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Inclusion Criteria: * Written informed consent. * Age ≥18 years old * Histologically or cytologically documented diagnosis of HR+, HER2-negative breast cancer based on local laboratory results and who are not amenable to resection or radiation therapy with curative intent. HR+ tumor is defined as ER and/or PgR expression in greater than 1% of tumor cells. HER2-negative breast cancer is defined as a negative in situ hybridization test or an immunohistochemistry (IHC) status of 0 or 1+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required to confirm the HER2-negative status (based on the most recently analyzed tissue sample tested by a local laboratory). * Currently on treatment and have received ≥ 2 months of CDK4/6i + hormone therapy as their initial endocrine based treatment for their metastatic disease in concordance with local CDK4/6i label or treatment guideline. * No evidence of clinical or radiological disease progression per investigator assessment. * Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2. Exclusion Criteria: * History of significant neurological or psychiatric disorders that would prohibit the understanding and giving of informed consent. * Patient has a concurrent invasive malignancy and /or is concurrently using other anti-neoplastic therapy.

Inclusion Criteria: 1. Male or female over 18 years of age 2. Patient who has received information about the study and has not expressed any objection 3. Patient who is a beneficiary or entitled person under a social security scheme 4. Patient requiring thoracic surgery for an acute or chronic acquired pathology with planned resection of lung parenchyma. 5. Group A: patients on the lung transplant list with chronic lung disease and pulmonary hypertension\*. Group B: control patients with chronic lung disease without pulmonary hypertension on the lung transplant list or with an indication for lung resection surgery for diagnostic or therapeutic purposes. Group C: control patients without chronic lung disease or pulmonary hypertension with an indication for lung resection. \*Pulmonary hypertension is defined by a mean resting pulmonary arterial pressure of 20 mmHg and pulmonary vascular resistances \> 2UW and an occlusion pulmonary arterial pressure ≤ 15 mmHg. Exclusion Criteria: 1. Person in exclusion period from another research protocol at the time the no-objection is collected 2. Subjects covered by articles L1121-5 to 1121-8 of the French Public Health Code (minors, adults under guardianship or trusteeship, patients deprived of their liberty, pregnant or breast-feeding women).

Inclusion Criteria: * Enrolled in a Medicare plan * Diagnosis of uncontrolled hypertension * On a stable regimen of antihypertensive therapy Exclusion Criteria: * A prior RDN procedure * Diagnosis of secondary hypertension * Any condition for which RDN is contraindicated

Inclusion criteria: 1. The patient has been diagnosed with the first locoregional recurrence (LRR) after receiving definitive treatment for primary breast cancer. LRR includes one or more of the following: (i) Ipsilateral breast tumor recurrence (ii) Ipsilateral chest wall recurrence (iii) Regional lymph node recurrence 2. At least one LRR lesion must be confirmed by a biopsy, surgical specimen, or cell block from cytology, and must meet all of the following: (i) Pathologically confirmed as invasive breast cancer, or diagnosed as breast cancer in a cytology cell block (in cases where only a cell block is available, the initial primary breast cancer must have been invasive). (ii) Hormone receptor (HR) expression is positive. (iii) HER2 expression is negative. ※ If multiple lesions are pathologically evaluated and any lesion is HR-negative or HER2-positive, the patient is ineligible. 3. No prior diagnosis of distant metastasis of breast cancer. 4. Imaging assessment before registration confirms: No lymph nodes ≥10 mm in short axis No evidence of distant metastasis 5. Age ≥18 years at the time of registration. 6. ECOG Performance Status of 0 or 1. 7. Chemotherapy for LRR is allowed prior to enrollment. 8. The patient does not have bilateral breast cancer. 9. No prior history of treatment with CDK4/6 inhibitors. 10. Written informed consent has been obtained for participation in this clinical trial. Exclusion Criteria: 1. Presence of active double cancer (synchronous malignancy requiring treatment). 2. Ongoing infectious disease requiring systemic therapy. 3. Fever ≥38.0°C at the time of registration. 4. Women who are pregnant, possibly pregnant, within 28 days postpartum, or breastfeeding; men whose partners intend to become pregnant. 5. Psychiatric illness or symptoms that interfere with daily living and may compromise trial participation. 6. Ongoing systemic administration (oral or IV) of steroids equivalent to ≥10 mg/day of prednisolone or other immunosuppressive agents. 7. Unstable angina (developed or worsened within the past 3 weeks) or myocardial infarction within the past 6 months. 8. Uncontrolled hypertension. 9. Uncontrolled diabetes mellitus despite continuous insulin or oral antidiabetic therapy. 10. Positive for HBs antigen or HCV antibodies (Patients positive for HCV antibodies are not excluded if HCV-RNA is undetectable.) 11. Positive for HIV antibodies (HIV testing is not mandatory.) 12. Presence of interstitial pneumonia, pulmonary fibrosis, or severe emphysema as diagnosed by chest CT.

Inclusion Criteria: * Aged ≥18 and older * Breast cancer patients meeting current guideline recommendations and planning to receive trastuzumab deruxtecan * ECOG 0-1 Exclusion Criteria: * During pregnancy and lactation

Inclusion Criteria: 1. Women with a verified breast cancer diagnosis over 18 years of age; 2. ECOG 0-1; 3. Stage: clinical T1, T2 or T3, N0-3, M0; 4. The thickness of subcutaneous adipose tissue (Pinch Test) is more than 5 mm 5. Signed informed voluntary consent. Exclusion Criteria: 1. Women under 18 years of age; 2. ECOG 2-4; 3. Stage: clinical T4, M1; 4. The thickness of subcutaneous adipose tissue (Pinch Test) is less than 5 mm; 5. Intolerance and / or allergic reaction to the mesh endoprosthesis, implant and/or its component;

Inclusion Criteria: 1. Patients with both eyes with open angle glaucoma. 2. Abnormal VF (glaucomatous pattern with PSD abnormal at p\<0.05 or GHT outside normal limits) on most recent two clinic visits on chart review 3. Glaucomatous disc abnormality on chart review and confirmed on baseline disc photograph 4. Overall average NFL thickness \> 55 μm measured by Heidelberg Spectralis OCT -Glaucoma Module Premium Edition (chart review), consistent with early glaucoma 5. NFLP-CD deficit (below 5 percentile of normal) in any of the 8 sectors on the initial baseline visit 6. The difference in baseline NFLP-CD between the left and right eye should be less than 5% (% of area). 7. IOP \>= 17 mm Hg on the most recent two clinic visits (chart review) after monotherapy with latanoprost in both eyes. Exclusion Criteria: 1. Best corrected visual acuity worse than 20/30 on chart review of most recent clinic visit 2. Age \< 21 years at baseline 3. Eye disease that could affect VF, NFL thickness, or NFLP (e.g., visually significant cataract, AMD, diabetic retinopathy, and optic neuropathy) at any study visit 4. OCT and OCTA scans not meeting quality criteria at baseline 5. Inability to cooperate with study procedures 6. Inability to commit to the study visits

Inclusion Criteria: 1. Participant must meet Diagnostic and Statistical Manual of Mental Disorders (5th edition) (DSM-5) diagnostic criteria for Major Depressive Disorder (MDD), without psychotic features, based upon clinical assessment and confirmed by the Mini International Psychiatric Interview (MINI) . 2. Participants must have current suicidal ideation with intent, confirmed by a "Yes" response to Question B3 \[Think (even momentarily) about harming or of hurting or of injuring yourself: with at least some intent or awareness that you might die as a result; or think about suicide (ie, about killing yourself)?\] and Question B10 \[Intend to act on thoughts of killing yourself?\] obtained from the MINI. 3. Participant has a Montgomery Asberg Depression Rating Scale (MADRS) total score of greater than (≥) 28 and the score for item 10"suicide ideation" of greater than (≥) 3 predose on Day 1 Exclusion Criteria: 1. Participant has a current DSM-5 diagnosis of bipolar (or related disorders), antisocial personality disorder, or obsessive compulsive disorder. 2. Participant has a current clinical diagnosis of autism, dementia, or intellectual disability. 3. Participant has a current or prior DSM-5 diagnosis of a psychotic disorder, or MDD with psychotic features . 4. Participant meets the DSM-5 severity criteria for moderate or severe substance or alcohol use disorder, within the 6 months before screening 5. Participant has a current or prior diagnosis of a reatment resistant depression 6. Any nasal conditions or diseases that, in the investigator's judgment, may significantly affect the administration or absorption of a nasal product. 7. Participant has a history of malignancy within 5 years before screening 8. Pregnant or breastfeeding women, or those with a positive pregnancy test result during screening. 9. Previous participation in another clinical trial and receiving the investigational drug within 3 months prior to dosing.

Inclusion Criteria: * Those aged 18 and above * Primary clinical diagnosis of MDD or bipolar disorder based on DSM-5/ICD-11 diagnostic criteria * Participant is willing and able to give informed consent for participation in the study * Possesses sufficient command of the English language required to complete study requirements, as assessed by the study team Exclusion Criteria: * Inability to complete study activities as assessed by the study team * Presentation requires immediate emergency treatment * Presentation requires clinical input not available within the research clinic

Inclusion Criteria: * PSVD group : * Patient with PSVD according VALDIG criteria * TIPS for digestive hemorrhage on portal hypertension * TIPS for refractory ascite * TIPS for portal vein thrombosis * Cirrhosis group with PH : (appaired by age, sexe, type of PH complications) * Confirmed cirrhosis with : * TIPS for digestive hemorrhage on portal hypertension * TIPS for refractory ascite * TIPS for portal vein thrombosis Exclusion Criteria: * no PSVD confirmed diagnosis * Budd Chiari syndrome * Rendu Osler disease; Heart failure * Fontan; Sarcoïdosis * Schistosomiase * Congenitale liver fibrosis * Abernathy syndrome * Tumor infiltration by lymphoma * Bone graft

Inclusion Criteria: * Adults aged 18 years or older. * Diagnosed with type 1 diabetes mellitus or type 2 diabetes mellitus. * Able to communicate in Thai. * Willing and able to provide written informed consent. Exclusion Criteria: * Presence of neuropathy due to other causes (e.g., alcohol, chemotherapy, HIV, other systemic diseases). * Significant cognitive impairment or neurological conditions that prevent comprehension of the questionnaire. * Severe psychiatric illness that interferes with study participation.

Inclusion Criteria: * Age ≥ 18 years * Metastatic or unresectable breast cancer * HER2-negative (defined as having an IHC 0+, IHC 1+, or IHC 2+ and ISH non-amplified, per ASCO/CAP guidelines) on last assessable tumor sample * Having received ≥ 2 previous chemotherapy lines for advanced breast cancer: including at least one line of conjugated antibody, at the investigator's discretion or if a germinal BRCA mutation is present, a PARP inhibitor. * Class IV or V somatic ERBB3 mutation as determined on a tumor sample obtained during the molecular screening step * ECOG performance status ≤ 2 (Appendix A) * Evaluable disease, per RECIST v1.1 inclusion criteria * Left ventricular ejection fraction (LVEF) ≥50% as assessed by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) documented within 4 weeks prior to first dose of study treatment * Adequate organ function: 1. Creatinine clearance ≥ 50 mL/min as calculated per institutional guidelines 2. Total bilirubin ≤1.5 X upper limit of normal (ULN), except for patients with known Gilbert's disease, who may enroll if the conjugated bilirubin is ≤1.5 X ULN. 3. Transaminases (aspartate aminotransferase and alanine aminotransferase) ≤ 2.5 X ULN (≤ 5 X ULN if the patient has liver metastases) * Women of childbearing potential (WCBP) must have a negative serum pregnancy test \< 7 days prior to first dose of treatment. A woman is considered of childbearing potential following menarche and until becoming post-menopausal unless permanently sterile. A postmenopausal state is defined as the absence of menses for 12 months without an alternative cause. * WCBP (as defined above) and men with partners of childbearing potential must agree to use a highly effective birth control method during the study and for 3 months after completion of investigational treatment. * Patients should be eligible for the treatment step according to the investigator's opinion. * Patients must be covered by a health insurance plan. * Patients able to provide signed informed consent. Exclusion Criteria: * Having received any prior treatment targeting HER2. Prior treatment with trastuzumab deruxtecan is allowed, per label, in patients with HER2-low metastatic breast cancer (IHC 1+ or 2+, ISH non-amplified) * History of allergic reactions to trastuzumab or tucatinib or chemically similar drugs * Patients who are pregnant, breastfeeding, or planning a pregnancy from time of informed consent until 7 months after the final dose of study drug * Inability to swallow pills or having a significant gastro-intestinal disease or a history of surgery which would preclude the adequate oral absorption of medications * Having used a strong CYP2C8 inhibitor within a duration of 5 half-lives prior to the first dose of study treatment, or have used a strong CYP3A4 or CYP2C8 inducer within 5 days prior to first dose of study treatment (see Appendix B and Appendix C) * Treatment with any systemic anti-cancer therapy (including hormonal therapy), non-central nervous system (CNS) radiation, or experimental agent ≤ 3 weeks prior to the first dose of study treatment, except gonadotropin releasing hormone (GnRH) agonists * Participation in another interventional clinical trial. * Symptomatic and untreated brain metastases or brain metastases requiring urgent treatment, or brain metastases requiring a dose \> 2 mg of dexamethasone (or equivalent) * Whole brain radiotherapy \< 21 days prior to first dose of treatment, stereotactic radiotherapy \< 7 days prior to first dose of treatment * Leptomeningeal metastases * Major surgery (including surgery of brain metastases) \< 21 days prior to first dose of treatment * Evidence within 2 years of the start of study treatment of another malignancy that required systemic treatment * Have known myocardial infarction or unstable angina within 24 weeks prior to first dose of study treatment * Have clinically significant cardiopulmonary disease such as: * Ventricular arrhythmia requiring therapy, * Uncontrolled hypertension (defined as persistent systolic blood pressure \>150 mmHg and/or diastolic blood pressure \> 100 mm Hg on antihypertensive medications) * Any history of symptomatic congestive heart failure * Severe dyspnea at rest (CTCAE v5.0 Grade 3 or above) due to complications of advanced malignancy * Hypoxia requiring supplementary oxygen therapy except when oxygen therapy is needed only for obstructive sleep apnea * Presence of ≥ Grade 2 QTc prolongation on screening ECG * Conditions potentially resulting in drug-induced prolongation of the QT interval or torsade de pointes: * Congenital or acquired long QT syndrome * Family history of sudden death * History of previous drug-induced QT prolongation * Current use of medications with known and accepted associated risk of QT prolongation (see row "Accepted Association" in Appendix D) * Are known carriers of active Hepatitis B or Hepatitis C or have other known chronic liver disease * Are known to be positive for human immunodeficiency virus (HIV) * Altered mental status or psychiatric disorder that, in the opinion of the investigator, would preclude a valid patient informed consent. * Patients who have difficulty undergoing trial procedures for geographic, social or psychological reasons * Person deprived of liberty or under guardianship

Inclusion Criteria: 1. Jordanian women aged 18 to 45 years. 2. Primigravida or multigravida 3. Able to speak and read Arabic 4. Between six and eight weeks postpartum 5. EPDS score of ≥13 6. Access to an Android-compatible smartphone Exclusion Criteria: 1. Complications during or after childbirth 2. Newborn death or need for special/intensive care 3. Positive response ("yes") to the suicidal ideation item on the EPDS (these participants will be referred to the Prince Basma Outpatient Clinics, Mental Health Department)

Inclusion Criteria: * Patients with type 2 diabetes mellitus or gestational diabetes who require a multi-dose insulin regimen Exclusion Criteria: * T1DM, primary language non-English or Spanish, use of an insulin pump

Inclusion Criteria: Children aged 2-18 years with obstructive snoring or sleep apnea features on initial ENT outpatient screening. Adults (\>18 years) with suspected OSAS in a sleep or respiratory clinic, presenting with chronic snoring, witnessed apneas, or daytime sleepiness, and without severe chronic heart, liver, kidney failure, psychiatric disorders, or pregnancy. Signed written informed consent by the participant or their legal guardian. Not currently enrolled in any other registered clinical trial. Exclusion Criteria: Presence of congenital craniofacial malformations. Severe heart, lung, liver, or kidney failure, or major neurological disease. Recent use of anti-inflammatory or other immunomodulatory medications. Current psychiatric disorder or pregnancy

Inclusion Criteria: * Residing in or participating in the district catchment areas * Receiving services from participating health care facilities * Health providers and district health officials consent to participate in data collection Exclusion Criteria: * Individuals (health workers or patients) who decline to provide informed consent. * Individuals who are not directly involved in or accessing services from health care facilities or district health offices. * Inability to provide consent due to cognitive impairment or acute illness for health workers or district health officials involved in data collection

Inclusion Criteria: 1. Participant must have a histologically diagnosed adenocarcinoma of the prostate 2. Participant has to be ≥ 18 years of age 3. Participant must have either localized, locally advanced, or metastatic PC which has been treated or is planned to be treated either by RP, EBRT, androgen deprivation therapy (ADT), androgen receptor signaling inhibitor (ARSI), or any combination 4. Participant must understand and remember the training regimen 5. Participant must have a smartphone to connect a wearable device 6. Participant must have a smartphone or computer to access the online platform 7. Participant has to be able to speak, understand, and read German or English 8. Participant must sign an informed consent form (ICF) Exclusion Criteria: 1. Cardiovascular/neurological/musculoskeletal comorbidities with contraindications for resistance or aerobic training 2. High risk of pathological fracture due to unstable bone metastases (note: patients with bone metastasis are generally eligible for participation in the study and program as long as there is no acute high risk of fracture) 3. Any condition for which it may not be in the best interest of the patient to participate in the study

Inclusion Criteria: * The study will be carried on female patients who diagnosed as breast cancer based on pathological and radiological confirmation, recruited from Clinical Oncology Departments and outpatient clinics, SECI, Assiut University Exclusion Criteria: * Patients diagnosed with other concomitant cancer. * Patients who have already received chemotherapy or radiotherapy.

Inclusion Criteria: * DOSE ESCALATION PHASE ONLY: Patients must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective * DOSE EXPANSION PHASE ONLY: Participants must have histologically or cytologically confirmed invasive breast cancer, with either locally advanced or metastatic disease * Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of CX-5461 (pidnarulex) in combination with T-DXd in patients \< 18 years of age, children are excluded from this study * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%) * Absolute neutrophil count (ANC) ≥ 1,500/mcL * No administration of granulocyte colony-stimulating factor (G-CSF) is allowed within 1 week prior to screening assessment * Platelets ≥ 100,000/mcL * No transfusions with red blood cells or platelets are allowed within 1 week prior to screening assessment * Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN) (or ≤ 2 × institutional ULN in patients with documented Gilbert's syndrome) * Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) ≤ 3 × institutional ULN (or ≤ 5 × ULN in patients with liver metastases) * International normalized ratio (INR)/prothrombin time (PT) and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN * Glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m\^2 (using the Cockcroft-Gault equation for participants with creatinine levels above institutional ULN) * Patients must have had at least one prior line of cytotoxic chemotherapy. Patients can have received an unlimited number of additional lines of chemotherapy, targeted therapy, biologic therapy, or hormonal therapy. Patients must not have progressed on a prior anthracycline in the metastatic setting. Receipt of anthracycline in the (neo)adjuvant setting is allowed, provided that disease recurrence occurred later than 6 months after the completion of treatment * Prior poly (ADP-ribose) polymerase (PARP) inhibition is allowed * No specific germline mutation is required * DOSE ESCALATION PHASE ONLY: * HER2-positive (IHC 3+) solid cancers, * HR+ HER2 positive/low/ultralow breast cancer or triple negative breast cancer (TNBC) HER2-low breast cancer, with HER2 positive defined by the current American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines, * HER2-low, with HER2-low defined as IHC 2+/in situ hybridization (ISH)-, IHC 1+/ISH-, or IHC 1+/ISH untested * DOSE EXPANSION PHASE ONLY: * Either the primary invasive tumor and/or the metastasis must be: * HER2-low, with HER2-low defined as IHC 2+/ISH-, IHC 1+/ISH-, or IHC 1+/ISH untested. Any estrogen receptor (ER) and progesterone receptor (PR) expression is permitted but must be known, or * HR+ HER2-ultralow defined as IHC 0 with membrane staining * Participants must have at least one lesion that is not within a previously radiated field that is measurable per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1. Bone lesions are not considered measurable by definition. Biopsy of the lesion that will be used for disease evaluation (measurable disease) is not allowed in the dose expansion portion of this study * Peripheral neuropathy grade ≤ 1 * Patients must have left ventricular ejection fraction (LVEF) ≥ 50% by either an echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan within 28 days before randomization/enrollment * Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial * For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated * Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load * Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression * Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy * Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class II or better * Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial * The effects of CX-5461 (pidnarulex) and T-DXd on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) 14 days prior to study entry and for the duration of study participation and for at least 7 months (women of childbearing potential \[WOCBP\] only) after the last dose of study drug. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Women should not breastfeed while taking CX-5461 (pidnarulex) and T-DXd and for 7 months after cessation of treatment. Men treated or enrolled on this protocol must also agree to use adequate contraception 14 days prior to the study, for the duration of study participation, and 6 months after completion of CX-5461 (pidnarulex) and T-DXd administration * Women of non-child-bearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases, a blood sample with simultaneous follicle-stimulating hormone \[FSH\] \> 40 mIU/mL and estradiol \< 40 pg/mL \[\< 147 pmol/L\] is confirmatory) or on ovarian suppression are eligible. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods outlined for women of child-bearing potential if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method * Male patients must not freeze or donate sperm starting at screening and throughout the study period, and at least 6 months after the final study drug administration. Preservation of sperm should be considered prior to enrollment in this study * Female patients must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 7 months after the final study drug administration * Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives (LAR) may sign and give informed consent on behalf of study participants * Patients who have had chest radiation therapy within 4 weeks (2 weeks for palliative stereotactic radiation therapy). These patients will be excluded because T-DXd is known to i

Inclusion Criteria: * Histologically confirmed diagnosis of HR+, HER2 negative metastatic breast cancer. * Estrogen receptor (ER) and/or progesterone receptor (PR) expression positivity is defined as at least 10% of tumor cells nuclei positive by immunohistochemistry in the sample on testing. * HER2 negative: defined as IHC staining of 0 or 1+. If HER2 overexpression is equivocal by IHC, defined as 2+, the tumor must be non-gene amplified by FISH (ratio \<2 and HER2 copy number \<4). * Progression on treatment with a CDK 4/6 inhibitor and hormonal therapy in the metastatic setting * The CDK 4/6 inhibitor must be ribociclib or abemaciclib. Patients on palbociclib are not eligible. * Patient may have been on palbociclib previously but must have been stable on ribociclib or abemaciclib for at least three months prior to enrolling. In this case, the switch from palbociclib to either ribociclib or abemaciclib must have been of toxicity management and not progression of disease. * Hormonal therapy is defined as an aromatase inhibitor (anastrozole, letrozole, exemestane) or fulvestrant. * Patients on tamoxifen are not eligible. * Both men and pre/perimenopausal women must be on ovarian suppression with a luteinizing hormone-releasing hormone (LHRH) agonist. * Patients must have measurable disease based on RECIST 1.1 criteria. * Females of child-bearing potential (FOCBP) who engage in intercourse must agree to use adequate contraception (e.g., hormonal or an intrauterine device \[IUD\] or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 3 weeks following completion of therapy. NOTE: A FOCBP is any woman who meets the following criteria: * Has not undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy * Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for \> 12 months) * FOCBP must have a negative serum pregnancy test within 7 days prior to registration. * Patients must be ≥ 18 years of age at the time of signing consent. * Patients must have an estimated life expectancy of at least 12 weeks. * Patients must exhibit an ECOG performance status of 0 or 1. * Patients must have adequate organ and bone marrow function as defined below: * Leukocytes (WBC) ≥ 3,000/mcL * Absolute neutrophil count (ANC) ≥ 1000/mcL * Hemoglobin (Hgb) ≥ 7 g/dL * Platelets (PLT) ≥ 100,000/mcL * Total bilirubin \< 1.5 x Institutional upper limit of normal (ULN); ≤ 3.0 x ULN for patients with Gilbert's syndrome * AST (SGOT)/ALT (SGPT) \< 3 x institutional ULN, or \< 5 x ULN if liver metastasis present * Creatinine \< 1.5 Institutional ULN * Patients with treated brain metastases are eligible if follow-up brain imaging at least 6 weeks after central nervous system (CNS)-directed therapy shows no evidence of progression. * Patients must have sufficient samples available to meet Menarini Silicon Biosystems (MSB) specimen requirements. * Patients with known history or current symptoms of cardiac disease, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better. * Patients must have the ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: * Patients who have any systemic therapy in the metastatic setting except hormonal therapy in combination with a CDK 4/6 inhibitor. Previously palliative targeted radiation therapy is allowed. Bone targeting agents such as bisphosphonates and rank ligand inhibitors for metastatic breast cancer to the bone is also allowed prior and during this trial. * Patients with untreated new or progressive brain metastases or leptomeningeal disease * Use of concomitant nitrates and PDE5 inhibitors. * Use of potent CYP3A4 inhibitors or inducers and not able to discontinue two weeks prior to enrolling onto the trial. * Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient's safety or study endpoints. Note: Patients with HIV or infectious hepatitis must exhibit well controlled disease with stable treatment regimen (where applicable) that in the opinion of the treating physician should not preclude them from participating in the study. * Patients who are currently pregnant or breast feeding. * Patients with a history of another invasive malignancy within 2 years of registration with the exception of local squamous cell or basal cell carcinoma of the skin.