The four seas will be shocked, and watch the young talents in the field of breast cancer talk and laugh

Embrace all rivers and look at the world; The crowd is full of talents
.
In order to build a platform for young and middle-aged scholars to interact and promote the development and progress of breast cancer diagnosis and treatment, the Four Seas Meeting, hosted by the Breast Cancer Professional Youth Committee of Shanghai Anti-Cancer Association, was held
in Shanghai on October 30, 2022.
The conference specially invited Professor Liu Guangyu of Fudan University Cancer Hospital as the honorary chairman, Professor Yu Keda of Fudan University Cancer Hospital and Professor Jin Yiting of Huashan Hospital affiliated to Fudan University as the chairmen of the conference.

Figure 1.
Group photo of participants

Keep loving and go to the mountains and seas together

At the beginning of the conference, Professor Jin Yiting introduced that in recent years, the development of ADC drugs can be described as radiant, today's topic is more around the progress and controversy of ADC drugs, and at the same time, there are also views on breast cancer laparoscopic surgery from the perspective of young doctors, in-depth interpretation of blockbuster research, enthusiastic debate competitions and other links, I hope that on today's stage, everyone can actively show themselves
.

Professor Liu Guangyu, Honorary Chairman, mentioned that the Four Seas Club is literally full of the four seasons, but also full of knowledge and the world, and hopes that under the leadership of Professor Yu Keda, everyone will know a wide range of people from all over the world and continue to make common progress
in medical skills.
At the same time, he pointed out that the development of young doctors should learn to be inclusive, critical and condensed, and he hopes to encourage
everyone.

Professor Yu Keda put forward the expectation in his speech, under the haze of the epidemic, even if the stars change, everyone still goes to the mountains and seas together, and continues to move forward bravely on the academic road to improve themselves
.
And I sincerely hope that the Four Seas Conference will not only be held in Shanghai, but will develop to different cities across the country, so that all people in the same path can participate in it
.

Figure 2.
Professor Liu Guangyu made an opening speech

Figure 3.
Professor Yu Keda made an opening speech

Figure 4.
Professor Jin Yiting made an opening speech

Knowledge iteration, imagining the future

ADCs lead the future of breast cancer anti-HER2 diagnosis and treatment

In the first chapter, co-chaired by Professor Yu Keda and Professor Jiang Yizhou, Professor Fan Lei of Fudan University Cancer Hospital first shared the wonderful topic
of "ADC Leading the Future of Anti-HER2 Diagnosis and Treatment of Breast Cancer" 。 Professor Fan Lei systematically explained the R&D background and design concept of ADC drugs, among which the new ADC drug DS-8201 adopts a tetrapeptide-based cleavable linker, a highly active topoisomerase I inhibitor as the drug carrier, and the drug-antibody ratio (DAR) reaches 8, and has a strong bystander effect, and its unique properties in structure and mechanism have great advantages
over a series of current anti-HER2 ADCs.

When talking about the clinical value of the new ADC drugs for HER2-positive breast cancer, Professor Fan Lei said that the progression-free survival (PFS) of the first-line treatment of HER2-positive advanced breast cancer was about 20 months, and the second-line treatment was only 6-10 months, but the amazing performance of DS-8201 in the DESTINY-Breast03 (DB-03) study changed this situation.
The median PFS assessed by investigators was 25.
1 months, with p-values as low as 10-22, and DS-8201 showed an absolute PFS (BICR) benefit advantage
over T-DM1 in all subgroups.
The objective response rate (ORR) is as high as 79.
7%, and the tumor shrinkage effect is very significant
.
Based on the research results, DS-8201 has successively been recommended by authoritative guidelines at home and abroad, and has also been recommended as a second-line "optional" recommendation
in the 2022 CBCS Essential Edition Guidelines (Little Red Book).
Although there are no head-to-head studies to compare, DS-8201 has demonstrated efficacy advantages over other HER2-targeted ADCs, and has a good overall safety profile, with a low
incidence of intermediate pneumonia (ILD) in actual diagnosis and treatment.
Not only that, DS-8201 also actively deploys early (new) adjuvant and advanced first-line treatment, covering the future of
HER2-positive breast cancer.

For breast cancer with low HER2 expression, Professor Lei Fan emphasized that low HER2 expression accounts for about 50% of the total breast cancer, and there is still controversy about whether low HER2 expression can become a unique subgroup of breast cancer, but most studies believe that it has a large correlation with HR status, and overall low HER2 expression does not predict worse prognostic outcomes
。 Based on the breakthrough results of the DESTINY-Breast04 (DB-04) study, DS-8201 has been recommended by NCCN guidelines as a class of evidence for breast cancers with low HER2 expression (regardless of HR status).

In 2022, Xiaohongshu also recommended it as an "optional" back-line treatment for HR-positive patients
.

Finally, Professor Fan Lei systematically sorted out the R&D trend and future prospect of ADC drugs, and the focus of future R&D of ADC drugs is mainly to overcome drug resistance and reduce toxicity
.
In the future, bispecific antibodies, immunostimulatory drug-loaded ADCs, dual-drug-loaded ADCs, radionuclide ADCs, etc.
will become the exploration direction
of accurate upgrading of ADC drugs.
More drug development
may be carried out on biomarkers, especially gene mutations and protein-specific expression.

Figure 5.
Professor Fan Lei

How to view the development and status of laparoscopic surgery for breast cancer

Professor Martin of Fudan University Cancer Hospital gave a wonderful explanation
on the current status and future development of laparoscopic surgery in breast cancer from the two aspects of breast-conserving surgery and total breast resection plus reconstructive surgery, and taking oncology safety and patient satisfaction (cosmetic effect) as the main considerations.
Laparoscopic breast-conserving surgery for breast cancer has limited cosmetic effects and is suitable for fewer patients; In terms of safety, there is a lack of high-quality long-term follow-up data, and the margin is a key limiting factor
.
Laparoscopic mastectomy plus reconstructive surgery is suitable for patients with high cosmetic requirements, and although there are relatively many research data compared with breast-conserving surgery, and there are some good retrospective data to support its safety, prospective research evidence is still needed to provide more detailed clinical guidance
.

Professor Martin said that laparoscopic surgery for breast cancer is expected to become a useful supplement to the existing surgical system, but the next ten years are still a stage of gradually accumulating data, and it is not appropriate to carry out blindly large-scale at present, and more needs to be more standardized and orderly development
.
Specifically, there is a need for better clinical evidence, standardized operation training, scientific case selection, and strict qualification certification
.

Figure 6.
Professor Martin

Foresee the future

Subsequently, under the chairmanship of Professor Jiang Yizhou, Professor Xiao Qin and Professor Zhang Yingying of Fudan University Cancer Hospital and Professor Zhao Junyong of Shanghai Tenth People's Hospital affiliated to Tongji University expressed their views on the above topics: the excellent efficacy of DS-8201 is undoubted, and the overall safety is good, and its future application prospects are also desirable
.
Laparoscopic surgery for breast cancer can be used as a complement to mainstream techniques, but its clinical application is generally conservative
.

The mountains are high and the moon is wide, and the peaks are bravely climbed

New advances in targeted therapy for early-stage breast cancer

Under the chairmanship of Professor Jin Yiting and Professor Huang Liang, Professor Qin Wenxing of Fudan University Cancer Hospital first explained the clinical research progress of I-SPY2, PREDIX HER2, TRAIN-2 and Per ELISA in the four fields of targeted therapy for early breast cancer, elaborated on how to evaluate the efficacy of targeted therapy for early breast cancer, and discussed whether existing immunohistochemical molecular typing can truly predict clinical efficacy
。 Among them, the subgroup analysis of the TRAIN-2 study showed that TIL score was not significantly related
to the prognosis of HER2-positive breast cancer patients receiving chemotherapy + anti-HER2 dual-target neoadjuvant therapy.
However, this study shows that genetic testing has a good predictive effect
on patient prognosis.
Per ELISA study showed that HER2DX pCR scores and HER2DX ERBB2 scores were positively correlated with the pCR rate of neoadjuvant tropa dual target + letrozole (chemotherapy-de-chemotherapy) regimen selected according to the baseline response of Ki67 after two weeks of letrozole treatment, which suggested possible predictors and was of great significance
for screening HR+/HER2+ people who could be exempted from chemotherapy.

Finally, Professor Qin Wenxing said that in general, the current research on efficacy predictors is very hot, and there are many relevant advances in the field of targeted therapy for early breast cancer, such as the DESTINY-Breast11 (DB-11) study of the new ADC drug DS-8201 neoadjuvant therapy, and the DESTINY-Breast05 (DB-05) study for neoadjuvant residual lesions are in full swing.
It is believed that the publication of future research results will further improve patient survival and change the pattern of targeted therapy for
early-stage breast cancer.

Figure 7.
Professor Qin Wenxing

Harmless first: cancer risk after breast cancer treatment

Professor Yang Zhaozhi of Fudan University Cancer Hospital gave a detailed interpretation of a retrospective cohort study of breast cancer treatment-associated chest soft tissue sarcoma recently published in Lancet Oncology, which was derived from the Kaiser Permanente (KP) cohort and the SEER cohort
of 13 registered studies.
The results showed that of the KP cohort, 19 (0.
1%) of the 15,940 eligible female breast cancer patients developed chest soft tissue sarcomas (11 angiosarcomas, 8 other subtypes).

Most (94.
7%; 18/19) Thoracic soft tissue sarcoma occurs in women receiving radiotherapy; Thus, radiation therapy was associated with a significantly increased risk of chest soft tissue sarcoma (RR = 8.
1; p=0.
0052), but not
with prescribed dose, segmentation, or push.
In the SEER cohort, 430 (0.
1%) of the 457,300 patients developed chest soft tissue sarcoma (268 angiosarcomas, 162 other subtypes) after a median follow-up of 8.
3 years (IQR 4.
3~13.
9).

Most (77.
9%; 335/430) cases occurred after radiotherapy; It was also suggested that radiotherapy was associated with a significantly increased risk of developing chest soft tissue sarcoma (RR=3.
0; p<0.
0001).

Based on the results of the study, Professor Yang Zhaozhi said that breast cancer radiotherapy is a double-edged sword, and it is necessary to weigh the pros and cons during treatment, and try to ensure that all treatment decisions are not harmful to patients, in order to maximize the benefits of
treatment.

Figure 8.
Professor Yang Zhaozhi

Pulse of the times

Next, under the chairmanship of Professor Huang Liang, Professor Chen Jiajian of Fudan University Cancer Hospital, Professor Chu Chengyu of Huashan Hospital Affiliated to Fudan University, and Professor Wang Zhengyuan of Shanghai Jiahui International Hospital respectively expressed their profound insights on the relevant content of the above topics, the main points include: ADC drugs are an important exploration direction for targeted therapy for early breast cancer in the future, and the overall trend is to screen out key targets, combined with continuous update and iteration of technology, to develop a broader spectrum of ADC drugs; Later, with the disclosure of DB-11 and DB-05 research data, DS-8201 will undoubtedly bring a new round of treatment changes to HER2-positive early breast cancer; It is important to fully communicate with patients before breast-conserving surgery, and it is necessary to objectively inform the risk of the second primary tumor after radiotherapy, and fully analyze the benefit-risk ratio to better make clinical decisions
.

Flourishing, living up to Shaohua

The words were shocked, and the argument was unmatched

Under the chairmanship of Professor Zhang Jian of Fudan University Cancer Hospital, the conference was held in an enthusiastic debate session, and the participating experts had a fierce discussion
on "Second-line preferred ADC (DS-8201) or TKI (pyrrotinib) after the progress of first-line treatment of HER2-positive advanced breast cancer".
Professor Ji Yajie of Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Professor Ye Xin of International Peace Maternal and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, and Professor Zhuang Ming, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine, supported DS-8201
as square debaters.
Professor Cai Fengfeng of Yangpu Hospital affiliated to Tongji University, Professor Cao Lu of Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, and Professor Wang Min of the First People's Hospital affiliated to Shanghai Jiao Tong University supported pyrrotinib
as counter-debaters.
The debaters from both sides debated the following topics, which pushed the whole meeting to a climax
.

Figure 9.
Debate Tournament Guest

The efficacy is definite, and the guidelines escort it

Square view:

Thanks to its unique structure and mechanical attributes, the DS-8201 can be called "gifted, starting and hanging, fighting alone, and killing all the way"
.
Single-agent second-line therapy has brought unprecedented PFS benefits (25.
1 months) to patients with HER2-positive metastatic breast cancer, with an ORR of 79.
7%.

It is worth mentioning that the DB-03 study not only included patients who had previously received trastuzumab and TKI treatment, but also included about 60% of patients treated with double target tripa, which is more in line with China's current clinical practice
.
In addition, the DB-03 study enrolled a considerable proportion of Asian patients, of which 57.
1% were Asian and 23.
5% were Chinese in the DS-8201 group, and the treatment benefits of Asian subgroup patients were consistent with the general population
.
Therefore, DS-8201 is well deserved
as the "strongest warrior" of a single drug.
Based on the excellent results of DB-03 research, DS-8201 has been recommended by domestic and foreign guidelines as a new standard
for second-line treatment of HER2-positive advanced breast cancer.

Counterarguments:

PHASE III CLINICAL STUDIES OF PHENIX AND PHOEBE JOINTLY CONFIRMED THE EXCELLENT EFFICACY OF PYRROTINIB IN CHINESE PATIENTS, ORR (PHENIX: 68.
6%; PHOEBE: 67.
2%) and PFS (PHENIX: 11.
1 months; PHOEBE: 12.
5 months) showed significant improvement
.
At present, pyrrotinib is the second-line preferred regimen
recommended by many domestic guidelines.
And since its approval for 4 years, its efficacy has been verified
by a number of real-world research data.

Both stable and active brain metastases are effective

Square view:

The DB-03 study included 23.
8% of patients with stable brain metastases, with a median PFS of 15 months in the subgroup and an intracranial ORR of up to 64%, of which 27.
8% were patients with CR, surpassing the benefit data
of patients with stable brain metastases in previous DB-01 studies.
Not only that, the performance of DS-8201 in active brain metastases is also remarkable, TUXEDO-1 research showed that DS-8201 treated active brain metastases, intracranial ORR reached 73.
3%, PFS up to 14 months
.
Whether it is stable brain metastases or active brain metastases, DS-8201 performs well
.

Counterarguments:

As a small molecule TKI, pyrrotinib easily penetrates the blood-brain barrier
.
The PHENIX study showed that pyrrotinib was equally effective in patients with stable brain metastases at baseline (6.
9 months for PFS).

THE PERMEATE STUDY SHOWED A PFS OF 11.
3 MONTHS AND AN INTRACRANIAL ORR OF 74.
6%
IN PATIENTS WITH ACTIVE BRAIN METASTASES WHO HAD NOT PREVIOUSLY RECEIVED RADIOTHERAPY.

Small side reactions, safe and reliable

Square view:

In the DB-03 study, the incidence of grade ≥ diarrhea was low (0.
4%)
.
The incidence of ILD of any grade was 10.
9%, and most of them were grade 1 and 2, and the incidence of grade 3 was 0.
8%, and grade 4 or 5 was absent
.
Most ILD events recovered from ongoing follow-up without fatal pneumonia
.
And the incidence of early ILD is lower, which is different
from the understanding of clinical experts.
In addition, the duration of treatment for DS-8201 can reach 14.
3 months, with a treatment interruption rate of 35.
4% and a dose adjustment rate of 21.
4%; In phase III clinical trials of pyrrotinib≥ the incidence of grade 3 diarrhea ranged from 31% to 46.
5%, treatment interruption rate ranged from 54.
2% to 61.
9%, and dose adjustment rate ranged from 25.
9% to 47%.

Overall, DS-8201 has a good safety profile and is tolerated
by continued use.

Counterarguments:

Second-line treatment with pyrrotinib has a good safety profile and does not cause ILD
.
In the PHOEBE study≥ grade 3 adverse events were common in the pyrrotinib group only diarrhea (30.
6%), while the incidence of diarrhea gradually decreased with treatment, and grade 3 diarrhea accumulated for only about 1 week, which was clinically easy to manage
.

Assist moments, the excitement continues

After the confrontation between the two sides, a wonderful "assist moment"
followed.
Under the chairmanship of Professor Ge Rui of East China Hospital affiliated to Fudan University, Professor Cao Jun and Professor Tao Zhonghua of Fudan University Cancer Hospital respectively elaborated their views
on "assist".
Both professors highly affirmed the excellent efficacy of DS-8201, and mentioned that any treatment needs to be comprehensively laid out to give full play to the efficacy value of drugs, and look forward to the exploration
of more combination protocols of DS-8201.

Quote scriptures and talk eloquently

In the final session of the conference, under the chairmanship of Professor Qu Qing of Ruijin Hospital affiliated to Shanghai Jiao Tong University, Professor Yu Yue of Shanghai Changhai Hospital shared the wonderful topic
of "The Integration of Knowledge and Action of Breast Surgeons".
Professor Yu Yue ingeniously explained the establishment process of the philosophical system of the historical sage Wang Yangming, and explained in simple terms how as a breast surgeon can continue to accumulate theoretical knowledge and put it into clinical practice while adhering to the original intention, so as to truly achieve the "unity of knowledge and action", in order to benefit the majority of patients
.
Finally, Professor Yu Yue summarized the report with a poem by Wang Yangming, "A person has a Zhongni in his heart, he will be confused by smelling and suffering, and now he refers to the true face, but his conscience is more doubtful", and called on fellow doctors to carry forward their conscience and make more contributions
to others and society.

Figure 10.
Professor Yu Yue

summary

At the end of the conference, Professor Yu Keda expressed his profound insights on the above debate, "From the current form, there is actually a time lag in our debate today, because the life cycle and development of each drug are not consistent
.
DS-8201's second-line status has been gradually consolidated and moved forward with new evidence-based results
.
Here, I also wish that every drug can obtain a good treatment status and application prospects, and ultimately benefit
patients.
Professor Jin Yiting concluded that this conference not only took stock of the latest research progress in the field, but also brought together the profound insights and reflections of multidisciplinary doctors on the diagnosis and treatment of breast cancer, not only set up an intense and exciting debate competition, but also carefully arranged thought-provoking humanistic knowledge sharing
.
The participating scholars were all passionate and full of talents, presenting a praiseworthy academic feast
.
It is hoped that through this erudite and eloquent exchange conference, everyone can think and gain, and strive to contribute to
the development of breast cancer diagnosis and treatment.
Finally, I also hope that when the next meeting comes, all the young talents present can continue to forge ahead and create glory
again.