Mechanisms of Resistance to CDK4/6 Inhibitors in Breast Cancer and Potential Biomarkers of Response

Randomized clinical trials demonstrated that CDK4/6 inhibitors are highly effective in patients with hormone receptor-positive (HR+), HER2-negative (HER2-) metastatic breast cancer in combination with endocrine therapy. The use of CDK4/6 inhibitors in clinics is becoming common for patients with HR+/HER2- metastatic breast cancer and will certainly increase in the near future. However, patients might show de novo or acquired resistance to these drugs. Molecular alterations have been suggested as determinants for de novo resistance to CDK4/6 inhibitors, but have never been validated in a clinical setting. In addition, molecular mechanisms of acquired resistance to palbociclib have been analyzed only in preclinical studies. Here we review the current knowledge on the available preclinical data about the mechanisms of de novo and acquired resistance to CDK4/6 inhibitors in breast cancer, and clinical data about potential biomarkers of response.

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Hormonal treatment combined with targeted therapies in endocrine-responsive and HER2-positive metastatic breast cancer

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835919894105 ◽

2019 ◽

Vol 11 ◽

pp. 175883591989410 ◽

Cited By ~ 2

Author(s):

Emilia Montagna ◽

Marco Colleoni

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Signaling Pathways ◽

Targeted Therapies ◽

De Novo ◽

Current Knowledge ◽

Metastatic Breast ◽

Her2 Positive ◽

Her2 Positive Breast Cancer ◽

Positive Breast Cancer

Approximately 50% of HER2 positive breast cancer cases are also estrogen receptor (ER) positive. Data supports a role for close cross-talk between the ER and HER2 signaling pathways as an important contributor to the development of de novo or acquired resistance to hormone therapies. Therefore a strategy that simultaneously blocks both signaling pathways is a reasonable approach to prevent or overcome either endocrine or anti-HER2 therapy resistance. Moreover, preclinical data support the idea that PI3K inhibitors and CDK4/6 could be an attractive target that functions downstream of both ER and HER2 pathways. We conducted a literature review of the results of phase II and III studies testing targeted therapies in metastatic breast cancer with HER2-positive and hormonal-receptor-positive disease. The analyses included efficacy and toxicity data from earlier studies with a single anti-HER2 drug combined with hormonal therapy up to more recent studies testing new molecules targeting these signaling pathways. The aims of this review are to summarize current knowledge and to discuss research development including the possibility to spare chemotherapy in this subgroup of HER2-positive breast cancer patients.

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Paclitaxel as second and subsequent therapy for metastatic breast cancer: activity independent of prior anthracycline response.

Journal of Clinical Oncology ◽

10.1200/jco.1995.13.5.1152 ◽

1995 ◽

Vol 13 (5) ◽

pp. 1152-1159 ◽

Cited By ~ 148

Author(s):

A D Seidman ◽

B S Reichman ◽

J P Crown ◽

T J Yao ◽

V Currie ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

De Novo ◽

Objective Response ◽

Acquired Resistance ◽

Metastatic Breast ◽

Stage Iv ◽

High Dose ◽

Significant Activity ◽

Two Phase

PURPOSE Two phase II clinical trials were performed to determine efficacy and tolerability of paclitaxel (Taxol; Bristol-Myers Squibb Co, Wallingford, CT) and granulocyte colony-stimulating factor ([G-CSF] Neupogen; Amgen, Inc, Thousand Oaks, CA) as second or subsequent therapy for metastatic breast cancer. PATIENTS AND METHODS Paclitaxel plus G-CSF was administered as a second stage IV regimen to 25 patients with metastatic breast cancer at a dose of 250 mg/m2 intravenously over 24 hours. Fifty-two patients received paclitoxel plus G-CSF at 200 mg/m2 as a third or subsequent regimen (no restriction on number of prior regimens or on prior high-dose chemotherapy). All patients had received prior anthracycline treatment, and ultimately had progressive bidimensionally measurable disease. RESULTS Twenty-five of 76 patients (32.8%) had a major objective response (95% confidence interval [CI], 14% to 37%). The median duration of response was 7 months (range, 1 to 20+). Responses were as likely in patients with disease demonstrated to be unresponsive to anthracycline, ie, de novo resistance (11 of 37, or 30%) as in those with disease that once exhibited anthracycline sensitivity, ie, acquired resistance, (10 of 31, or 32%). G-CSF administration was associated with febrile neutropenic episodes in 36 of 402 cycles (9%) in 16 of 76 patients (21%). CONCLUSION Paclitaxel's clinically significant activity against metastatic breast cancer extends to patients with many prior chemotherapy regimens. The lack of impact of prior doxorubicin therapy on the likelihood of subsequent response to paclitaxel suggests an important role for this agent in the treatment of refractory metastatic breast cancer.

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Epidemiology of De Novo Metastatic Breast Cancer

Clinical Breast Cancer ◽

10.1016/j.clbc.2021.01.017 ◽

2021 ◽

Author(s):

Karen Daily ◽

Emily Douglas ◽

Paul A Romitti ◽

Alexandra Thomas

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

De Novo ◽

Metastatic Breast

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Locoregional Therapy for the Primary Tumour in Women with a De Novo Diagnosis of Metastatic Breast Cancer

Current Breast Cancer Reports ◽

10.1007/s12609-021-00408-0 ◽

2021 ◽

Author(s):

Katie Miller ◽

Kieran Horgan ◽

David Dodwell

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

De Novo ◽

Primary Tumour ◽

Metastatic Breast ◽

Locoregional Therapy

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Real-world Indian scenario of CDK4/6 inhibitors (palbociclib and ribociclib) with endocrine therapy in upfront hormone positive metastatic breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e13028 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e13028-e13028

Author(s):

Ajay Gogia ◽

Shalabh Arora ◽

Priyanshu Choudhary ◽

Rakesh Kumar ◽

Sanjay Thulkar ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Endocrine Therapy ◽

Real World ◽

De Novo ◽

Metastatic Breast ◽

Common Side Effect ◽

Drug Discontinuation ◽

Grade 3 ◽

Visceral Disease

e13028 Background: CDK4/6 inhibitors (CDKi), in combination with endocrine therapy (ET), has become the standard of care in the treatment of hormone positive (HR+)/ HER2 neu negative metastatic breast cancer (MBC) patients. We evaluated clinical outcomes and toxicity in MBC patients, who have received ET with two CDKi, namely palbociclib and ribociclib. Methods: This is an ambispective, single institutional analysis of de-novo HR+ MBC patients treated with CDKi (palbociclib 125 mg and ribociclib 600 mg once a day for 21 days /28 days cycle) from November 2016- October 2020 at AIIMS, New Delhi, India. The primary endpoint was progression-free survival (PFS) and the secondary endpoint was response rate and toxicity. A total of 157 female patients were recruited in this study however the response and toxicity data were available in 120 cases. All premenopausal women received ovarian suppression or ovarian ablation. Results: A total of 120 patients were included in this study with a median age of 57 years (35-75) and 93 (77.5%) cases were postmenopausal. Twenty-three (19.1%) patients had a bone-only disease, 49 (40.9%) had bone and visceral disease and 48 (40%) had only visceral disease. In this study 91 (75.9%) patients received palbociclib and 29 (24.2%) received ribociclib. The median PFS was 18 months (4-36). Twenty four (20%) patients achieved a complete response, 69 (57.5%) patients attained partial response, 18(15%) patients had stable disease and 9 (7.5%) had disease progression. Grade 3–4 neutropenia, thrombocytopenia, and anaemia were observed in 18(15%), 8 (6.7%), and 4 (3.3%) cases respectively. None of the patients developed febrile neutropenia. Cutaneous, renal, hepatic, and gastrointestinal toxicity was observed in 1,1,3,4 cases respectively. Prolonged QTc was observed in one case. Grade 3 fatigue was observed in 7 cases. Dose interruption/delay (mean dose delay of 7 days), dose modification, and drug discontinuation were observed in 24 (20%), 12 (10%), and 10 (8.3%) of cases respectively. Conclusions: This is one of the largest real-world Indian data on CDK4/6 inhibitors on upfront HR+ MBC. Side effects are less than published literature with similar efficacy. Neutropenia was the most common side effect which was managed by brief dose interruption.

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Occult Breast Carcinoma Presenting as Scalp Metastasis

Case Reports in Oncology ◽

10.1159/000484346 ◽

2017 ◽

Vol 10 (3) ◽

pp. 992-997 ◽

Cited By ~ 2

Author(s):

Ricardo L.B. Costa ◽

Rubens B. Costa-Filho ◽

Marilin Rosa ◽

Brian J. Czerniecki

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Breast Tumor ◽

Rare Case ◽

De Novo ◽

Metastatic Breast ◽

Primary Breast Tumor ◽

Occult Breast Cancer ◽

Scalp Metastasis ◽

Occult Breast Carcinoma

Breast cancer is the most common tumor among women, and approximately 6% of the patients have de novo metastatic breast cancer. Occult breast cancer accounts for only 0.1–0.8% of the cases and most commonly presents with axillary lymphadenopathy. Scalp metastases are rare and have been described as a sign of progression or widespread metastatic disease. Here, we describe a rare case of de novo metastatic breast cancer to the scalp as the single site of spread and without an identifiable primary breast tumor.

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Changes in Overall Survival Over Time for Patients With de Novo Metastatic Breast Cancer

10.20944/preprints202105.0093.v1 ◽

2021 ◽

Author(s):

Toshiaki Iwase ◽

Tushaar Vishal Shrimanker ◽

Ruben Rodriguez-Bautista ◽

Onur Sahin ◽

Anjali James ◽

...

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

Metastatic Breast Cancer ◽

De Novo ◽

Metastatic Breast ◽

Locoregional Therapy ◽

Cancer Center ◽

Her2 Positive ◽

Time Periods ◽

Over Time

The purpose of this study was to determine the change in overall survival (OS) for patients with de novo metastatic breast cancer (dnMBC) over time. We conducted a retrospective cohort study with 1981 patients with dnMBC diagnosed between January 1995 and December 2017 at The University of Texas MD Anderson Cancer Center. OS was measured from the date of diagnosis of dnMBC. OS was compared between patients diagnosed during different time periods: 5-year periods and periods defined according to when key agents were approved for clinical use. The median OS was 3.4 years. The 5- and 10-year OS rates improved over time across both types of time periods. A subgroup analysis showed that OS improved significantly over time for the estrogen-receptor-positive/HER2-positive (ER+/HER2+) subtype, and exhibited a tendency toward improvement over time for the ER-negative (ER-)/HER2+ subtype. Median OS was significantly longer in patients with non-inflammatory breast cancer (P = .02) and in patients with ER+ disease, progesterone-receptor-positive disease, HER2+ disease, lower nuclear grade, locoregional therapy, and metastasis to a single organ (all P &lt;.0001). These findings showed that OS at 5 and 10 years after diagnosis in patients with dnMBC improved over time. The significant improvements in OS over time for the ER+/HER2+ subtype and the tendency toward improvement for ER-/HER2+ subtype suggest the contribution of HER2-targeted therapy to survival.

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