ROF Breast Cancer Session | Thinking and Prospects of HR Positive Breast Cancer Treatment: Endless Exploration and Innovation

On July 9, 2022, the latest Roche Oncology Summit invited Many academic experts in the field of oncology at home and abroad jointly conducted in-depth discussions on the latest research trends, hot issues and academic progress of tumor diagnosis and treatment. In the breast cancer session, Professor Wang Shusen from Sun Yat-sen University Cancer Hospital and Professor Chen Yiding from the Second Affiliated Hospital of Zhejiang University School of Medicine were invited to preside over the sailing session of the sea of ​​stars, focusing on HR+/HER2 – Breast cancer, Professor Song Chuangui from Union Hospital Affiliated to Fujian Medical University and Professor Yang Jin from Xi’an Jiaotong University First Hospital shared new thoughts on the treatment of HR-positive early breast cancer and HR-positive advanced breast cancer Excellent report on therapeutic hotspots and outlook.

New thoughts on the treatment of HR-positive early breast cancer

In recent years, breast cancer has surpassed lung cancer and become the malignant tumor with the highest incidence in the world. Cancer accounts for about 60%, and endocrine therapy is the cornerstone of the treatment of HR-positive breast cancer patients. Professor Song Chuangui pointed out that although patients with HR-positive early breast cancer have a better prognosis and more patients have been “cured” after years of adjuvant endocrine therapy, some patients still have recurrence and distant metastasis. Therefore, early treatment strategies for patients with high recurrence risk Still to be optimized.

It is well known that neoadjuvant therapy is a critical step in maximizing the chance of cure in breast cancer patients. Among them, the importance of chemotherapy in the neoadjuvant treatment stage of breast cancer is self-evident. However, HR-positive tumors are less sensitive to chemotherapy than other subtypes, and chemotherapy has high toxicity and poor tolerance, which has many limitations. Numerous studies in HR-positive early breast cancer have shown that neoadjuvant endocrine therapy has similar efficacy to neoadjuvant chemotherapy, and may be used as an alternative< span>. Overall, pathological complete response (pCR) rates were lower with neoadjuvant therapy in HR-positive breast cancer and were more associated with disease-free survival (DFS) and overall survival (OS) than in HER2-positive and triple-negative breast cancer Cancer is poor. The Z1031B and IMPACT study results showed that reduced Ki67 values ​​were associated with better recurrence-free survival (RFS). In addition, more and more surrogate endpoints such as PEPI score, ESDR score and PAM50 are used in neoadjuvant therapy studies of HR-positive breast cancer, but the most suitable surrogate endpoints need further exploration. , currently inconclusive. Regarding the selection of neoadjuvant endocrine therapy population, currentlyrecommendations of neoadjuvant endocrine therapy in domestic and foreign guidelines are more based on menopausal status. The 2022 Chinese expert consensus on neoadjuvant therapy for breast cancer wrote, Postmenopausal patients usually use an aromatase inhibitor (AI) for neoadjuvant endocrine therapy< span>; Neoadjuvant endocrine therapy should not be routinely performed in premenopausal patients unless they enter clinical studies or have contraindications to chemotherapy (optional ovarian function suppression [OFS] + AI/fulvestrant). In the future, it is hoped that the subgroups who may benefit from neoadjuvant therapy can be more precisely identified by clinical and molecular features. In the selection of neoadjuvant endocrine therapy, a number of classic studies have shown that the efficacy of AI in postmenopausal populations is better than that of tamoxifen, and the efficacy of different AIs and between AI and fulvestrant is similar. The results of the phase II neoMONARCH study showed that the Ki67 reduction of abeccil combined with anastrozole was greater than that of anastrozole single-agent neoadjuvant therapy for 2 weeks, providing new evidence for neoadjuvant endocrine single-agent combined with CDK4/6 inhibitors. A new generation of oral selective estrogen receptor downregulator (SERD) combined with CDK4/6 inhibitor for neoadjuvant treatment of HR-positive early breast cancer is also being explored. The coopERA study is the first in The neoadjuvant phase confirms that oral SERD Giredestrant is more effective than AI in a randomized controlled phase II study. This study aimed to compare the efficacy and safety of Giredestrant and anastrozole combined with palbociclib in neoadjuvant treatment of HR-positive early breast cancer patients, respectively. The study met its primary endpoint, Ki67 decreased by 75% in the Giredestrant group at week 2 compared with 67% in the anastrozole group, reaching a statistical difference; in the final analysis at the 2022 ASCO meeting , Giredestrant was superior to anastrozole for Ki67 inhibition observed at week 2, and this advantage was maintained by the time of surgery with the addition of palbociclib (81% in the Giredestrant+piperoccil group vs. %). In addition, complete cell cycle arrest (CCCA) was stronger in the Giredestrant group than in the anastrozole group at week 2 (20% vs 13%), and by the time of surgery, the CCCA in the Giredestrant group was still stronger than that in the anastrozole group ( 24% vs 16%). Combining the convenience of oral administration and excellent safety profile, Giredestrant is expected to become one of the options for neoadjuvant endocrine therapy for HR-positive early breast cancer.

Figure 1 coopERA results

< For adjuvant stratified treatment of HR-positive early breast cancer, Prof. Song Chuangui said that recurrence risk stratification of patients can be performed according to clinicopathological factors and multi-gene arrays to guide decision-making of adjuvant endocrine therapy and chemotherapy.For low-risk and some intermediate-risk (such as 1-3 lymph node metastases, and 21 gene score below 25) postmenopausal patients can be exempted from chemotherapy and only receive adjuvant endocrine therapy. For intermediate and high-risk patients, further intensification is required Adjuvant therapy. Studies have confirmed that endocrine therapy in postmenopausal women can be extended to 7-8 years compared with 5 years, while invasive disease survival (iDFS) and OS are beneficial. SOFT The results of combined analysis with TEXT study suggest that the combination of OFS on the basis of endocrine therapy in premenopausal women is superior to tamoxifen alone, and the adjuvant AI±OFS in premenopausal/postmenopausal women is superior to tamoxifen±OS. Strong endocrine therapy drugs such as a new generation of oral SERDs are also being explored in adjuvant therapy (eg, the LidERA phase III study of Giredestrant versus standard endocrine monotherapy adjuvant therapy in HR+/HER2- early breast cancer patients). At present, the results of the monarchE study have been Compared with endocrine therapy alone, abecici combined with standard endocrine therapy has been confirmed to significantly improve invasive disease-free survival (iDFS) in high-risk HR-positive early breast cancer. For HR-positive early breast cancer, clinical research is increasingly focusing on screening true For high-risk or higher-risk groups, more accurate selection of appropriate adjuvant treatment options.

Hot spots and prospects for HR-positive advanced breast cancer treatment< /p>

In the past decade, many breakthroughs have been made in the research and development of new drugs for various subtypes of advanced breast cancer. Professor Yang Jin said that the current treatment hotspots and progress of HR-positive advanced breast cancer are mainly focused on CDK4/6 inhibitors, including OS benefits, drug resistance mechanisms, and follow-up treatment strategies. At the same time, there have also been a series of research progress for people with low HER2 expression, PIK3CA mutation and gBRCA mutation. Overall, with the extension of follow-up time, the OS benefit of CDK4/6 inhibitor became more and more obvious. CDK4/6 inhibitor combined with endocrine therapy has become the best choice for patients with HR-positive advanced breast cancer. Standard treatment regimen.

In terms of future partners of CDK4/6 inhibitors, Professor Yang Jin said that new oral SERDs are the current research hotspot. Drugs are under development, such as Giredestrant, Camizestrant and Amcenestrant. Among them, Giredestrant is a novel and highly effective oral SERD, which can completely antagonize estrogen receptor (ER), block ER signaling pathway, and achieve ER degradation, thereby inhibiting tumor cell proliferation< /span>. Oral administration of Giredestrant offers greater convenience and higher ER binding (>90%) than the first-generation SERD fulvestrant intramuscularly, which is known to be associated with worse prognosis. Not only that, the oral dose of Giredestrant 30mg gave exposures 6 times and more than the standard dose of fulvestrant. Results of Giredestrant’s Ib GO39932 study show clinical benefit of Giredestrant 30mg monotherapy in patients with locally advanced or metastatic ER+/HER2- breast cancer who have received ≤2 prior therapies The rate (CBR) was 54%, and the median PFS was 7.2 months. The clinical benefit rate (CBR) of patients in the Giredestrant 100mg combined with palbociclib group reached 81%, and the median PFS was 18.2 months. Regardless of the presence or absence of ESR1 mutation, previous fulvestrant treatment or previous CDK4/6 inhibitor treatment did not affect its efficacy, and Giredestrant combined with palbociclib had no clinically relevant drug interactions and had good safety< /strong>. In addition, compared with other oral SERDs, whether it is a single drug or a combination of palbociclib, Giredestrant has a good performance and is expected to become one of the best endocrine therapy drugs in the future. Currently, the phase III persevERA study of Giredestrant combined with palbociclib versus AI combined with palbociclib in the first-line treatment of HR-positive advanced breast cancer is ongoing, and the results are promising.

Fig 2

Oral efficacy of monotherapy

Figure 3 Efficacy of oral SERDs combined with palbociclib

The choice of regimen after the progression of CDK4/6 inhibitor therapy , there is no standard answer. Combined with the current clinical practice and research direction, the options that can be considered include replacing endocrine therapy drugs (such as new oral SERD or ARV-471), CDK4/6 inhibitor cross-line therapy and choosing other targeted therapy drugs (such as PI3K inhibitors, mTOR inhibitors, HDAC inhibitors, ADC drugs, CDK2 inhibitors, CDK7 inhibitors), etc. Among them, PI3Kα inhibitors bring new hope for PIK3CA mutant HR+/HER2- breast cancer patients and are expected to open A new era of precise targeted therapy for breast cancer. About 40% of HR+/HER2- advanced breast cancer patients have PIK3CA mutations. Such patients have poor prognosis and are resistant to endocrine therapy and chemotherapy. There is a huge unmet clinical need.The results of the SOLAR-1 study confirmed that Alpelisib combined with fulvestrant compared with fulvestrant alone prolonged the PFS of patients with PIK3CA mutations from 5.7 months to 11 months. However, the adverse reactions of Alpelisib occurred The high rate (36.6% for grade ≥3 hyperglycemia and 9.9% for grade ≥3 rash) limited patient tolerance to the drug. About 25% of patients discontinued due to AEs, and the median treatment duration was only 5.5 months. A new generation of PI3Kα inhibitor Inavolisib is under development and has made good progress.Inavolisib can selectively inhibit PI3Kα , the selective inhibition of PI3Kα is more than 300 times that of other PI3K isoforms. At the same time, inavolisib can also specifically degrade PI3Kα mutants, achieving continuous inhibition of PI3K pathway. SABCS announced in 2021 Inavolisib combined with fulvestrant in the treatment of PIK3CA-mutated HR+/HER2- advanced breast cancer (GO39374 Study Group D) data showing that Inavolisib in combination with fulvestrant has significant antitumor activity, including in patients with disease progression after prior CDK4/6 inhibitor therapy. About 26% of patients with measurable lesions achieved partial response (PR), the clinical benefit rate (CBR) was 48%, and the PFS was 7.1 months. Good safety is another big advantage of Inavolisib. The 2022 ASCO meeting updated the long-term safety data from the GO39374 study inavolisib. Of the 193 patients evaluated for safety, 61 patients were treated for more than 1 year. In the long-term treatment population (≥1 year), 39% had received CDK4/6 inhibitor treatment, and the median duration of inavolisib treatment was 20.6 months. Currently, the INAVO120 study of inavolisib in combination with a CDK4/6 inhibitor in advanced first-line treatment and the INAVO121 study in the CDK4/6 inhibitor-treated population are also underway.

Figure 4 Efficacy and long-term safety of Inavolisib alone and in combination with palbociclib >

Overall, for HR+/HER2-positive advanced breast cancer, CDK4/6 inhibitor combined with endocrine therapy is the standard treatment. The advantages of higher efficacy and better safety of new oral SERD drugs such as Giredestrant make it expected to be one of the most effective endocrine therapy drugs and the golden partner of CDK4/6 inhibitors. For patients with PIK3CA mutation, whether the triple combination of PI3K inhibitor combined with endocrine therapy and CDK4/6 inhibitor can further increase the efficacy and reverse or delay drug resistance deserves further exploration. In addition, more drugs targeting endocrine and CDK4/6 inhibitor resistance mechanisms are still under development, and the powerful combination of oral drugs in the future is worth looking forward to.

Majors discuss the hotspots and prospects of HR-positive breast cancer treatment

Each collision of thinking contains great energy, guiding the clinician. Under the auspices of Prof. Chen Yiding, Prof. Yang Jin and Prof. Hao Chunfang from Tianjin Medical University Cancer Hospital focused on the selection of endpoints for evaluating the efficacy of neoadjuvant therapy for HR-positive early breast cancer, the future application prospects of new oral SERD and PI3K inhibitors in HR-positive breast cancer, and Topics such as genetic testing were hotly debated.

With regard to the treatment of HR-positive breast cancer, more and more excellent treatment options have indeed emerged in recent years. For example, new oral SERD drugs such as Giredestrant, in addition to the amazing efficacy, convenience is a very important advantage, especially during the epidemic prevention and control period, I believe that there will be broader application prospects in the future. For patients with advanced HR-positive breast cancer, drug resistance is inevitable, and activation of the PAM pathway is a very important mechanism of bypass activation of drug resistance. The emergence of PI3Kα inhibitors such as Inavolisib provides treatment for patients with PIK3CA-mutated HR+/HER2- advanced breast cancer. a powerful weapon.

About Prof. Hao Chunfang SERD drugs, we have seen research results show that after the failure of CDK4/6 inhibitor therapy, they still have better performance, especially in the ESR1 mutation population; and in neoadjuvant therapy, Giredestrant is superior to the existing endocrine therapy drug Anastrox azole. In addition, compared with intramuscular injection, the clinical demand for oral SERD drugs will be greater, and the future application scenarios will be broader. Regarding the genetic testing of HR-positive breast cancer patients, in fact, in addition to the PIK3CA mutation in the PI3K pathway, there are also Abnormalities of genes such as AKT and PTEN, with the continuous development and clinical application of drugs targeting pathways and specific targets, the importance and status of genetic testing will increase day by day. high. At present, genetic testing tends to be performed after the failure of CDK4/6 inhibitor therapy. Whether genetic testing is required before this has not yet reached a clear conclusion and needs further exploration. As far as genetic testing samples are concerned, some studies have shown that there is little difference between tissue and blood ctDNA, and I personally think that tissue samples may cover genetic abnormalities with relatively low mutation frequencies