Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Breast Neoplasms

Adenocarcinoma

Breast Diseases

Skin Diseases

Menopause

Kennedy Disease

All Drugs and Chemicals

Antineoplastic Agents

Androgens

Testosterone

Afimoxifene

Stratum A - patients with endocrine responsive-HER2neg BC

Stratum B - patients with triple-negative and confirmed ARpos BC

400 mg, corresponding to two 4 g stick packs applications twice daily

CR1447

Marcus Vetter, MD

Beat Thürlimann, Prof

SAKK 21/12 is a stratified, multicenter Phase II first in-human trial with transdermal CR1447 (4-OH-testosterone) and is directed to patients with endocrine responsive-HER2neg and TN-ARpos metastatic or locally advanced breast cancer.

The trial will be conducted in Switzerland with max. 90 patients. CR1447 has a very good safety and tolerability profile and combines two mechanisms of action, interaction with the AR and the aromatase enzyme may have a higher activity than drugs with a single mechanism and might offer the possibility of non-chemotherapy based endocrine therapy to the limited treatment options in TN-ARpos BC. Transdermal application of CR1447 might have the advantage to continuously release of 4-OHT into the blood stream, thus omitting a first pass effect.

In Phase II the main objective is to assess activity and to determine the efficacy and tolerability of CR1447. Phase II will consist of two strata, into which patients will be stratified according to their hormonal receptor status: Stratum A for patients with endocrine responsive-HER2neg disease, regardless of their AR status and Stratum B for patients with triple-negative and determined ARpos disease. Patients with triple-negative disease tested negative for AR will be excluded from the trial.

In both strata patients will be treated with 400 mg of CR1447 until disease progression, patients' wish or physicians' decision to end treatment. Biopsies of one defined metastatic lesion in those patients who gave informed consent will be performed at baseline and within the third week of treatment with CR1447.

Measurement of AR expression, expression of downstream targets of ERα, ERβ, PR, AR, angiogenesis and other translational studies as described in this protocol should help confirming the hypothesis of an increased benefit of CR1447 due to its dual action, efficacy of topical application, tolerability and in deciding whether one should proceed to a large randomized trial.

Breast cancer is the most frequently diagnosed cancer and a heterogeneous disease and tumor categorization based on molecular characteristics beyond the currently used markers such as the estrogen receptor (ER), progesterone receptor (PR), and HER2, makes tumor categorization and treatment a demanding task.

The treatment and prevention of relapses of breast cancer is mainly based on I) surgery of primary tumors, II) radiotherapy, III) chemotherapy, IV) endocrine therapy, and V) specific interventions. Although there have been advances in breast cancer therapy with three out of four women with breast cancer now being cured, one out of four patients will relapse or present with metastatic disease at the time of first diagnosis and hence be incurable and die of their disease.

The endocrine responsive breast cancer is defined by the immunohistochemical detection of the ER (estrogen receptor) and/or the PR (progesterone receptor) on at least 1% of tumor cells on the tissue sample to a variable degree and offers the possibility of treatment using endocrine strategies in about 80% of patients. Endocrine responsive breast cancers may also express HER2. The triple negative breast cancer (TNBC) is defined by the lack of expression of ER, PR, and HER2. The analysis is made on the pathological tumor tissue sample. While for ER and PR, the threshold is less than 1% of tumor cells expressing both receptors, HER2 negativity is defined as immunohistochemical scores of 0/1+ or tumors with scores of 0/1+ or 2+ that are lacking HER2 gene amplification after in situ hybridization. Approximately 15% of all breast cancers are found to be triple-negative. However, due to the biologically more aggressive behavior of these tumors, the patient group suffering from this type of disease are overrepresented within the first five years after initial diagnosis.

Recently, androgen receptor (AR) targeted therapies gained new interest due to the fact that the AR is the most abundantly expressed sex hormone receptor in breast cancer (approx. 70% of all breast tumors) and, importantly, in about 20% (range 10% to 50% depending on the respective reference) of triple-negative breast tumors. The threshold for ARpos breast cancer is that \>0% of tumor cells expresses the AR. In addition, a significant association was found between AR expression and longer overall survival of breast cancer patients. Androgens can induce proliferative changes in breast cancer cell lines, and testosterone acts as a tumor promoter in several animal models of breast cancer.

Endocrine responsive breast cancer Anti-estrogen therapy includes ovariectomy, to remove the primary source of female sex hormone in premenopausal women, and the application of luteinizing hormone releasing hormone (LHRH) agonists, to decrease the release of LH and prevent gonadal estrogen synthesis. These therapies induce a postmenopausal status. The hormonal treatment of choice for premenopausal women with ER positive metastatic breast tumors is the use of ER antagonists such as tamoxifen. Tamoxifen and aromatase inhibitors, preventing the final conversion of androgens to estrogens, are the main endocrine treatment options for postmenopausal women with metastatic breast cancer. The persisting estrogen levels in postmenopausal women are mainly due to aromatase activity in extragonadal sources such as breast tissue, skeletal muscle and adipose tissue. Thus, both ER blockade by tamoxifen and inhibition of estrogen synthesis inhibit the growth signal for breast cancer cells expressing ER.

Aromatase, the key enzyme of estrogen production in women, is expressed in and around breast tumors, in ovaries, and in skeletal muscle and adipose tissue in postmenopausal women. Several aromatase inhibitors (AI) have been developed. The first generation aromatase inhibitors include testolactone and aminogluthetimide that were replaced by the more potent second generation inhibitors fadrazole and formestane (4-hydroxy-4-androstenedione, 4-OHA), and later on by the even more potent third generation inhibitors exemestane, letrozole and anastrozole. 4OHA and exemestane are steroidal AI and irreversibly block aromatase while the non-steroidal AI letrozole and anastrozole are reversible inhibitors. Importantly, there seems to exist no cross-resistance between the two aromatase inhibitor classes, and 4-OHA or exemestane may still show efficacy after relapse upon letrozole/anastrozole treatment.

In summary, there is a great demand for novel and improved therapeutic strategies, especially to overcome resistance to chemotherapy or presently available endocrine therapy in postmenopausal women.

While patients with ER and/or PR positive tumors can be treated with endocrine therapies and patients with HER2pos disease with treatments directed against HER2 such as trastuzumab, lapatinib, and trastuzumab/pertuzumab combination therapy, no endocrine or targeted anti-HER2 directed therapy exists for patients suffering from triple negative disease.

For these patients, only chemotherapy is a therapeutic option. Unfortunately, these tumors tend to be aggressive and quickly growing with a high relapse rate even after intensive adjuvant chemotherapy. Due to the absence of estrogen receptors, endocrine therapy based on anti-estrogen intervention strategies must fail.

There are currently no suitable treatment options for patients with metastatic triple-negative breast tumors whose disease has failed to respond to chemotherapy. Thus, there is a great demand for novel and improved therapeutic strategies in this patient group and in all patients with acquired resistance to combat breast cancer.

Testosterone was already used extensively between the 1930s and 1960s for breast cancer treatment, with anecdotal tumor responses (especially bone metastases) seen in up to 20% of treated women. Side effects such as hirsutism and aggressive behavior as signs of virilization in treated women and the evidence that testosterone may be easily be converted to estrogens in the body led to the discontinuation of its use.

CR1447 (4-hydroxytestosterone \[4-OHT\]) is a steroidal small molecule which has two distinct properties, acting as a steroidal aromatase inhibitor (AI) and binding to the AR with high affinity (IC50 4.4 nM). In vitro studies indicate that human breast cancer cell lines are inhibited by CR1447 in their growth if they express the androgen receptor, while knock out of the AR abolishes this effect. A significant proportion of 4-OHT is converted to 4-OHA (4-hydroxyandrostenedione, formestane). In vivo 4-OHT and 4-OHA, form a redox system. 4-OHA is the 17-beta-oxidized isoform of CR1447. 4-OHA had previously been approved as an aromatase inhibitor for the treatment of BC via intramuscular (i.m.) injection (Formestane, Lentaron®) injection, but was discontinued by Novartis due to the development of oral aromatase inhibitors. Unlike testosterone, both compounds, 4-OHA and 4-OHT, are not converted to estrogens in vivo. Due to a high first pass effect after oral dosing, 4-OHA had to be administered parentally e.g. as an intramuscular injection. While this regimen was clinically effective, local side effects were a dose limiting issue.

A clinical feasibility study of transdermally applied 4-OHA showed that significant amounts of 4-OHA are absorbed by the skin. Intramuscular and transdermally (twice daily) applied 4-OHA achieved comparable the same plasma levels from day 3 on.

CR1447 in Endocrine Responsive-HER2neg and TN-ARpos Breast Cancer

A Stratified, Multicenter Phase II Trial of Transdermal CR1447 (4-OH-testosterone) in Endocrine Responsive-HER2 Negative and Triple Negative-androgen Receptor Positive Metastatic or Locally Advanced Breast Cancer

DC24 is obtained in a patient who achieves complete response (CR) or partial response (PR) within the first 24 ± 2 weeks of treatment or stable disease (SD) for at least 24 weeks after treatment start according to the RECIST 1.1 criteria.

For patients without CR or PR and no PD before 24 weeks:

* If the tumor assessment at 24 ± 2 weeks is missing but a later assessment shows SD, the patient will be counted as obtaining DC24.
* If the tumor assessment at 24 ± 2 weeks is missing and there are no further tumor assessments or the subsequent assessment shows PD, the patient will be counted as not obtaining DC24.

Tumor assessments showing CR or PR have to be confirmed after 4 weeks.

Swiss Group for Clinical Cancer Research

Taxane

Cabazitaxel(XRP6258) will be administered on day 1 of each cycle, every 21 days, at a dose of 25 mg/m² by i.v. route in 1 hour. Treatment can be continued until patient's consent withdrawal, intolerable toxicity or documented disease progression.

Cabazitaxel

Angelos Koutras, MD

The purpose of this study is to determine whether cabazitaxel is effective in the treatment of metastatic breast cancer.

Study of Cabazitaxel in Patients With Metastatic Breast Cancer Previously Treated With Taxanes

Phase II Study of Cabazitaxel as 2nd Line Treatment in Patients With HER-2 Negative Metastatic Breast Cancer Previously Treated With Taxanes

Distribution of adverse events according to severity grade.

βΙ,βΙΙ,βΙΙΙ,βIVb, βV-tubulin isotypes,HIF1α,microtubule-associated proteins such as Tau,MAP2,MAP4 \& microtubule-sequestering proteins such as stathmin, will be assessed. Moreover, evaluation of p53,BCL2,BIM,γ-actin,LIMK2, TGFBI,Aurora-A,as well as the expression of the enzyme CYP3A and multidrug transporters such as P-glycoprotein. The abovementioned factors will be assessed by immunohistochemistry at the protein level and by quantitative real-time PCR at the RNA level.

Also, given the clinical significance of the anti-angiogenic effects of cytotoxic chemotherapy,we will investigate the effect of treatment on surrogate biomarkers of angiogenesis, such as VEGF-A as well as the effect of chemotherapy on kinetics of soluble biomarkers,using ELISA.

In addition,genetic polymorphisms in drug-metabolizing enzymes and drug transporters, such as the CYP3A and ABCB1 genes, will be explored in blood DNA and their association with the toxicity and efficacy of cabazitaxel will be assessed.

Sanofi

Hellenic Cooperative Oncology Group

Symptoms and General Pathology

Recurrence

Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Disease Attributes

Paclitaxel

Docetaxel

Albumin-Bound Paclitaxel

Trastuzumab

Pertuzumab

Atezolizumab

Antibodies

Antibodies, Monoclonal

Immunoglobulins

Trastuzumab biosimilar HLX02

Immunoglobulins, Intravenous

Tubulin Modulators

Antimitotic Agents

Immunologic Factors

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Patients receive pertuzumab IV over 30-60 minutes on days 1 and 22, trastuzumab IV over 30-90 minutes on days 1 and 22, and paclitaxel IV over 60 minutes on days 1, 8, 15, 22, 29, and 36 or docetaxel IV over 60 minutes on days 1 and 22. Cycles repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive atezolizumab IV over 30-60 minutes on day 22 of cycle 1 and days 1 and 22 of subsequent cycles. Cycles repeat every 6 weeks for 2 years in the absence of disease progression or unacceptable toxicity. Patients may undergo a biopsy at baseline. Patients undergo a CT or MRI at baseline, prior to weeks 10, 19, 28 and then at 9, 12, 15, 18, 21, and 24 months from study entry, every 3 months through year 3, every 6 months for years 4 and 5, and then every 6 months for years 6 through 10 from study entry. Patients undergo a bone scan at baseline, every 6 months from study entry, every 6 months through year 3, and every 12 months for years 4 and 5.

Patients receive pertuzumab, trastuzumab, and paclitaxel or docetaxel as in Arm I. Patients also receive placebo IV 30-60 minutes on day 1 of cycle 22 and days 1 and 22 of subsequent cycles. Cycles repeat every 6 weeks for 2 years in the absence of disease progression or unacceptable toxicity. Patients may undergo a biopsy at baseline. Patients undergo a CT or MRI at baseline, prior to weeks 10, 19, 28 and then at 9, 12, 15, 18, 21, and 24 months from study entry, every 3 months through year 3, every 6 months for years 4 and 5, and then every 6 months for years 6 through 10 from study entry. Patients undergo a bone scan at baseline every 6 months from study entry, every 6 months through year 3, and every 12 months for years 4 and 5.

Biopsy

Bone Scan

Computed Tomography

Magnetic Resonance Imaging

Placebo Administration

Quality-of-Life Assessment

Charles E Geyer

This randomized phase III trial studies how well paclitaxel, trastuzumab, and pertuzumab with or without atezolizumab works in treating patients with breast cancer that has spread to other parts of the body (metastatic). Chemotherapy drugs, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Trastuzumab is a form of "targeted therapy" because it works by attaching itself to specific molecules (receptors) on the surface of cancer cells, known as HER2 receptors. When trastuzumab attaches to HER2 receptors, the signals that tell the cells to grow are blocked and the cancer cell may be marked for destruction by the body's immune system. Monoclonal antibodies, such as pertuzumab, may interfere with the ability of cancer cells to grow and spread. Immunotherapy with monoclonal antibodies, such as atezolizumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving paclitaxel, trastuzumab, and pertuzumab with or without atezolizumab may kill more tumor cells.

\*NOTE: This study has a central confirmation step. The purpose of this step is to confirm by central testing that the patient's tumor has specific receptors. If the patient meets all the study requirements, the patient will join the study and begin therapy for breast cancer while the tumor is being tested.

PRIMARY OBJECTIVE:

I. To determine whether the addition of atezolizumab to a regimen of pertuzumab and trastuzumab combined with a taxane (paclitaxel or docetaxel) will improve the progression-free survival (PFS), assessed by investigator using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria, relative to the addition of a placebo to a regimen of pertuzumab and trastuzumab combined with a taxane (paclitaxel or docetaxel) in patients with newly documented HER2-positive measurable metastatic breast cancer.

SECONDARY OBJECTIVES:

I. To determine whether the addition of atezolizumab to a regimen of pertuzumab and trastuzumab combined with a taxane (paclitaxel or docetaxel) will improve the overall survival (OS) relative to the addition of placebo to a regimen of pertuzumab and trastuzumab, combined with a taxane (paclitaxel or docetaxel).

II. To determine whether the addition of atezolizumab to a regimen of pertuzumab and trastuzumab combined with a taxane (paclitaxel or docetaxel) will improve the overall objective response (OR) in the cohort of patients randomized 6 months or more prior to study accrual closure assessed by investigator using RECIST 1.1 criteria, relative to the addition of placebo to a regimen of pertuzumab and trastuzumab combined with a taxane (paclitaxel or docetaxel).

III. To determine the immune-related toxicity profile of the two treatment regimens.

IV. To determine the cardiac safety profile of the two treatment regimens.

EXPLORATORY OBJECTIVES:

I. To determine whether the addition of atezolizumab to a regimen of pertuzumab and trastuzumab combined with a taxane (paclitaxel or docetaxel) will decrease the incidence of subsequent brain metastases in patients without known brain metastases at study entry relative to the addition of a placebo to a regimen of pertuzumab and trastuzumab combined with a taxane (paclitaxel or docetaxel).

II. To determine the utility of PD-L1 immunohistochemistry (IHC) staining as a predictive and prognostic biomarker associated with clinical response, as assessed by investigator using RECIST 1.1 criteria, to atezolizumab in combination with trastuzumab and pertuzumab combined with a taxane (paclitaxel or docetaxel).

III. To identify potential biomarkers that can predict benefit from the addition of atezolizumab in patients with newly documented HER2-positive measurable metastatic breast cancer treated with a regimen of pertuzumab and trastuzumab combined with a taxane (paclitaxel or docetaxel).

IV. To explore the toxicity profile of the two treatment regimens using patient-reported symptomatic adverse events in addition to standard adverse event reports.

V. To determine the feasibility and added value of frequent assessment of toxicity using Patient Reported Outcomes (PRO)-Common Terminology Criteria for Adverse Events (CTCAE) with electronic(e)PRO reporting.

VI. To explore whether the addition of atezolizumab to a regimen of pertuzumab and trastuzumab combined with a taxane (paclitaxel or docetaxel) will contribute to increased patient-reported fatigue in comparison to the addition of placebo to a regimen of pertuzumab and trastuzumab combined with a taxane (paclitaxel or docetaxel).

OUTLINE:

STEP 1: Patients receive pertuzumab intravenously (IV) over 30-60 minutes on days 1 and 22, trastuzumab IV over 30-90 minutes on days 1 and 22, and paclitaxel IV over 60 minutes on days 1, 8, 15, 22, 29, and 36 or docetaxel IV over 60 minutes on days 1 and 22. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients may undergo a biopsy at baseline. Patients undergo computed tomography (CT), magnetic resonance imaging (MRI), and/or bone scan at baseline.

STEP 2: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive pertuzumab IV over 30-60 minutes on days 1 and 22 of each cycle, trastuzumab IV over 30-90 minutes on days 1 and 22 of each cycle, and paclitaxel IV over 60 minutes on days 1, 8, 15, 22, 29, and 36 of each cycle or docetaxel IV over 60 minutes on days 1 and 22 of each cycle. Cycles repeat every 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive atezolizumab IV over 30-60 minutes on day 22 of cycle 1 and days 1 and 22 of subsequent cycles. Cycles repeat every 6 weeks for 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo a CT or MRI at baseline, prior to weeks 10, 19, 28 and then at 9, 12, 15, 18, 21, and 24 months from study entry, every 3 months through year 3, every 6 months for years 4 and 5, and then every 6 months for years 6 through 10 from study entry. Patients undergo a bone scan at baseline, every 6 months from study entry, every 6 months through year 3, and every 12 months for years 4 and 5.

ARM II: Patients receive pertuzumab, trastuzumab, and paclitaxel or docetaxel as in Arm I. Patients also receive placebo IV 30-60 minutes on day 22 of cycle 1 and days 1 and 22 of subsequent cycles. Cycles repeat every 6 weeks for 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo a CT or MRI at baseline, prior to weeks 10, 19, 28 and then at 9, 12, 15, 18, 21, and 24 months from study entry, every 3 months through year 3, every 6 months for years 4 and 5, and then every 6 months for years 6 through 10 from study entry. Patients undergo a bone scan at baseline, every 6 months from study entry, every 6 months through year 3, and every 12 months for years 4 and 5.

After completion of study treatment, patients are followed up at 30 days and every 3 months for 3 years and then every 6 months for 5 years.

Testing the Drug Atezolizumab or Placebo With Usual Therapy in First-Line HER2-Positive Metastatic Breast Cancer

A Randomized, Double-Blind, Phase III Trial of Taxane/Trastuzumab/Pertuzumab With Atezolizumab or Placebo in First-Line HER2-Positive Metastatic Breast Cancer

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page

Will be determined using the current Response Evaluation Criteria in Solid Tumors 1.1 criteria. Analysis will be based on the intent to treat population. The stratified log-rank test will be used to compare the progression free survival between the two treatment arms with the following stratification factors: prior neoadjuvant or adjuvant therapy with trastuzumab (no; yes), estrogen receptor status (positive; negative), disease sites (any visceral without brain metastasis; non-visceral only without brain metastasis; brain metastasis), and choice of taxane (paclitaxel; docetaxel). The Kaplan-Meier estimates will be calculated by treatment arms. Stratified Cox proportional hazards models to estimate the hazard ratio.

Analysis will be based on the intent to treat population. The stratification factors are the same as what are used in the stratified log-rank test for the primary analysis on progression free survival. The Kaplan-Meier estimates will be calculated by treatment arms. Stratified Cox proportional hazards models to estimate the hazard ratio.

Defined as complete response or partial response. Will be determined using Response Evaluation Criteria in Solid Tumors 1.1 criteria. The stratified Cochran-Mantel-Haenszel test will be used to compare the object response between the treatment arms.

Will be categorized using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0. Comparisons of the adverse events between the two treatment arms will be done by the Fisher's exact test.

NRG Oncology

National Cancer Institute (NCI)

Palbociclib

Patients receive SOC treatment consisting of ribociclib or palbociclib plus AI. Patients undergo biopsy of tumor tissue at baseline and post-treatment. Patients also undergo collection of blood samples at baseline, on day 1 of SOC treatment cycles 2, 4, and 6, every 6 cycles thereafter, and at post-treatment.

Patients' tumor tissue collected during previous SOC treatment (ribociclib or palbociclib plus AI) is used for analysis.

Given standard of care ribociclib + AI or palbociclib + AI

Best Practice

Biospecimen Collection

Undergo analysis of previously collected tumor tissue

Laboratory Biomarker Analysis

Yuan Yuan

This clinical trial attempts to understand the differences between two chemotherapy drugs, ribociclib and palbociclib, and how they fight cancer. This study looks at tissue and blood characteristics of patients receiving these therapies in the hopes to develop a way to predict which medication would provide the most benefit to an individual patient.

PRIMARY OBJECTIVE:

I. To identify predictive immune biomarkers and mechanisms of response to ribociclib or palbociclib in advanced, hormone receptor positive breast cancer patients.

SECONDARY OBJECTIVES:

I. Identify changes in antigen presentation machinery and costimulatory molecules on circulating myeloid cells as a result of ribociclib or palbociclib treatment.

II. Characterize the dynamic remodeling of circulating myeloid cell composition that occur as a result of ribociclib or palbociclib treatment.

III. Characterize acquired immune tumor microenvironment features of resistance in patients that progress while undergoing ribociclib or palbociclib treatment.

EXPLORATORY OBJECTIVE:

I. To study the association between immune biomarkers and clinical response.

OUTLINE: Patients are assigned to 1 of 2 cohorts.

PROSPECTIVE COHORT: Patients receive standard of care (SOC) treatment consisting of ribociclib or palbociclib plus aromatase inhibitor (AI). Patients undergo biopsy of tumor tissue at baseline and post-treatment. Patients also undergo collection of blood samples at baseline, on day 1 of SOC treatment cycles 2, 4, and 6, every 6 cycles thereafter, and at post-treatment.

RETROSPECTIVE COHORT: Patients' tumor tissue collected during previous SOC treatment (ribociclib or palbociclib plus AI) is used for analysis.

Effects of Ribociclib and Palbociclib on Tumor and Blood Characteristics in Patients With Metastatic Breast Cancer

Comparative Effects of Ribociclib and Palbociclib on Circulating and Tumor Infiltrating Myeloid Cells in Metastatic Breast Cancer Patients

Will be assessed by high dimensional flow cytometry. One-way analysis of variance (ANOVAs) and non-parametric Kruskal-Wallis tests will be used to compare relative abundances across patient groups and over the course of therapy. Wilcoxon rank-sum test will be used to examine the association between each biomarker of each sample collection and pathological response as appropriate. Odds ratios and 95% conference intervals will be calculated to measure strength of associations. P-values \< 0.05 will be considered statistically significant. No adjustment for multiple comparisons will be used in view of the exploratory nature of this analysis.

Expected to identify \> 30 myeloid and lymphocyte immune subsets. Gene expression relating to maturation and function will be focused on in myeloid subsets especially. Will be assessed by single-cell ribonucleic acid (RNA) sequencing. Immune cell type identification and gene expression patterns will be identified by unsupervised clustering and non-linear dimensionality reduction approaches. Cluster biomarkers will be identified by Seurat for annotating cell types (or functions) for each cell. Within each cluster, will compare the cellular differences in RNA expression across response and non-response cohorts of tumor and peripheral blood mononuclear cell (PBMC) samples by built-in MAST package and Wilcoxon rank-sum test, respectively. Single-cell trajectory analysis for single-cell RNA expression profile will be implemented by Monocle 3 to discover the transitions of cell states in the blood over the course of treatment.

Will be assessed by multiplex immunofluorescence. Cell classifications based on panel design will be created for all cell objects detected in whole slide images of tissues. Tissue segmentation for tumor and stroma areas will be created. Densities of cell classifications within whole tissue, tumor areas, and stroma areas will be calculated. Neighborhood analysis, based off 25micron radius, will be examined using Cytomap to identify patterns of cell-cell interactions within tissues. All quantitative image analysis data between pre-treatment and post-treatment samples will be compared in the context of clinical response to CDK4/6i by Wilcoxon rank-sum tests.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
CR1447 in Endocrine Responsive-HER2neg and TN-ARpos Breast Cancer	NCT02067741	Metastatic Brea... Breast Cancer	CR1447	18 Years -	Swiss Group for Clinical Cancer Research
CR1447 in Endocrine Responsive-HER2neg and TN-ARpos Breast Cancer	NCT02067741	Metastatic Brea... Breast Cancer	CR1447	18 Years -	Swiss Group for Clinical Cancer Research
Study of Cabazitaxel in Patients With Metastatic Breast Cancer Previously Treated With Taxanes	NCT01693549	Breast Cancer	Cabazitaxel	18 Years - 75 Years	Hellenic Cooperative Oncology Group
Testing the Drug Atezolizumab or Placebo With Usual Therapy in First-Line HER2-Positive Metastatic Breast Cancer	NCT03199885	Metastatic Brea... Metastatic HER2... Recurrent Breas... Recurrent HER2-... Stage III Breas... Stage IV Breast... Unresectable Br... Unresectable HE...	Atezolizumab Biopsy Bone Scan Computed Tomogr... Docetaxel Magnetic Resona... Paclitaxel Pertuzumab Placebo Adminis... Quality-of-Life... Trastuzumab	18 Years -	National Cancer Institute (NCI)
Effects of Ribociclib and Palbociclib on Tumor and Blood Characteristics in Patients With Metastatic Breast Cancer	NCT05244434	Advanced Breast... Advanced HER2-N... Anatomic Stage ... Anatomic Stage ... Anatomic Stage ... Anatomic Stage ... Anatomic Stage ... Hormone Recepto... Metastatic Brea... Metastatic HER2... Prognostic Stag... Prognostic Stag... Prognostic Stag... Prognostic Stag... Prognostic Stag...	Best Practice Biopsy Biospecimen Col... Laboratory Biom...	18 Years -	City of Hope Medical Center
Study of Cabazitaxel in Patients With Metastatic Breast Cancer Previously Treated With Taxanes	NCT01693549	Breast Cancer	Cabazitaxel	18 Years - 75 Years	Hellenic Cooperative Oncology Group

Spots Global Cancer Trial Database for metastatic breast adenocarcinoma