2022 SABCS East Wind is Coming Today, Green Lake Up the Mountain - New Dynamics of CDK4/6 Inhibitors in HR+/HER2-Breast Cancer!

Recently, the 45th San Antonio Breast Cancer Symposium (SABCS) in 2022 was successfully held
.
SABCS is one of the largest, highest level and most influential international academic conferences in the field of breast cancer in the world, with physicians and researchers from more than 90 countries sharing cutting-edge information
on basic research, translational science and clinical research on breast cancer and precancerous breast diseases every year.

In the era of precision diagnosis and treatment, new drugs have emerged one after another, and cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy have opened a new climax
of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer with its unique advantages.
So what are the hot research and reports on CDK4/6i at this conference? At the moment when the 2022 SABCS has just ended, we specially take everyone to "know everything about the world" and enjoy this "academic feast"
without leaving home.

Featured Study I (P4-01-19)

Real statistics on CDK4/6 inhibitor use in patients with advanced breast cancer with HR+/HER2- – focusing on age group differences

With the development of diagnosis and treatment technology, the concept of CDK4/6i application in first-line treatment has been continuously promoted
.
To explore whether age is a potential factor in CDK4/6i use, the researchers conducted a retrospective analysis
of the database.

Between 2015 and 2021, there were 313,978 patients with advanced breast cancer who received first-line treatment in the United States
.
The proportion of patients treated with first-line CDK4/6i combination therapy in China increased significantly from 20% (N=27,063) in 2015 to 53% (N=54,023)
in 2021.
In 2021, in the investigator's center, patients aged 18~49 years received CDK4/6i treatment at the highest proportion, 82%.

Finally, the researchers noted that despite the long-term promotion of first-line CDK4/6i combination therapy in patients with HR+/HER2- advanced breast cancer, the overall use of the drug is still not ideal
.
Analysing what hinders drug use is essential
to improve drug use and ensure effective drug use.

What is more noteworthy is that breast cancer is now showing a younger trend, and such breast cancer shows stronger aggressiveness and higher probability of recurrence and metastasis, and it is more urgent to need drugs such as CDK4/6i to bring the dawn of treatment
.
It is reassuring to see that CDK4/6i usage is also highest
in this population compared to other age groups.
In contrast, the proportion of young breast cancers receiving such drugs in China is still low
.
It is hoped that in the future, CDK4/6 inhibitors with premenopausal indications will be effective in improving this situation
.

Featured Study II (OT1-14-01)

Efficacy and safety of piperciclib in the treatment of locally advanced or metastatic breast cancer: a multicenter, real-world study

To evaluate the efficacy and safety of piperaciclib in patients with locally advanced or metastatic breast cancer, 267 patients with HR+/HER2-locally advanced or metastatic breast cancer were enrolled, of which about one-third (32.
83%, 31.
32%, 38.
85%)
were accounted for first-line, second- and third-line therapy.
30.
34% of patients had liver metastases, 35.
47% were sensitive to previous endocrine therapy, 18.
23% had primary endocrine resistance, and 46.
31% had secondary endocrine resistance
.

The median PFS was 12.
67 months (95% CI 11.
51-13.
92) and median overall survival (OS) was not reached
.
The overall effective rate (ORR) was 25.
84% and the disease control rate (DCR) was 78.
62
%.
The main adverse events related to treatment were neutropenia (91.
38%), leukopenia (90.
09%), anemia (43.
78%), and low platelet count (37.
93%)
.
The most common grade 3/4 adverse event was neutropenia (55.
61%)
.
Studies have verified the efficacy
of CDK4/6i in the real world.

Featured Study III (GS1-09)

Interim analysis of overall survival of MonarchE study: the application of CDK4/6i+ endocrine therapy in HR+/HER2-, node-positive, high-risk early breast cancer

Previous studies have shown that abecept in combination with standard endocrine therapy (ET) significantly improves survival without invasive disease (IDFS) and distant recurrence-free (DRFS)
in patients with HR+/HER2- and node-positive high-risk early-stage breast cancer.
The results of the interim analysis of this conference once again highlighted the therapeutic value of CDK4/6i in early breast cancer, and its 4-year IDFS and DRFS showed benefits in all preset subgroups.
And although the Ki-67 index has a prognostic nature, the benefit of abecilide is consistent
regardless of the Ki-67 index.
Although current OS data are immature, fewer deaths were observed in the abeclib combined with the ET group compared to ET alone
.
The data further support the addition of CDK4/6i to ET for adjuvant therapy in HR+/HER2-/node-positive/high-risk early-stage breast cancer patients
.

Featured Study IV (P5-02-02)

Relationship between ER+/HER2-metastatic breast cancer genome mapping and previous CDK4/6i treatment

To understand the molecular processes driving CDK4/6i resistance, the researchers genetically tested 1,853 patients with ER+/HR2 advanced breast cancer and found that patients who had previously received treatment showed significant ESR1 mutation rates
in solid tissue and liquid biopsies compared with patients who did not receive CDK4/6i.
In solid tissue biopsies, CCND1, FGF3, FGF4, and GATA3 mutation rates were higher in patients previously treated with CDK4/6i, while TP53 mutation rates were significantly reduced
.
However, after multiple test adjustments, the trend of gene mutation was not significant
.
Changes in CCND1, FGF3, FGF4, and FGF19 are all copy number amplifications, which may be consistent
with amplification at 11q13.
Further studies will continue to reveal the correlation
between the above gene change trends and the mechanism of CDK4/6i resistance.

Featured Study V (GS3-01)

Elacestrant can improve PFS in CDK4/6i-resistant patients and is expected to become a new treatment option for ER+/HER2- advanced breast cancer

Elacestrant, a novel oral selective estrogen receptor downregulator (SERD), was evaluated in a phase III trialevaluating elacestrant as
a second- or third-line monotherapy for patients with ER+/HER2- advanced or metastatic breast cancer.
The study enrolled patients who had previously been treated with CDK4/6i, and the primary endpoints were progression-free survival (PFS) in the general population and PFS
in patients with estrogen receptor α (ESR1) mutations.
The impact
of previous CDK4/6i treatment duration on the results of the study was presented.
The results showed that the duration of previous CDK4/6i use was positively correlated with PFS results, and the longer the previous CDK4/6i treatment, the more obvious the PFS advantage in the elacestrant group.
The security data is consistent
with the previous data.
This study confirmed that the improved effect of elacestrant on PFS was positively correlated with the duration of previous CDK4/6i use, providing a new option
for the treatment of ER+/HER2-breast cancer.

summary

For more than 100 years since the advent of oophorectomy in 1896, the treatment of HR+/HER2- recurrent metastatic breast cancer has mainly been chemotherapy, endocrine therapy and targeted therapy
.
In recent years, the advent of CDK4/6i has profoundly changed the treatment pattern of HR+/HER2- advanced breast cancer, and now major guidelines at home and abroad recommend that endocrine therapy alone or in combination with CDK4/6i should be used as the initial first-line treatment for such patients, and consideration should be given to weighing the patient's menopausal status, adjuvant therapy drugs, disease-free survival time and organ function to select the appropriate individualized treatment plan
.
CDK4/6i plays a pivotal role in advanced breast cancer, and researchers are actively exploring the use
of such drugs in patients with early-stage breast cancer.

At the same time, CDK4/6i as an endocrine resistance "nemesis" has shown positive efficacy in many clinical trials, but in fact, a series of follow-up problems (such as CDK4/6i resistance, etc.
) have also been paid attention
to by researchers in the application of CDK4/6i 。 It is believed that with the continuous refinement and deepening of relevant explorations, such as the segmentation of different treatment groups (age distribution, menopausal status, treatment process, etc.
), more patients will benefit from scientific research and clinical practice in the future; We also look at current research rationally, actively look for target innovation and differentiation, and explore higher quality research designs to guide clinical practice
.