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Impact of Neoadjuvant Immunotherapy in Early Stage Breast Cancer Before Standard Therapy (BIS-Program)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05180006
Recruitment Status : Recruiting
First Posted : January 6, 2022
Last Update Posted : March 24, 2022
Sponsor:
Collaborator:
Hoffmann-La Roche
Information provided by (Responsible Party):
Gustave Roussy, Cancer Campus, Grand Paris

Brief Summary:

The aim of this study is to determine, using immunohistochemistry (IHC) on biopsies and surgically removed tumor if short-treatment immunotherapy with atezolizumab monotherapy or in combination with other biologic agents (ipatasertib / Bevacizumab / Trastuzumab / Pertuzumab) is associated with increased levels of activated GzmB+ CD8+ T cells from baseline to post treatment sample.

Moreover, from baseline to post treatment sample, evolution of others biomarkers will be studied : GzmB/CD8, CD8/FoxP3, CD8/CD68 in IHC, cell proliferation, PD-L1, MHC-I, change in gene expression (RNA-Seq). Tjis study aim also to assess the safety and tolerability of study treatments in this population and to determine the effect of short-term immunotherapy treatment in pCR at surgery.

Patients will undergo tumor biopsies at screening and 15 days after the beginning of treatment (if they start neoadujavant chemotherapy) / at surgery, in order to evaluate in IHC evolution of activated GzmB+ CD8+ T cells and evaluate other markers

It targets 2 different cohorts: newly diagnosed, non-metastatic early-stage triple-negative (TNBC) or HER2+ breast cancer. TNBC cohort is composed of 4 open-label, randomized arms, HER2+ of 2 arms.

A maximum of 210 patients will be included in the trial (147 in TNBC cohort and 63 in HER2+ cohort).

Tumor evaluation will be performed by clinical examination and Breast echography at baseline and end of treatment visit.

The safety of the product will be assessed at each cycle, through complete clinical exams, biological tests and through the collection of ongoing toxicities or adverse events.


Condition or disease Intervention/treatment Phase
Breast Cancer Drug: Atezolizumab Injection Drug: Ipatasertib Drug: Bevacizumab Drug: Pertuzumab Drug: Trastuzumab Phase 2

Detailed Description:

Cohort 1 In TNBC patients t will be composed of 4 open-label, randomized arms:

Arm 1A: control arm; no treatment Arm 1B: atezolizumab alone, administered as one single IV infusion on day -15 +/- 48 h (D1) prior to the date of surgery or the start of neoadjuvant chemotherapy Arm 1C: atezolizumab as one single IV infusion on day -15 +/- 48 h (D1) prior to the date of surgery or the start of neoadjuvant chemotherapy, in combination with daily oral ipatasertib for 14 days starting at the same time as atezolizumab administration Arm 1D: atezolizumab and bevacizumab as one single IV infusion on day -15 +/- 48 h (D1) prior to the date of surgery or the start of neoadjuvant chemotherapy

Cohort 2 in HER2-positive patients will be composed of 2 arms:

Arm 2A: no treatment Arm 2B: atezolizumab as one single IV infusion in combination with trastuzumab + pertuzumab for one IV infusion on day -15 +/- 48 h (D1) prior to the date of surgery or the start of neoadjuvant chemotherapy

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 210 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

The design of this study follows an adaptive, open, prospective randomized model : Cohort 1 TNBC patients: they will be randomized 1:2:2:2 to either no treatment, or atezolizumab alone administered as one single IV infusion on day -15 +/- 48 h (D1) prior to the date of surgery or the start of neoadjuvant CT, or atezolizumab as one single IV infusion on day -15 +/- 48 h (D1) prior to the date of surgery or the start of neoadjuvant CT in combination with daily oral ipatasertib for 14 days starting at the same time as atezolizumab, or atezolizumab and bevacizumab as one single IV infusion on day -15 +/- 48 h (D1) prior to the date of surgery or the start of neoadjuvant CT.

Cohort 2 in HER2-positive patients: they will be randomized 1:2 to either no treatment, or atezolizumab as one single IV infusion in combination with trastuzumab and pertuzumab for one IV infusion on day -15 +/- 48 h (D1) prior to the surgery or the start of neoadjuvant chemotherapy.

Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Impact of Neoadjuvant Immunotherapy in Early Stage Breast Cancer Before Standard Therapy
Actual Study Start Date : February 24, 2022
Estimated Primary Completion Date : February 2024
Estimated Study Completion Date : February 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
No Intervention: Arm 1A: control arm; no treatment, in TNBC patients (cohort 1)
Control arm : no treatment
Experimental: Arm 1B: Atezolizumab, in TNBC patients (cohort 1)
atezolizumab alone, administered as one single IV infusion on day -15 +/- 48 h (D1) prior to the date of surgery or the start of neoadjuvant chemotherapy
Drug: Atezolizumab Injection
Patients randomized to an atezolizumab arm will receive atezolizumab 840 mg IV on D1 (15 days +/- 48 h before the surgery date or the biopsy prior to the start of the neoadjuvant CT).

Experimental: Arm 1C: Atezolizumab + Ipatasertib, in TNBC patients (cohort 1)
atezolizumab as one single IV infusion on day -15 +/- 48 h (D1) prior to the date of surgery or the start of neoadjuvant chemotherapy, in combination with daily oral ipatasertib for 14 days starting at the same time as atezolizumab administration
Drug: Atezolizumab Injection
Patients randomized to an atezolizumab arm will receive atezolizumab 840 mg IV on D1 (15 days +/- 48 h before the surgery date or the biopsy prior to the start of the neoadjuvant CT).

Drug: Ipatasertib
Patients in the atezolizumab plus ipatasertib arm will receive treatment (ipatasertib) for 2 weeks unless unacceptable toxicity occurs. Patients will receive ipatasertib at a dose of 400 mg orally once a day on Days 1-14 until the day before the surgery or the biopsy before start neoadjuvant therapy.

Experimental: Arm 1D: Atezolizumab + Bevacizumab, in TNBC patients (cohort 1)
atezolizumab and bevacizumab as one single IV infusion on day -15 +/- 48 h (D1) prior to the date of surgery or the start of neoadjuvant chemotherapy
Drug: Atezolizumab Injection
Patients randomized to an atezolizumab arm will receive atezolizumab 840 mg IV on D1 (15 days +/- 48 h before the surgery date or the biopsy prior to the start of the neoadjuvant CT).

Drug: Bevacizumab
Patients in the atezolizumab plus bevacizumab arm will receive a unique dose of bevacizumab as 10 mg/kg administered by IV infusion over 60 mins on day 1 cycle 1 (15 days before surgery +/- 48 h), the same day as atezolizumab.

No Intervention: Arm 2A: control arm; no treatment, in HER2+ patients (cohort 2)
no treatment
Experimental: Arm 2B: Atezolizumab + Trastuzumab + Pertuzumab, in HER2+ patients (cohort 2)
atezolizumab as one single IV infusion in combination with trastuzumab + pertuzumab for one IV infusion on day -15 +/- 48 h (D1) prior to the date of surgery or the start of neoadjuvant chemotherapy
Drug: Atezolizumab Injection
Patients randomized to an atezolizumab arm will receive atezolizumab 840 mg IV on D1 (15 days +/- 48 h before the surgery date or the biopsy prior to the start of the neoadjuvant CT).

Drug: Pertuzumab
Patients in the atezolizumab plus trastuzumab plus pertuzumab arm will receive single doses of pertuzumab on day 1 administered IV. Pertuzumab will be administered IV at a loading dose of 840 mg.

Drug: Trastuzumab
Patients in the atezolizumab plus trastuzumab plus pertuzumab arm will receive single doses of Trastuzumab on day 1 administered IV. Trastuzumab will be given at a loading dose of 8 mg/kg.




Primary Outcome Measures :
  1. Two-fold increase in GzmB+ CD8+ T cell levels from baseline to post-treatment window. [ Time Frame: From baseline to post-treatment (14 days) window. ]
    To determine, using immunohistochemistry (IHC) on biopsies and surgically removed tumor whether short-treatment immunotherapy with atezolizumab monotherapy or in combination with other biologic agents is associated with increased levels of activated GzmB+ CD8+ T cells from baseline to post treatment sample.


Secondary Outcome Measures :
  1. Clinical response after experimental therapy [ Time Frame: From baseline to post-treatment (14 days) window. ]
    Clinical response after experimental therapy, defined as a > 30% decrease in tumour diameter from baseline breast ultrasound based on investigator assessment

  2. pCR [ Time Frame: From baseline to post-treatment (14 days) window. ]
    pCR defined as the absence of any residual invasive cancer based on histological evaluation of the resected specimen during definitive breast cancer surgery.

  3. Changes in CD8+ expression (Translational Study) [ Time Frame: From baseline to post-treatment (14 days) window. ]
    Changes in CD8+ expression from baseline (pre-study) to end of study-treatment biopsies

  4. Changes in PD-L1 expression (Translational Study) [ Time Frame: From baseline to post-treatment (14 days) window. ]
    Changes in PD-L1 expression from baseline (pre-study) to end of study-treatment biopsies

  5. Changes in % of Ki67 (Translational Study) [ Time Frame: From baseline to post-treatment (14 days) window. ]
    Changes in % of Ki67 from baseline (pre-study) to end of study-treatment biopsies

  6. Changes in immune infiltrates (Translational Study) [ Time Frame: From baseline to post-treatment (14 days) window. ]
    Changes from baseline tumour tissue to end of treatment in immune infiltrates.

  7. Changes in immune-related gene expression (Translational Study) [ Time Frame: From baseline to post-treatment (14 days) window. ]
    Changes from baseline tumour tissue to end of treatment in immune-related gene expression



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patient should understand, sign, and date the written informed consent form prior to any protocol-specific procedures performed. Patient should be able and willing to comply with study visits and procedures as per protocol.
  • Female or male patients aged 18 years or older
  • Eastern Cooperative Group (ECOG) Performance Status 0-1
  • Histologically confirmed female breast cancer with no evidence of metastatic spread
  • Candidate to surgery upfront or patients with an indication of neoadjuvant chemotherapy, assuming chemotherapy starts after the completion of the pre-operative immunotherapy treatment, biopsies are undertaken before the start of the systemic chemotherapy and the decision to administer neoadjuvant chemotherapy is made before randomization
  • At least 11 mm in tumor size as determined by breast ultrasound
  • ER, PR and HER2 will be locally assessed and defined as per ASCO/CAP guidelines

    • For the TNBC cohort, ER < 1%, PR < 1% and HER2 not overexpressed/amplified
    • For the HER2-positive cohort, presence of a HER2 overexpression and/or amplification as per ASCO/CAP guidelines
  • Adequate haematologic and organ function defined by the following:

    • ANC ≥ 1,500 cells/µl
    • Platelet count ≥ 100,000/µl
    • Haemoglobin ≥ 9.0 g/dL (90g/L)
    • Serum albumin ≥ 2.5 g/dL
    • Creatinine ≤ 1.5 x ULN
    • Bilirubin ≤ 1.5 x ULN, AST or ALT < 3 x ULN, ALP < 2.5 x ULN (patients with known Gilbert disease who have serum bilirubin level ≤ 3 × the institutional ULN may be enrolled)
    • For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5 x ULN. For patients receiving therapeutic anticoagulation: stable anticoagulant regimen
  • Patients of child-bearing potential are eligible, provided they have a negative serum β-HCG pregnancy test within 2 weeks or urine pregnancy test within 48 hours prior to the first dose of study treatment, and agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for 5 months after the last dose of atezolizumab, 6 months after the last dose of bevacizumab, 28 days after the last dose of ipatasertib and 7 months after the last dose of pertuzumab and/or trastuzumab.
  • A woman is considered of childbearing potential following menarche and until becoming post-menopausal (≥ 12 months of non-therapy-induced amenorrhea) unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral oophorectomy and bilateral salpingectomy.
  • Sexually active women of childbearing potential must agree to use a highly effective method of contraception supplemented by a barrier method, or to abstain from sexual activity during the study and for at least 5 months after discontinuation of atezolizumab treatment, 6 months after the last dose of bevacizumab, 28 days after the last dose of ipatasertib and 7 months after the last dose of pertuzumab and/or trastuzumab. Female subjects should also refrain from breastfeeding throughout this period.
  • A highly effective birth control method is a one, which can achieve a failure rate of less than 1% per year when used consistently and correctly. Such methods include: combined (estrogen and progestogen containing) hormonal contraception; progestogen-only hormonal contraception associated with inhibition of ovulation; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomized partner (on the understanding that this is the only one partner during the whole study duration), and sexual abstinence during the entire period of risk associated with study treatment. To prevent the risk of interaction between the study drug and hormonal contraceptives, hormonal contraceptives should be supplemented with a barrier method (preferably male condom). Following methods are considered as unacceptable methods (non-exhaustive list): periodic abstinence (calendar, symptothermal, post-ovulation methods) and withdrawal (coitus interruptus).
  • Sexually actives males patients must agree to use condom during the study and for at least 5 months after discontinuation of atezolizumab treatment, 6 months after the last dose of bevacizumab, 28 days after the last dose of ipatasertib and 7 months after the last dose of pertuzumab and/or trastuzumab. Also, it is recommended their women of childbearing potential partner use a highly effective method of contraception for the same duration.
  • Patients must be affiliated to a social security system or beneficiary of the same.

Exclusion Criteria:

Patients who meet any of the following exclusion criteria will not be eligible for this study.

  • Evidence of metastatic breast cancer
  • HR+ and/or HER2+ (for the TNBC cohort) and HER2- (for the HER2+ cohort)
  • Any systemic therapy (e.g, chemotherapy, targeted therapy, immune-therapy) or radiotherapy for current breast cancer disease before study entry
  • Previous systemic treatment for other neoplasms within 1 year prior to randomization
  • Active malignancy (except for non-melanoma skin cancer, or histologically confirmed complete excision of carcinoma in-situ) within the past 36 months prior to study entry
  • Known intolerance to any of the study drugs or any of their excipients
  • Patients with prior allogeneic stem cell or solid organ transplantation
  • Administration of a live, attenuated vaccine within 4 weeks prior to enrolment or anticipation that such a live, attenuated vaccine will be required during the study or within 5 months after the last dose of atezolizumab
  • Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin-2) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to enrolment
  • Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate and thalidomide) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions:

    • Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids as premedication for hypersensitivity reaction (e.g., CT scan premedication)) are eligible for the study after Medical Monitor approval has been obtained
    • Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study
    • Patients who received intranasal, inhaled, topical or local steroid injections (e.g., intra articular injection)
  • Active or history of autoimmune disease or immune deficiency, with the exception of history of treated autoimmune-related hypothyroidism and Type 1 diabetes mellitus on insulin regimen
  • Symptomatic intrinsic lung disease or with extensive tumor involvement of the lungs, resulting in dyspnea
  • History of idio pathic pulmonary fibrosis (including pneumonitis or interstitial lung disease), drug-induced pneumonitis, organizing pneumonia (i.e. bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis (history of radiation pneumonitis in the radiation field (fibrosis) is permitted).
  • Patients who underwent major surgery within 28 days prior to inclusion or until the surgical wound is fully healed
  • History of HIV infection
  • Patients with active hepatitis infection (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA
  • Active tuberculosis
  • Current treatment with anti-viral therapy for HBV
  • Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including antiCTLA-4, antiPD-1, and antiPD-L1 therapeutic antibodies
  • Psychological, familial, sociological or geographical conditions that do not permit compliance with the study protocol
  • Participation in another clinical study with an investigational product during the last 28 days and while on study treatment
  • Currently known to have a history or ongoing serious retinopathy and/or history of retinal vein occlusion
  • History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
  • Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation or to any component of the other drugs on the study
  • Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
  • Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment
  • Significant cardiovascular disease, such as:

    • History of myocardial infarction, acute coronary syndromes or coronary angioplasty/stenting/bypass grafting within the past 6 months,
    • Congestive Heart Failure (CHF) NYHA class III or IV or history of CHF NYHA class III or IV, unless an echocardiogram or multi-gated acquisition scan performed within 3 months day 1 reveals a left ventricular ejection fraction ≥ 50%55%
  • Uncontrolled hypertension defined by systolic pressure > 150 and/or diastolic pressure > 110 mmHg, with or without anti-hypertensive medication. Patients with initial blood pressure elevations are eligible if initiation or adjustment of anti-hypertensive medication lowers blood pressure to meet entry criteria
  • History of stroke or transient ischemic attack within 6 months prior to randomisation
  • History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to randomisation
  • History of haemoptysis (> 1/2 teaspoon of bright red blood per episode) or other serious haemorrhage or at risk of bleeding (gastrointestinal history of bleeds, gastrointestinal ulcers etc.) within 1 month prior to randomization
  • Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that, in the investigator's opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, may affect the interpretation of the results, render the patient at high risk from treatment complications or interferes with obtaining informed consent.
  • Pregnant or breastfeeding women
  • Patient under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving its consent.

For the TNBC cohort (exclusion criteria in relation to bevacizumab and ipatasertib):

  • Uncontrolled hypertension defined by systolic pressure > 150 and/or diastolic pressure > 110 mmHg, with or without anti-hypertensive medication. Patients with initial blood pressure elevations are eligible if initiation or adjustment of anti-hypertensive medication lowers blood pressure to meet entry criteria
  • Currently known to have a history or ongoing serous retinopathy and/or history of retinal vein occlusion
  • History of stroke or transient ischemic attack within 6 months prior to randomization
  • History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to randomization
  • History of haemoptysis (> 1/2 teaspoon of bright red blood per episode) or other serious haemorrhage or at risk of bleeding (gastrointestinal history of bleeds, gastrointestinal ulcers etc.) within 1 month prior to randomization
  • Instability to swallow medication or malabsorption condition that would alter the absorption of orally administered medications
  • Clinically significant abnormalities of glucose metabolism as defined by any of the following:

    • Glycosylated haemoglobin (HbA1c) ≥ 7.5% at screening (64 mmol/mol)
    • Fasting plasma glucose ≥ 7.0 mmol/L (126 mg/dl) at screening. Fasting is defined as no caloric intake for at least 8 hours
    • History of type I or Type II diabetes mellitus requiring insulin. Patients who are stable on dose of oral diabetes medication ≥ 2 weeks prior to initiation of study treatment are eligible for enrolment
  • History of active inflammatory bowel disease (e.g. Crohn's disease and ulcerative colitis) or active bowel inflammation ( e.g. diverticulitis)
  • Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 2 weeks or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study drug
  • Grade ≥ 2 uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia
  • Lung disease: pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, cystic fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic infections (pneumocystis pneumonia or cytomegalovirus pneumonia)
  • Known clinically significant history of liver disease consistent with Child Pugh Class B or C, including active viral or other hepatitis (e.g., positive for hepatitis B surface antigen [HBsAg] or hepatitis C virus [HCV] antibody at screening), current drug or alcohol abuse, or cirrhosis

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05180006


Contacts
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Contact: Barbara Pistilli, Dr +33 (0)1 42 11 42 11 ext 61 62 barbara.pistilli@gustaveroussy.fr
Contact: Joana Mourato Ribeiro, Dr +33 (0)1 42 11 42 11 ext 38 55 Joana-mourato.RIBEIRO@gustaveroussy.fr

Locations
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France
Gustave Roussy Recruiting
Villejuif, France, 94800
Contact: Barbara Pistilli, Dr    +33 (0)1 42 11 42 11 ext 61 62    barbara.pistilli@gustaveroussy.fr   
Sponsors and Collaborators
Gustave Roussy, Cancer Campus, Grand Paris
Hoffmann-La Roche
Investigators
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Study Director: Barbara Pistilli, Dr Gustave Roussy, Cancer Campus, Grand Paris
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Responsible Party: Gustave Roussy, Cancer Campus, Grand Paris
ClinicalTrials.gov Identifier: NCT05180006    
Other Study ID Numbers: 2020-004696-41
2020/3130 ( Other Identifier: CSET number )
First Posted: January 6, 2022    Key Record Dates
Last Update Posted: March 24, 2022
Last Verified: March 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Gustave Roussy, Cancer Campus, Grand Paris:
triple-negative breast cancer
HER2+ breast cancer
non-metastatic breast cancer
immunotherapy
atezolizumab
ipatasertib
bevacizumab
trastuzumab
pertuzumab
GzmB+
CD8+
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Bevacizumab
Trastuzumab
Pertuzumab
Atezolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors