Clinical trial NCT05163106: Neoadjuvant Treatment of Locally-advanced Breast Cancer Patients With Ribociclib and Letrozole
Official title: Presurgical Treatment With Ribociclib and Letrozole in Patients With Locally Advanced Breast Cancer: the NEOLETRIB Study.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Cancer
HER2-negative Breast Cancer
ER-positive Breast Cancer
Locally Advanced Breast Cancer
Luminal A Breast Cancer
Luminal B Breast Cancer
Keywords: Breast Cancer
Letrozole
Ribociclib
Combination Therapy
Lead sponsor: University Hospital, Akershus
Sponsor class: OTHER
Collaborators: name: Novartis
name: Vestre Viken Hospital Trust
First posted: 2021-12-20
Enrollment: 85
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Multicentre, single-arm, open-label, neoadjuvant study model
Primary purpose: TREATMENT

Brief summary: Patients with locally advanced (stage III) breast cancer (LABC) are characterized by a significantly worse prognosis compared to patients with primarily operable breast cancer. While neoadjuvant chemotherapy has been the first choice in this situation for several decades, recent evidence suggests that some patients may experience an extraordinary effect from neoadjuvant endocrine treatments involving aromatase inhibitors as monotherapy or in modern drug combinations.Selected LABC patients admitted for treatment will be offered combination therapy including letrozole and ribociclib. The overall goal of the project is to improve understanding of tumor responses and resistance in patients suffering from ER-positive/HER-2 negative locally advanced breast cancer, focusing on the role of the immune system including the gut microbiome.

Detailed description: Neoadjuvant endocrine therapy (NET) offers a good treatment option to reduce the size of large (inoperable) primary breast tumors and/or advanced axillary lymph node metastasis prior to definite surgery. For selected patients (postmenopausal women with ER-positive breast cancer), primary endocrine therapy has been shown to be as effective as standard neoadjuvant chemotherapy. It is the general opinion that aromatase inhibitors of the "third-generation" (letrozole, anastrozole, exemestane) are the preferable drugs for neoadjuvant endocrine therapy in ER-positive, postmenopausal breast cancer patients. Anastrozole, letrozole and exemestane have been shown to suppress total body aromatisation as well as plasma and tissue estrogen levels by \> 90% in vivo. All three drugs are currently used as standard care in the neoadjuvant, adjuvant and metastatic setting worldwide, including in Norway.

In 2015, a new class of anti-cancer drugs was introduced known as cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors. Following pivotal trials showing dramatic effects when combined with aromatase inhibitors or steroidal antiestrogens like fulvestrant, these compounds are now well established in distinct combinations during therapy for metastatic breast cancer. All in all, the addition of a CDK4/6 inhibitor to standard anti-hormone therapy for breast cancer doubled the time to disease progression and caused significant improvements in overall survival. Based on these findings, CDK4/6 inhibitors have also been tested in the neoadjuvant setting in clinical trials with very promising results. However, the combination of an aromatase inhibitor and a CDK4/6-inhibitor is not currently approved as standard neoadjuvant treatment for patients with locally advanced breast cancer (LABC) in Norway. Thus, the study described here will make this highly promising drug combination available for all patients who participate in this study. At the same time, the protocol will allow investigators to optimize the selection of patients benefitting from this treatment, highlight relevant biomarkers for personalized medicine and treatment, evaluate predictive markers and study the basic biology underlying treatment effects and resistance.

In recent years researchers have noted a growing body of evidence concerning the involvement of the immune system in the onset and prognosis of breast cancer both locally (in the tumor or connected tissues) and through the involvement of the immune system as a whole. Interestingly, the gastrointestinal (gut) microbiota seems to play an important role in determining whether the immune system is able to fight against several cancer types. Pre-clinical studies have shown that the microbes in the gut may influence the repertoire and activity of immune cells, such as T cells, potentially priming the immune system for cancer cell recognition and destruction. This hypothesis is supported by the finding that treatment responses to immune checkpoint inhibitors (ICIs) in a variety of cancer types is dependent on the distinct gut microbiome of an individual patient as the efficacy of the ICIs relies on the presence of cancer-recognizing T cells.

In addition, recent findings indicate that an emerging group of small molecules / targeting cancer therapies have immune altering properties. The MAPK kinase (MEK) inhibitors exemplify this by contributing to anti-tumor immunity through increasing the levels of cytotoxic T lymphocytes in preclinical model systems. Similar findings have recently been reported for both CDK4/6 inhibitors and PI3K-inhibitors. Thus, CDK4/6 inhibitors are believed to increase the antigen presentation of cancer cells, increase the activity of tumor infiltration by CD45+ cells and effector T cell activation, as well as decreasing Treg cell proliferation. While these mechanisms have been well described in in vitro and animal models, they need to be studied in humans as soon as possible to understand them and allow investigators to take advantage of these novel aspects in clinical decision making. These findings may also pave the way for microbiome and immune-related data to be used as potential biomarkers for patient selection and response evaluations during therapy.

In addition to the clinical effects of being the standard care for breast cancer patients suffering from locally advanced breast cancer, neoadjuvant therapy is widely used to study the endocrinology of breast cancer in general and is recognized as one of the best model systems to predict responses in other clinical settings (early breast cancer or metastatic breast cancer). Tumor biopsies obtained before initiation of treatment and following six months of therapy will allow correlations to the individual type of clinical response (partial responses vs complete responses etc.). The research will focus on intratumoral mechanisms of adaption through tumor characterization using single cell technology which will allow investigators to follow both the different cancer clones as well as the evolution of different immune cells during therapy. Investigators will use novel approaches to evaluate liquid biopsies (measurement of cytokines levels, metabolites and cell free DNA-fragments etc.) during letrozole and ribociclib therapy using state of the art laboratory methods available at the host hospital and in the laboratories of the listed collaborators.

Thus, all in all, the planned study will be able to contribute to the basic understanding of this very potent new drug combination that may be used in large groups of breast cancer patients in the future, including locally advanced breast cancer, hopefully reducing the use of traditional chemotherapy in this setting.

Eligibility criteria: Inclusion Criteria:

* Females ≥ 18 years old at the time of the ICF signature
* histologically confirmed locally advanced breast carcinoma, defined as either large T2 (\>3cm in diameter) or T3-T4, and/or N2-3 primary breast cancer
* ER-positive (defined by ER-pos. in ≥ 50% of cancer cells) and HER-2 negative, luminal A/B breast cancer
* postmenopausal status (natural status or induced by treatment with the LHRH-analogue goserelin 3.6mg implant s.c. given every 4 weeks); definition of natural post-menopausal status: age above 55 years or age above 50 years and at least 2 years of amenorrhea in addition to LH-, FSH-, and plasma estradiol levels in the post-menopausal range.
* Patient has adequate bone marrow and organ function as defined by the following laboratory values (as assessed by central laboratory eligibility): Absolute neutrophil count ≥ 1.0x109/L; platelets ≥ 100 x 109/L; Hemoglobin ≥ 9.0g/dL; INR≤1.5 (unless the patient is receiving anticoagulants and the INR is within the therapeutic range of intended use for that anticoagulant within 7 days prior to the first dose of study drug); Estimated glomerular filtration rate (eGFR) ≥ 30mL/min/1.73m2 according to the Modification of Diet in Renal Disease (MDRD) formula; total bilirubin \< ULN except for patients with Gilbert's syndrome who may only be included if the total bilirubin is ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN; aspartate transaminase (AST) \< 2.5 x ULN; Alanine transaminase (ALT) \< 2.5 x ULN; patient must have the following laboratory values within normal limits or corrected to within normal limits with supplements before the first dose of study medication: potassium, magnesium, total calcium (corrected for serum albumin).
* Standard 12-lead ECG values defined as the mean of the triplicate ECGs \[QTcF interval at screening \< 450 msec (QT interval using Fridericia's correction), mean resting heart rate 50-90 bpm (determined from the ECG)\]
* Performance status: Eastern Cooperative Oncology Group (ECOG) score 0-1
* Ability and willingness to comply with study visits, treatment, testing and to comply with the protocol.

Exclusion Criteria:

* Any prior treatment for primary invasive breast cancer
* Patient with a known hypersensitivity to any of the excipients of ribociclib or letrozole
* Patient with known hypersensitivity to peanuts or soya-products
* Any evidence of distant metastasis
* Triple-negative breast cancer
* HER-2 positive disease, suitable for neoadjuvant therapy with trastuzumab, pertuzumab and taxanes, etc.
* Other conditions rendering patients in need of other treatment options with immediate effect like chemotherapy
* Concomitant medications that are known strong inducers of CYP3A4/5
* Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, including any of the following: History of documented myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to study entry; documented cardiomyopathy; Left Ventricular Ejection Fraction (LVEF) \< 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO); Long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome, or any of the following: Risk factors for Torsades de Pointe (TdP) including uncorrected hypocalcemia, hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia, Concomitant medication(s) with a known risk to prolong the QT interval and/or known to cause Torsades de Pointe that cannot be discontinued or replaced by safe alternative medication (e.g., within 5 half-lives or 7 days prior to starting study drug) or Inability to determine the QTcF interval; Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block); Systolic Blood Pressure (SBP) \>160 or \<90 mmHg
* Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to starting study drug, or who have not fully recovered from side effects of such treatment. Note: The following uses of corticosteroids are permitted: a short duration (\<5 days) of systemic corticosteroids; any duration of topical applications (e.g. for rash), inhaled sprays (e.g., for obstructive airways diseases), eye drops or local injections (e.g., intraarticular).
* Pregnant or breast-feeding (lactating) women or women who plan to become pregnant or breast-feed during the trial
* Women of child-bearing potential defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during the study treatment and for 21 days after stopping the treatment. Highly effective contraception methods include: Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception; Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least 6 weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment; Male partner sterilization (at least 6 months prior to screening). For female patients on the study, the vasectomized male partner should be the sole partner for that patient and the success of the vasectomy must be medically confirmed as per local practice; Placement of an intrauterine device (IUD); Note: Use of oral (estrogen and progesterone), transdermal, injected, implanted, hormone containing intrauterine systems (IUS) or any other hormonal methods of contraception is not allowed in this study
* Autoimmune disorders or significant allergies (i.e. rheumatoid arthritis, asthma, psoriasis, etc.)
* Known HIV infection, Hepatitis B or C infection (testing not mandatory)
* History of autoimmune celiac, inflammatory bowel disease, or other chronic GI disease
* Recent use (within past month) of more than 3 days of antibiotics use
* Current use of probiotic supplements
* Taking proton pump inhibitors, steroids, other non-steroidal antiinflammatory drugs such as ibuprofen or acetyl salicylic acid
* Past bariatric surgery

Primary outcomes:
measure: To study the change in levels of direct and indirect immunologic biomarkers of targeted cancer therapy with letrozole and ribociclib given in combination for patients with locally-advanced, ER-positive, HER-2 negative, luminal A7B breast cancer
timeFrame: Baseline, Day 21 and at time of surgery (Day 180)
Secondary outcomes:
measure: Measurement of changes in the tumor through DNA profiling throughout the treatment cycle with letrozole and ribociclib
timeFrame: Baseline, Day 21 and at time of surgery (Day 180)
measure: Confirmation of the breast cancer subtype
timeFrame: Baseline
measure: Changes in neoantigens and single T-cell receptor function after treatment with letrozole and ribociclib
timeFrame: Baseline, Day 21 and at time of surgery (Day 180)
measure: Determination of the histopathological sub-type and status of the tumour
timeFrame: Baseline, Day 21 and at time of surgery (Day 180)
measure: Determination of the early and late mechanisms of adaptation and/or resistance to letrozole in combination with ribociclib
timeFrame: Baseline and at time of surgery (Day 180)
measure: Change in PEPI status from baseline in response to targeted neoadjuvant therapy with letrozole and ribociclib
timeFrame: Baseline, Day 21, Day 90, Day 180
measure: Change in Ki67 from baseline in response to targeted neoadjuvant therapy with letrozole and ribociclib
timeFrame: Baseline, Day 21, Day 90, Day 180
measure: Change in PROSIGNA Risk of Recurrence (ROR) score from baseline in response to targeted neoadjuvant therapy with letrozole and ribociclib
timeFrame: Baseline, Day 21, Day 90, Day 180
measure: Changes in the composition of the gut microbiota
timeFrame: Baseline, 21 and 90, at time of surgery (Day 180), and annually in years 1-5 (extension if patient relapses)
measure: Identification of anti-tumor effects via changes in levels of circulating serum cytokines in liquid biopsies
timeFrame: Baseline, 21 and 90, and at time of surgery (Day 180).
measure: Identification of anti-tumor effects via changes in levels of circulating serum metabolites in liquid biopsies
timeFrame: Baseline, 21 and 90, and at time of surgery (Day 180).
measure: Identification of anti-tumor effects via circulating free tumor DNA (cftDNA) in liquid biopsies
timeFrame: Baseline, 21 and 90, and at time of surgery (Day 180).
Other outcomes:
Locations:
city: Lørenskog
country: Norway
facility: Akershus University Hospital
state: Viken
Study officials:
affiliation: University Hospital, Akershus
name: Jürgen Geisler, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Semiglazov VF, Semiglazov VV, Dashyan GA, Ziltsova EK, Ivanov VG, Bozhok AA, Melnikova OA, Paltuev RM, Kletzel A, Berstein LM. Phase 2 randomized trial of primary endocrine therapy versus chemotherapy in postmenopausal patients with estrogen receptor-positive breast cancer. Cancer. 2007 Jul 15;110(2):244-54. doi: 10.1002/cncr.22789.
citation: Smith IE, Dowsett M, Ebbs SR, Dixon JM, Skene A, Blohmer JU, Ashley SE, Francis S, Boeddinghaus I, Walsh G; IMPACT Trialists Group. Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: the Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) multicenter double-blind randomized trial. J Clin Oncol. 2005 Aug 1;23(22):5108-16. doi: 10.1200/JCO.2005.04.005. Epub 2005 Jul 5.
citation: Geisler J, Detre S, Berntsen H, Ottestad L, Lindtjorn B, Dowsett M, Einstein Lonning P. Influence of neoadjuvant anastrozole (Arimidex) on intratumoral estrogen levels and proliferation markers in patients with locally advanced breast cancer. Clin Cancer Res. 2001 May;7(5):1230-6.
citation: Geisler J, Haynes B, Anker G, Dowsett M, Lonning PE. Influence of letrozole and anastrozole on total body aromatization and plasma estrogen levels in postmenopausal breast cancer patients evaluated in a randomized, cross-over study. J Clin Oncol. 2002 Feb 1;20(3):751-7. doi: 10.1200/JCO.2002.20.3.751.
citation: Geisler J, Helle H, Ekse D, Duong NK, Evans DB, Nordbo Y, Aas T, Lonning PE. Letrozole is superior to anastrozole in suppressing breast cancer tissue and plasma estrogen levels. Clin Cancer Res. 2008 Oct 1;14(19):6330-5. doi: 10.1158/1078-0432.CCR-07-5221.
citation: Geisler J, King N, Anker G, Ornati G, Di Salle E, Lonning PE, Dowsett M. In vivo inhibition of aromatization by exemestane, a novel irreversible aromatase inhibitor, in postmenopausal breast cancer patients. Clin Cancer Res. 1998 Sep;4(9):2089-93.
citation: Geisler J, King N, Dowsett M, Ottestad L, Lundgren S, Walton P, Kormeset PO, Lonning PE. Influence of anastrozole (Arimidex), a selective, non-steroidal aromatase inhibitor, on in vivo aromatisation and plasma oestrogen levels in postmenopausal women with breast cancer. Br J Cancer. 1996 Oct;74(8):1286-91. doi: 10.1038/bjc.1996.531.
citation: Gnant M, Steger GG, Bartsch R. CDK4/6 inhibitors in luminal breast cancer. Lancet Oncol. 2015 Jan;16(1):2-3. doi: 10.1016/S1470-2045(14)71188-X. Epub 2014 Dec 16. No abstract available.
citation: Lim JS, Turner NC, Yap TA. CDK4/6 Inhibitors: Promising Opportunities beyond Breast Cancer. Cancer Discov. 2016 Jul;6(7):697-9. doi: 10.1158/2159-8290.CD-16-0563.
citation: Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S, Campone M, Petrakova K, Blackwell KL, Winer EP, Janni W, Verma S, Conte P, Arteaga CL, Cameron DA, Mondal S, Su F, Miller M, Elmeliegy M, Germa C, O'Shaughnessy J. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol. 2018 Jul 1;29(7):1541-1547. doi: 10.1093/annonc/mdy155.
citation: Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S, Campone M, Petrakova K, Blackwell KL, Winer EP, Janni W, Verma S, Conte P, Arteaga CL, Cameron DA, Mondal S, Su F, Miller M, Elmeliegy M, Germa C, O'Shaughnessy J. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol. 2019 Nov 1;30(11):1842. doi: 10.1093/annonc/mdz215. No abstract available.
citation: Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, Harbeck N, Lipatov ON, Walshe JM, Moulder S, Gauthier E, Lu DR, Randolph S, Dieras V, Slamon DJ. Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med. 2016 Nov 17;375(20):1925-1936. doi: 10.1056/NEJMoa1607303.
citation: Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA, Petrakova K, Bianchi GV, Esteva FJ, Martin M, Nusch A, Sonke GS, De la Cruz-Merino L, Beck JT, Pivot X, Vidam G, Wang Y, Rodriguez Lorenc K, Miller M, Taran T, Jerusalem G. Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: MONALEESA-3. J Clin Oncol. 2018 Aug 20;36(24):2465-2472. doi: 10.1200/JCO.2018.78.9909. Epub 2018 Jun 3.
citation: Turner NC, Ro J, Andre F, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, Huang Bartlett C, Zhang K, Giorgetti C, Randolph S, Koehler M, Cristofanilli M; PALOMA3 Study Group. Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2015 Jul 16;373(3):209-19. doi: 10.1056/NEJMoa1505270. Epub 2015 Jun 1.
citation: Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, Colleoni M, DeMichele A, Loi S, Verma S, Iwata H, Harbeck N, Zhang K, Theall KP, Jiang Y, Bartlett CH, Koehler M, Slamon D. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016 Apr;17(4):425-439. doi: 10.1016/S1470-2045(15)00613-0. Epub 2016 Mar 3.
citation: Turner NC, Slamon DJ, Ro J, Bondarenko I, Im SA, Masuda N, Colleoni M, DeMichele A, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, Andre F, Puyana Theall K, Huang X, Giorgetti C, Huang Bartlett C, Cristofanilli M. Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer. N Engl J Med. 2018 Nov 15;379(20):1926-1936. doi: 10.1056/NEJMoa1810527. Epub 2018 Oct 20.
citation: McCaw ZR, Vassy JL, Wei LJ. Palbociclib and Fulvestrant in Breast Cancer. N Engl J Med. 2019 Feb 21;380(8):796. doi: 10.1056/NEJMc1816595. No abstract available.
citation: Prat A, Saura C, Pascual T, Hernando C, Munoz M, Pare L, Gonzalez Farre B, Fernandez PL, Galvan P, Chic N, Gonzalez Farre X, Oliveira M, Gil-Gil M, Arumi M, Ferrer N, Montano A, Izarzugaza Y, Llombart-Cussac A, Bratos R, Gonzalez Santiago S, Martinez E, Hoyos S, Rojas B, Virizuela JA, Ortega V, Lopez R, Celiz P, Ciruelos E, Villagrasa P, Gavila J. Ribociclib plus letrozole versus chemotherapy for postmenopausal women with hormone receptor-positive, HER2-negative, luminal B breast cancer (CORALLEEN): an open-label, multicentre, randomised, phase 2 trial. Lancet Oncol. 2020 Jan;21(1):33-43. doi: 10.1016/S1470-2045(19)30786-7. Epub 2019 Dec 11.
citation: Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA, Petrakova K, Bianchi GV, Esteva FJ, Martin M, Nusch A, Sonke GS, De la Cruz-Merino L, Beck JT, Pivot X, Sondhi M, Wang Y, Chakravartty A, Rodriguez-Lorenc K, Taran T, Jerusalem G. Overall Survival with Ribociclib plus Fulvestrant in Advanced Breast Cancer. N Engl J Med. 2020 Feb 6;382(6):514-524. doi: 10.1056/NEJMoa1911149. Epub 2019 Dec 11.
citation: Rocca A, Melegari E, Palleschi M. Ribociclib and Endocrine Therapy in Breast Cancer. N Engl J Med. 2019 Oct 17;381(16):1592. doi: 10.1056/NEJMc1911188. No abstract available.
citation: Im SA, Lu YS, Bardia A, Harbeck N, Colleoni M, Franke F, Chow L, Sohn J, Lee KS, Campos-Gomez S, Villanueva-Vazquez R, Jung KH, Chakravartty A, Hughes G, Gounaris I, Rodriguez-Lorenc K, Taran T, Hurvitz S, Tripathy D. Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer. N Engl J Med. 2019 Jul 25;381(4):307-316. doi: 10.1056/NEJMoa1903765. Epub 2019 Jun 4.
citation: Johnston S, Puhalla S, Wheatley D, Ring A, Barry P, Holcombe C, Boileau JF, Provencher L, Robidoux A, Rimawi M, McIntosh SA, Shalaby I, Stein RC, Thirlwell M, Dolling D, Morden J, Snowdon C, Perry S, Cornman C, Batten LM, Jeffs LK, Dodson A, Martins V, Modi A, Osborne CK, Pogue-Geile KL, Cheang MCU, Wolmark N, Julian TB, Fisher K, MacKenzie M, Wilcox M, Huang Bartlett C, Koehler M, Dowsett M, Bliss JM, Jacobs SA. Randomized Phase II Study Evaluating Palbociclib in Addition to Letrozole as Neoadjuvant Therapy in Estrogen Receptor-Positive Early Breast Cancer: PALLET Trial. J Clin Oncol. 2019 Jan 20;37(3):178-189. doi: 10.1200/JCO.18.01624. Epub 2018 Dec 6.
citation: Gianni L, Bisagni G, Colleoni M, Del Mastro L, Zamagni C, Mansutti M, Zambetti M, Frassoldati A, De Fato R, Valagussa P, Viale G. Neoadjuvant treatment with trastuzumab and pertuzumab plus palbociclib and fulvestrant in HER2-positive, ER-positive breast cancer (NA-PHER2): an exploratory, open-label, phase 2 study. Lancet Oncol. 2018 Feb;19(2):249-256. doi: 10.1016/S1470-2045(18)30001-9. Epub 2018 Jan 8.
citation: Cottu P, D'Hondt V, Dureau S, Lerebours F, Desmoulins I, Heudel PE, Duhoux FP, Levy C, Mouret-Reynier MA, Dalenc F, Frenel JS, Jouannaud C, Venat-Bouvet L, Nguyen S, Ferrero JM, Canon JL, Grenier J, Callens C, Gentien D, Lemonnier J, Vincent-Salomon A, Delaloge S. Letrozole and palbociclib versus chemotherapy as neoadjuvant therapy of high-risk luminal breast cancer. Ann Oncol. 2018 Dec 1;29(12):2334-2340. doi: 10.1093/annonc/mdy448.
citation: Chow LWC, Morita S, Chow CYC, Ng WK, Toi M. Neoadjuvant palbociclib on ER+ breast cancer (N007): clinical response and EndoPredict's value. Endocr Relat Cancer. 2018 Feb;25(2):123-130. doi: 10.1530/ERC-17-0396. Epub 2017 Nov 20.
citation: Ma CX, Gao F, Luo J, Northfelt DW, Goetz M, Forero A, Hoog J, Naughton M, Ademuyiwa F, Suresh R, Anderson KS, Margenthaler J, Aft R, Hobday T, Moynihan T, Gillanders W, Cyr A, Eberlein TJ, Hieken T, Krontiras H, Guo Z, Lee MV, Spies NC, Skidmore ZL, Griffith OL, Griffith M, Thomas S, Bumb C, Vij K, Bartlett CH, Koehler M, Al-Kateb H, Sanati S, Ellis MJ. NeoPalAna: Neoadjuvant Palbociclib, a Cyclin-Dependent Kinase 4/6 Inhibitor, and Anastrozole for Clinical Stage 2 or 3 Estrogen Receptor-Positive Breast Cancer. Clin Cancer Res. 2017 Aug 1;23(15):4055-4065. doi: 10.1158/1078-0432.CCR-16-3206. Epub 2017 Mar 7.
citation: Buyukkaramikli NC, de Groot S, Riemsma R, Fayter D, Armstrong N, Portegijs P, Duffy S, Kleijnen J, Al MJ. Ribociclib with an Aromatase Inhibitor for Previously Untreated, HR-Positive, HER2-Negative, Locally Advanced or Metastatic Breast Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal. Pharmacoeconomics. 2019 Feb;37(2):141-153. doi: 10.1007/s40273-018-0708-4.
citation: Tekpli X, Lien T, Rossevold AH, Nebdal D, Borgen E, Ohnstad HO, Kyte JA, Vallon-Christersson J, Fongaard M, Due EU, Svartdal LG, Sveli MAT, Garred O; OSBREAC; Frigessi A, Sahlberg KK, Sorlie T, Russnes HG, Naume B, Kristensen VN. An independent poor-prognosis subtype of breast cancer defined by a distinct tumor immune microenvironment. Nat Commun. 2019 Dec 3;10(1):5499. doi: 10.1038/s41467-019-13329-5.
citation: Jabeen S, Zucknick M, Nome M, Dannenfelser R, Fleischer T, Kumar S, Luders T, von der Lippe Gythfeldt H, Troyanskaya O, Kyte JA, Borresen-Dale AL, Naume B, Tekpli X, Engebraaten O, Kristensen V. Serum cytokine levels in breast cancer patients during neoadjuvant treatment with bevacizumab. Oncoimmunology. 2018 Aug 6;7(11):e1457598. doi: 10.1080/2162402X.2018.1457598. eCollection 2018.
citation: Vetizou M, Pitt JM, Daillere R, Lepage P, Waldschmitt N, Flament C, Rusakiewicz S, Routy B, Roberti MP, Duong CP, Poirier-Colame V, Roux A, Becharef S, Formenti S, Golden E, Cording S, Eberl G, Schlitzer A, Ginhoux F, Mani S, Yamazaki T, Jacquelot N, Enot DP, Berard M, Nigou J, Opolon P, Eggermont A, Woerther PL, Chachaty E, Chaput N, Robert C, Mateus C, Kroemer G, Raoult D, Boneca IG, Carbonnel F, Chamaillard M, Zitvogel L. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015 Nov 27;350(6264):1079-84. doi: 10.1126/science.aad1329. Epub 2015 Nov 5.
citation: Elkrief A, Derosa L, Zitvogel L, Kroemer G, Routy B. The intimate relationship between gut microbiota and cancer immunotherapy. Gut Microbes. 2019;10(3):424-428. doi: 10.1080/19490976.2018.1527167. Epub 2018 Oct 19.
citation: Routy B, Gopalakrishnan V, Daillere R, Zitvogel L, Wargo JA, Kroemer G. The gut microbiota influences anticancer immunosurveillance and general health. Nat Rev Clin Oncol. 2018 Jun;15(6):382-396. doi: 10.1038/s41571-018-0006-2.
citation: Kroemer G, Zitvogel L. Cancer immunotherapy in 2017: The breakthrough of the microbiota. Nat Rev Immunol. 2018 Jan 30;18(2):87-88. doi: 10.1038/nri.2018.4. No abstract available.
citation: Chew CS. Parietal cell protein kinases. Selective activation of type I cAMP-dependent protein kinase by histamine. J Biol Chem. 1985 Jun 25;260(12):7540-50.
citation: Zitvogel L, Galluzzi L, Viaud S, Vetizou M, Daillere R, Merad M, Kroemer G. Cancer and the gut microbiota: an unexpected link. Sci Transl Med. 2015 Jan 21;7(271):271ps1. doi: 10.1126/scitranslmed.3010473.
citation: Viaud S, Saccheri F, Mignot G, Yamazaki T, Daillere R, Hannani D, Enot DP, Pfirschke C, Engblom C, Pittet MJ, Schlitzer A, Ginhoux F, Apetoh L, Chachaty E, Woerther PL, Eberl G, Berard M, Ecobichon C, Clermont D, Bizet C, Gaboriau-Routhiau V, Cerf-Bensussan N, Opolon P, Yessaad N, Vivier E, Ryffel B, Elson CO, Dore J, Kroemer G, Lepage P, Boneca IG, Ghiringhelli F, Zitvogel L. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science. 2013 Nov 22;342(6161):971-6. doi: 10.1126/science.1240537.
citation: Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, Prieto PA, Vicente D, Hoffman K, Wei SC, Cogdill AP, Zhao L, Hudgens CW, Hutchinson DS, Manzo T, Petaccia de Macedo M, Cotechini T, Kumar T, Chen WS, Reddy SM, Szczepaniak Sloane R, Galloway-Pena J, Jiang H, Chen PL, Shpall EJ, Rezvani K, Alousi AM, Chemaly RF, Shelburne S, Vence LM, Okhuysen PC, Jensen VB, Swennes AG, McAllister F, Marcelo Riquelme Sanchez E, Zhang Y, Le Chatelier E, Zitvogel L, Pons N, Austin-Breneman JL, Haydu LE, Burton EM, Gardner JM, Sirmans E, Hu J, Lazar AJ, Tsujikawa T, Diab A, Tawbi H, Glitza IC, Hwu WJ, Patel SP, Woodman SE, Amaria RN, Davies MA, Gershenwald JE, Hwu P, Lee JE, Zhang J, Coussens LM, Cooper ZA, Futreal PA, Daniel CR, Ajami NJ, Petrosino JF, Tetzlaff MT, Sharma P, Allison JP, Jenq RR, Wargo JA. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018 Jan 5;359(6371):97-103. doi: 10.1126/science.aan4236. Epub 2017 Nov 2.
citation: Kala M, Chrobok J, Dvorak P. A surprising finding by a surgery for lumbar intervertebral disk herniation--Ewing's sarcoma. Acta Univ Palacki Olomuc Fac Med. 1987;117:185-9. No abstract available.
citation: Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillere R, Fluckiger A, Messaoudene M, Rauber C, Roberti MP, Fidelle M, Flament C, Poirier-Colame V, Opolon P, Klein C, Iribarren K, Mondragon L, Jacquelot N, Qu B, Ferrere G, Clemenson C, Mezquita L, Masip JR, Naltet C, Brosseau S, Kaderbhai C, Richard C, Rizvi H, Levenez F, Galleron N, Quinquis B, Pons N, Ryffel B, Minard-Colin V, Gonin P, Soria JC, Deutsch E, Loriot Y, Ghiringhelli F, Zalcman G, Goldwasser F, Escudier B, Hellmann MD, Eggermont A, Raoult D, Albiges L, Kroemer G, Zitvogel L. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018 Jan 5;359(6371):91-97. doi: 10.1126/science.aan3706. Epub 2017 Nov 2.
citation: Ebert PJR, Cheung J, Yang Y, McNamara E, Hong R, Moskalenko M, Gould SE, Maecker H, Irving BA, Kim JM, Belvin M, Mellman I. MAP Kinase Inhibition Promotes T Cell and Anti-tumor Activity in Combination with PD-L1 Checkpoint Blockade. Immunity. 2016 Mar 15;44(3):609-621. doi: 10.1016/j.immuni.2016.01.024. Epub 2016 Mar 2.
citation: Deng J, Wang ES, Jenkins RW, Li S, Dries R, Yates K, Chhabra S, Huang W, Liu H, Aref AR, Ivanova E, Paweletz CP, Bowden M, Zhou CW, Herter-Sprie GS, Sorrentino JA, Bisi JE, Lizotte PH, Merlino AA, Quinn MM, Bufe LE, Yang A, Zhang Y, Zhang H, Gao P, Chen T, Cavanaugh ME, Rode AJ, Haines E, Roberts PJ, Strum JC, Richards WG, Lorch JH, Parangi S, Gunda V, Boland GM, Bueno R, Palakurthi S, Freeman GJ, Ritz J, Haining WN, Sharpless NE, Arthanari H, Shapiro GI, Barbie DA, Gray NS, Wong KK. CDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation. Cancer Discov. 2018 Feb;8(2):216-233. doi: 10.1158/2159-8290.CD-17-0915. Epub 2017 Nov 3.
citation: Goel S, DeCristo MJ, Watt AC, BrinJones H, Sceneay J, Li BB, Khan N, Ubellacker JM, Xie S, Metzger-Filho O, Hoog J, Ellis MJ, Ma CX, Ramm S, Krop IE, Winer EP, Roberts TM, Kim HJ, McAllister SS, Zhao JJ. CDK4/6 inhibition triggers anti-tumour immunity. Nature. 2017 Aug 24;548(7668):471-475. doi: 10.1038/nature23465. Epub 2017 Aug 16.
citation: Zhang J, Bu X, Wang H, Zhu Y, Geng Y, Nihira NT, Tan Y, Ci Y, Wu F, Dai X, Guo J, Huang YH, Fan C, Ren S, Sun Y, Freeman GJ, Sicinski P, Wei W. Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance. Nature. 2018 Jan 4;553(7686):91-95. doi: 10.1038/nature25015. Epub 2017 Nov 16.
citation: Petroni G, Formenti SC, Chen-Kiang S, Galluzzi L. Immunomodulation by anticancer cell cycle inhibitors. Nat Rev Immunol. 2020 Nov;20(11):669-679. doi: 10.1038/s41577-020-0300-y. Epub 2020 Apr 28.
citation: Goel S, Tolaney SM. CDK4/6 inhibitors in breast cancer: a role in triple-negative disease? Lancet Oncol. 2019 Nov;20(11):1479-1481. doi: 10.1016/S1470-2045(19)30627-8. Epub 2019 Sep 28. No abstract available.
citation: Wang L, Ellsworth KA, Moon I, Pelleymounter LL, Eckloff BW, Martin YN, Fridley BL, Jenkins GD, Batzler A, Suman VJ, Ravi S, Dixon JM, Miller WR, Wieben ED, Buzdar A, Weinshilboum RM, Ingle JN. Functional genetic polymorphisms in the aromatase gene CYP19 vary the response of breast cancer patients to neoadjuvant therapy with aromatase inhibitors. Cancer Res. 2010 Jan 1;70(1):319-28. doi: 10.1158/0008-5472.CAN-09-3224.
citation: Geisler J, Smith I, Miller W. Presurgical (neoadjuvant) endocrine therapy is a useful model to predict response and outcome to endocrine treatment in breast cancer patients. J Steroid Biochem Mol Biol. 2012 Sep;131(3-5):93-100. doi: 10.1016/j.jsbmb.2011.12.006. Epub 2011 Dec 22.
citation: Bathen TF, Geurts B, Sitter B, Fjosne HE, Lundgren S, Buydens LM, Gribbestad IS, Postma G, Giskeodegard GF. Feasibility of MR metabolomics for immediate analysis of resection margins during breast cancer surgery. PLoS One. 2013 Apr 17;8(4):e61578. doi: 10.1371/journal.pone.0061578. Print 2013.
citation: Ellis MJ, Tao Y, Luo J, A'Hern R, Evans DB, Bhatnagar AS, Chaudri Ross HA, von Kameke A, Miller WR, Smith I, Eiermann W, Dowsett M. Outcome prediction for estrogen receptor-positive breast cancer based on postneoadjuvant endocrine therapy tumor characteristics. J Natl Cancer Inst. 2008 Oct 1;100(19):1380-8. doi: 10.1093/jnci/djn309. Epub 2008 Sep 23.