the differential expression analysis of the pre- and post- drug response phenotypes. Similarly, CIBERSORT estimates cell composition from RNA transcriptomic data (e.g. immune cell populations).
• Effect of abemaciclib on the phenotype of peripheral blood mononuclear cells (PBMC) [ Time Frame: Up to 60 days ]
  Will be assessed using mass cytometry (e.g,. CyTOF) to analyze a panel of 29 cell surface markers optimized for identification of human immune cell subsets, including the following targets: CD45, CD195 (CCR6), CD19, CD127, CD38, IgD, CD11c, CD16, CD194 (CCR4), CD123/IL-3R, TCRgd, CD185 (CXCR5), CD3, CD45RA, CD27, CD29, CD66b, CD183 (CXCR3), CD161, CD45RO, CD197 (CCR7), CD8a, CD25/IL-2R, CD20, HLA-DR, CD4, CD14, CD56/NCAM. Identification of specific immune cell subsets will be assessed using consensus clustering methods of predefined combination of markers.
• Effect of abemaciclib on formalin-fixed paraffin-embedded (FFPE) tumor sections [ Time Frame: Up to 60 days ]
  Will include (imaging mass cytometry multiplex quantitative RNA/protein immune-based profilings, such as Hyperion TM, Nanostring GeoMX, Codex, and may include the examination of genes directly involved in tumor cell antigen presentation (e.g. B2M, HLA-A, HLA-B, HLA-C, TAP1, TAP2, TAPBP), interferon-stimulated genes (ISGs) that regulate antigen presentation (e.g. STAT1, NLRC5) and other ISGs (e.g. IRFs, OAS2), genes involved in double strand RNA response (e.g. DDX58, DHX58), genes encoding interferons, including type 3 IFNs (e.g. IFNL1, IFNL2, IFNL3), genes indicating a cytotoxic T cell response (e.g. PRF1, GZMB), regulatory T cell-specific transcription factor genes (e.g., FOXP3, IKZF2)
• Change in in frequency of JAK-2 amplifications [ Time Frame: Baseline up to time of surgery ]
  The collection of JAK-2 will be used to assess the difference in the frequency of JAK-2 amplification among patients whose post-abemaciclib CD8/FOXP3 ratio >= 1.6 and that among patients whose post-abemaciclib CD8/FOXP3 ratio < 1.6. A 95% binomial confidence for the difference in two independent proportions will be constructed for the difference in the percentage of patients with a post-abemaciclib CD8/FOXP3 ratio >= 1.6 among those with JAK-2 amplified TNBC and those with JAK-2 non-amplified TNBC.
• Change in microbiome with exposure to abemaciclib [ Time Frame: Baseline up to prior to surgery ]
  The collection of microbiome information via stool collection will be used to generate descriptive analyses about the study population, as the total number of samples is expected to be insufficient for full statistical analysis. Will explore putative mechanistic connections underlying bacteria-drug interactions in all patients and attempt to identify the biomolecular features within the gut (stool) microbiome and its association with the pharmacokinetics and pharmacodynamics of abemaciclib.

• Changes in mitoses [ Time Frame: Up to 60 days ]
  Examined graphically overall and by triple negative breast cancer (TNBC) subtypes.
• Changes in nuclear pleomorphism [ Time Frame: Up to 60 days ]
  Examined graphically overall and by TNBC subtypes.
• Changes in tubule formation [ Time Frame: Up to 60 days ]
  Examined graphically overall and by TNBC subtypes.
• Changes in tumor Ki-67 [ Time Frame: Up to 60 days ]
  Examined graphically overall and by TNBC subtypes.
• Changes in serum tyrosine kinase inhibitor (TKI) [ Time Frame: Up to 60 days ]
  Examined graphically overall and by TNBC subtypes.
• Changes in SNAIL [ Time Frame: Up to 60 days ]
  Examined graphically overall and by TNBC subtypes.
• Changes in SLUG [ Time Frame: Up to 60 days ]
  Examined graphically overall and by TNBC subtypes.
• Changes in E-Cadherin [ Time Frame: Up to 60 days ]
  Examined graphically overall and by TNBC subtypes.
• Changes in tumor-infiltrating lymphocytes [ Time Frame: Up to 60 days ]
  Examined graphically overall and by TNBC subtypes.
• Effect of abemaciclib on tumor ribonucleic acid (RNA)-sequencing (seq) data [ Time Frame: Up to 60 days ]
  The Gene set enrichment analysis (GSEA) method will be used to determine whether an a priori set of genes are over-represented in the differential expression analysis of the pre- and post- drug response phenotypes. CIBERSORT will be used to estimate the cell composition from RNA transcriptomic data (e.g. immune cell populations).
• Effect of abemaciclib on the phenotype of peripheral blood mononuclear cells (PBMC) [ Time Frame: Up to 60 days ]
• Effect of abemaciclib on formalin-fixed paraffin-embedded (FFPE) tumor sections (imaging mass cytometry (HyperionTM system) [ Time Frame: Up to 60 days ]
  Examination of genes directly involved in tumor cell antigen presentation (B2M, HLA-A, HLA-B, HLA-C, TAP1, TAP2, TAPBP), interferon-stimulated genes (ISGs) that regulate antigen presentation (e.g. STAT1, NLRC5) and other ISGs (IRFs, OAS2), genes involved in double strand (ds)RNA response (DDX58, DHX58), genes encoding interferons, including type 3 IFNs (IFNL1, IFNL2, IFNL3), genes indicating a cytotoxic T cell response (PRF1, GZMB), and regulatory T cell (Treg)-specific transcription factor genes (FOXP3, IKZF2).

PRIMARY OBJECTIVE:

I. To examine the effects of abemaciclib on the CD8/FOXP3 ratio in chemotherapy resistant triple negative breast cancer (TNBC) patients following neoadjuvant chemotherapy.

SECONDARY OBJECTIVES:

I. Assess abemaciclib toxicities. II. To examine the effects of abemaciclib on the percentage of vimentin expressing invasive cancer cells.

III. Within TNBC molecular subtypes (basal, mesenchymal, and luminal androgen receptor [LAR]), to evaluate the effects of abemaciclib on:

IIIa. The individual elements of tumor grade (mitoses, nuclear pleomorphism, and tubule formation).

IIIb. Tumor proliferation (as measured by tumor Ki-67 and serum tyrosine kinase inhibitor [TKI]).

IIIc. pDUB3 as well as epithelial-mesenchymal transition (EMT) markers including SNAIL/SLUG, TWIST, and E-Cadherin as measured by immunohistochemistry (IHC).

IIId. Quantification of tumor-infiltrating lymphocytes (as examined by hematoxylin and eosin [H&E]).

EXPLORATORY OBJECTIVES:

I. To evaluate the effect of abemaciclib on tumor ribonucleic acid (RNA)-seq data.

II. To evaluate the effects of abemaciclib on the immune phenotype of peripheral blood mononuclear cells (PBMC), by evaluating expression of a panel of cell surface markers optimized of identification of human immune cell subpopulations.

III. To evaluate the effects of abemaciclib on tumor-infiltrating immune cells in formalin-fixed paraffin-embedded (FFPE) tumor sections, using multiplexed imaging technologies (e.g imaging mass cytometry, Nanostring digital spatial profiling [DSP] or CODEX) which will include:

IIIa. Genes directly involved in tumor cell antigen presentation (e.g. B2M, HLA-A, HLA-B, HLA-C, TAP1, TAP2, TAPBP).

IIIb. Interferon-stimulated genes (ISGs) that regulate antigen presentation (e.g. STAT1, NLRC5) and other ISGs (e.g. IRFs, OAS2).

IIIc. Genes involved in double-strand ribonucleic acid (dsRNA) response (e.g. DDX58, DHX58).

IIId. Genes encoding interferons, including type 3 IFNs (e.g. IFNL1, IFNL2, IFNL3).

IIIe. Genes indicating a cytotoxic T cell response (e.g. PRF1, GZMB). IIIf. Regulatory T-cell (Treg)-specific transcription factor genes (e.g. FOXP3, IKZF2).

IV. To assess the difference in the frequency of JAK-2 amplification among patients whose post-abemaciclib CD8/FOXP3 ratio >= 1.6 and that among patients whose post-abemaciclib CD8/FOXP3 ratio < 1.6.

V. To generate organoids for future research. VI. To evaluate changes in the microbiome with exposure to abemaciclib.

OUTLINE: Patients are assigned to 1 of 2 groups.

GROUP 1: Patients undergo standard of care surgical resection.

GROUP 2: Patients receive abemaciclib orally (PO) twice daily (BID) on days 1-14 or days 1-21 in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care surgical resection no later than 12 weeks after the last dose of neoadjuvant chemotherapy.

After completion of study treatment, patients in group 2 are followed up within 30-60 days.

• Anatomic Stage I Breast Cancer AJCC v8
• Anatomic Stage IA Breast Cancer AJCC v8
• Anatomic Stage IB Breast Cancer AJCC v8
• Anatomic Stage II Breast Cancer AJCC v8
• Anatomic Stage IIA Breast Cancer AJCC v8
• Anatomic Stage IIB Breast Cancer AJCC v8
• Anatomic Stage III Breast Cancer AJCC v8
• Anatomic Stage IIIA Breast Cancer AJCC v8
• Anatomic Stage IIIB Breast Cancer AJCC v8
• Anatomic Stage IIIC Breast Cancer AJCC v8
• Breast Ductal Carcinoma In Situ
• Breast Fibrocystic Change
• Breast Lobular Carcinoma In Situ
• Invasive Breast Carcinoma
• Prognostic Stage I Breast Cancer AJCC v8
• Prognostic Stage IA Breast Cancer AJCC v8
• Prognostic Stage IB Breast Cancer AJCC v8
• Prognostic Stage II Breast Cancer AJCC v8
• Prognostic Stage IIA Breast Cancer AJCC v8
• Prognostic Stage IIB Breast Cancer AJCC v8
• Prognostic Stage III Breast Cancer AJCC v8
• Prognostic Stage IIIA Breast Cancer AJCC v8
• Prognostic Stage IIIB Breast Cancer AJCC v8
• Prognostic Stage IIIC Breast Cancer AJCC v8
• Triple-Negative Breast Carcinoma

• Drug: Abemaciclib
  Given PO
  Other Names:

  • LY-2835219
  • LY2835219
  • Verzenio
• Procedure: Therapeutic Conventional Surgery
  Undergo standard of care surgical resection

• Experimental: Group 1 (surgery)
  Patients undergo standard of care surgical resection.
  Intervention: Procedure: Therapeutic Conventional Surgery
• Experimental: Group 2 (abemaciclib, surgery)
  Patients receive abemaciclib PO BID on days 1-14 or days 1-21 in the absence of disease progression or unacceptable toxicity. Patients then undergo standard of care surgical resection no later than 12 weeks after the last dose of neoadjuvant chemotherapy.
  Interventions:

  • Drug: Abemaciclib
  • Procedure: Therapeutic Conventional Surgery

Inclusion Criteria:

• PRE-REGISTRATION: Clinical T1-4, N0-3, M0 breast cancer at diagnosis (prior to the start of neoadjuvant chemotherapy) by American Joint Committee on Cancer (AJCC) staging version 8.

  • Note: Benign breast disease, lobular carcinoma in situ (LCIS) or ductal carcinoma in situ (DCIS) in the contralateral breast is allowed.
  • Note: Contralateral invasive breast cancer is allowed if disease is of clinically lower stage, and the higher stage lesion will be the study lesion for all biopsies and tissue samples.
• PRE-REGISTRATION: Histological confirmation of triple negative invasive breast cancer (defined as estrogen receptor [ER] =< 10%, progesterone receptor [PR] =< 10% and HER2 not amplified by in situ hybridization [ISH] or immunohistochemistry [IHC] 0/1) at diagnosis.

• PRE-REGISTRATION: Neoadjuvant chemotherapy (NAC) with one of the following regimens that was not discontinued early due to intolerability with less than 50% of planned treatment given due to disease progression or patient request:

  • Paclitaxel or docetaxel followed by one of the following: the combination of doxorubicin and cyclophosphamide (AC); the combination of epirubicin and cyclophosphamide (EC) or the combination of 5-fluorouracil, epirubicin and cyclophosphamide (FEC)

    • Note: Carboplatin may be added to these regimens

  • AC or EC or FEC followed by docetaxel or paclitaxel

    • Note: Carboplatin may be added to these regimens
  • Docetaxel in combination with doxorubicin and cyclophosphamide (TAC)
  • Docetaxel in combination with cyclophosphamide (TC) (for patients who are not candidates for anthracyclines)
  • Carboplatin or cisplatin in combination with a taxane (paclitaxel, docetaxel, or nab-paclitaxel) (for patients who are not candidates for anthracyclines)
• PRE-REGISTRATION: Residual lesion/enhancement seen in the breast on breast imaging performed after completion of NAC.
• PRE-REGISTRATION: Able to swallow oral medication.
• PRE-REGISTRATION: Willing to undergo biopsy for research.
• PRE-REGISTRATION: Willing to provide tissue and blood samples for correlative research purposes.
• PRE-REGISTRATION: Willing to stop use of strong and moderate inducers and/or strong inhibitors of cytochrome P450 3A =< 7 days prior to registration.
• PRE-REGISTRATION: Provide written informed consent.
• REGISTRATION: Registration must occur =< 56 days after last dose of NAC.
• REGISTRATION: Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2.
• REGISTRATION: GROUP 2 ONLY: Absolute neutrophil count (ANC) >= 1500/mm^3 (obtained after completion of NAC but =< 14 days prior to registration).
• REGISTRATION: GROUP 2 ONLY: Platelets (PLT) >= 100,000/mm^3 (obtained after completion of NAC but =< 14 days prior to registration).
• REGISTRATION: GROUP 2 ONLY: Hemoglobin (HgB) >= 8.0 g/dL (obtained after completion of NAC but =< 14 days prior to registration).
• REGISTRATION: GROUP 2 ONLY: Total bilirubin =< 1.5 x upper limit of normal (ULN) (obtained after completion of NAC but =< 14 days prior to registration).
• REGISTRATION: GROUP 2 ONLY: Aspartate transaminase (AST) serum glutamic oxaloacetic transaminase (SGOT) =< 3 x ULN (obtained after completion of NAC but =< 14 days prior to registration).
• REGISTRATION: GROUP 2 ONLY: Alanine transaminase (ALT) serum glutamate pyruvate transaminase (SGPT) =< 3 x ULN (obtained after completion of NAC but =< 14 days prior to registration).
• REGISTRATION: GROUP 2 ONLY: Serum creatinine =< 1.5 x ULN (obtained after completion of NAC but =< 14 days prior to registration).
• REGISTRATION: GROUP 2 ONLY: Negative pregnancy test done =< 7 days prior to registration, for persons of childbearing potential only.

Exclusion Criteria:

• PRE-REGISTRATION: History of deep venous thrombosis (DVT) or pulmonary embolisms (PE) =< 12 months prior to preregistration; OR Active DVT and/or PE requiring anti-coagulant therapy.

  • NOTE: Patients who are on anti-coagulant therapy for maintenance are eligible as long as the DVT and/or PE was > 12 months prior to enrollment and there is no evidence for active thrombosis (either DVT or PE).
  • NOTE: Patients on anticoagulation are eligible; however peri-biopsy and peri-surgical management of anticoagulation is per the institutional standard of care.
• PRE-REGISTRATION: Prior treatment with CDK 4/6 inhibitors (e.g. palbociclib, ribociclib, abemaciclib, etc.)
• PRE-REGISTRATION: Prior treatment with immunotherapy or radiation for this breast cancer.
• PRE-REGISTRATION: Prior incisional or excisional breast biopsy for this cancer.
• PRE-REGISTRATION: Any contraindications to pre-registration biopsy (such as bleeding diatheses, etc.).
• PRE-REGISTRATION: Receiving any investigational agent which would be considered as a treatment for the primary neoplasm.

• PRE-REGISTRATION: Other active malignancy =< 3 years prior to registration.

  • EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix.
  • NOTE: If there is a history of prior malignancy, they must not be receiving another specific treatment for prior malignancy.
• PRE-REGISTRATION: Biopsy proven stage IV breast cancer.
• PRE-REGISTRATION: Serious pre-existing medical conditions that would preclude participation in this study (for example, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment [e.g., estimated creatinine clearance < 30 ml/min], history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition resulting in baseline grade 2 or higher diarrhea).

• PRE-REGISTRATION: History of any of the following conditions:

  • Syncope of cardiovascular etiology.
  • Ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation).
  • Sudden cardiac arrest.
  • NOTE: Patients on anticoagulation are eligible; however peri-biopsy and peri-surgical management of anticoagulation is per the institutional standard of care.

• REGISTRATION: GROUP 2 ONLY: Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:

  • Pregnant persons.
  • Nursing persons.
  • Persons of childbearing potential who are unwilling to employ adequate contraception.

• REGISTRATION: GROUP 2 ONLY: Failure to recover to grade 1 or lower from effects of neoadjuvant chemotherapy.

  • Exceptions: Residual alopecia and grade 2 peripheral neuropathy are allowed.
• REGISTRATION: GROUP 2 ONLY: Concurrent use of strong and moderate inducers and/or strong inhibitors of cytochrome P450 3A =< 7 days prior to registration.

• REGISTRATION: GROUP 2 ONLY: Known infections as follows (NOTE: Screening is not required for enrollment):

  • Active systemic bacterial infection requiring intravenous antibiotics.
  • Active fungal infection (requiring intravenous or oral antifungal treatment).
  • Detectable viral infections (e.g. known human immunodeficiency virus [HIV], known active hepatitis B or C).