Clinical trial NCT04960839: Prophylactic Irradiation to the Contralateral Breast for BCAs Patients
Official title: Phase II Multicenter Clinical Trial of Prophylactic Irradiation to the Contralateral Breast for Breast Cancer Patients With BRCA1, BRCA2 and PALB2 Deleterious Mutation
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Breast Cancer
Keywords: BRCA1
BRCA2
PALB2
Deleterious mutation
Prophylactic irradiation
Contralateral breast cancer risk
Lead sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University
Sponsor class: OTHER
First posted: 2021-07-14
Enrollment: 323
Sex: FEMALE
Minimum age (years): 30
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Breast cancer is the most common cancer in women worldwide, with high mortality. About 5% to 10% of breast cancers are hereditary. Most inherited cases of breast cancer are associated with germline mutations in genes, such as BRCA1, BRCA2 and PALB2. The cumulative breast cancer risk for BRCA1, BRCA2 or PALB2 mutation carriers was high.

Besides the increased breast cancer risk for the inherited mutation carriers, the risk of subsequent contralateral breast cancer for the mutation carriers with breast cancer was also significantly increased. Contralateral prophylactic mastectomy was usually recommended to the breast cancer patients with BRCA mutation. However, many breast cancer patients refused the contralateral prophylactic mastectomy, due to the surgical injury, potential surgical complications, deleteriously affected body image and sexuality.

Solid evidence validated that radiotherapy after surgery resulted in a reduced local recurrence for three times lower than surgery alone. It is thought that radiation would eliminate the microscopic tumors which may already exist in the breast. Thus, we proposed that for the breast cancer patients with BRCA1, BRCA2 or PALB2 deleterious germline mutations, prophylactic irradiation to the contralateral breast may reduce the risk of subsequent contralateral breast cancer. And we would like to further compare the effect of prophylactic irradiation to the published data from traditional prophylactic contralateral mastectomy.

Detailed description: Breast cancer is the most common cancer in women worldwide, with high mortality. In the US in 2018, the number of estimated new cases of breast cancer accounted for 30% of all the new cancer cases in women, while the estimated deaths of breast cancer accounted for 14% of all new cancer deaths. In Chinese females, the most commonly diagnosed cancer was breast cancer, accounting for 19% of total cases. And breast cancer was the main 5 most common causes of cancer-related deaths in China.

About 5% to 10% of breast cancers are hereditary. Most inherited cases of breast cancer are associated with germline mutations in two genes: BRCA1 (BRCA1 DNA repair associated) and BRCA2 (BRCA2 DNA repair associated). The cumulative breast cancer risk for BRCA1 or BRCA2 mutation carriers at age 70 years reached as high as 50% in US population and 37% in Chinese population. Benefiting from the next generation sequencing technology, more inherited gene mutations were discovered. Among these new discovered susceptibility genes, PALB2 (Partner and localizer of BRCA2) was associated with high increased risks of breast cancer in both Chinese and US population.

Besides the increased breast cancer risk for the inherited mutation carriers, the risk of subsequent contralateral breast cancer for the mutation carriers with breast cancer was also significantly increased. For contralateral breast cancer in BRCA mutation carriers, the cumulative risk for 10 years after breast cancer diagnosis was as high as 25% and for 20 years reached to 40%, as compared 3% and 12% respectively in non-carriers. Contralateral prophylactic mastectomy was usually recommended to the breast cancer patients with BRCA mutation, as it can absolutely reduce the risk of contralateral primary cancer. However, many breast cancer patients refused the contralateral prophylactic mastectomy, due to the surgical injury, potential surgical complications, deleteriously affected body image and sexuality.

Solid evidence validated that radiotherapy after surgery resulted in a reduced local recurrence for three times lower than surgery alone. It is thought that radiation would eliminate the microscopic tumors which may already exist in the breast. Thus, we proposed that for the breast cancer patients with BRCA1, BRCA2 or PALB2 deleterious germline mutations, prophylactic irradiation to the contralateral breast may reduce the risk of subsequent contralateral breast cancer. And we would like to further compare the effect of prophylactic irradiation to the published data from traditional prophylactic contralateral mastectomy.

Eligibility criteria: Inclusion Criteria:

* Female patients, aged 30-70yrs, diagnosed with stage 0-III breast cancer (NCCN-Breast Cancer V2.2019), undergoing the lumpectomy or mastectomy no more than 1 year. ALND or SLNB should be carried out and the lymph node status should be known.
* Patients with a deleterious germline mutation of BRCA 1/2 or PALB2.
* The patients with no contraindictation for irradiation.
* The patients consent for prophylactic irradiation to the contralateral breast.
* The patient may receive any regimen of adjuvant, neoadjuvant chemotherapy, according to the treating physician. The radiation therapy should start at least 2 weeks after the completion of all the chemotherapy cycles.
* The patient may receive endocrine therapy before, during or after study entry.
* The patient may receive target therapy (Trastuzumab) before, during or after study entry.
* The patient must be eligible for MRI examination of the contralateral breast.
* The patient refused prophylactic contralateral mastectomy and oophorectomy.

Exclusion Criteria:

* Metastatic breast cancer.
* Past history of other cancer besides breast cancer
* Previous irradiation of the breast or chest wall, but not for breast cancer treatment
* Synchronous bilateral breast cancer
* Patients with active connective tissue diseases, pneumonia are excluded due to the potential risk of significant radiotherapeutic toxicity.

Primary outcomes:
measure: Contralateral breast cancer
timeFrame: up to 10 years
Secondary outcomes:
measure: Overal survival
timeFrame: up to 10 years
measure: Ipsilateral loco-regional recurrence
timeFrame: Every 3-6 months. Follow up will be continued until 10 years after lumpectomy or mastectomy for primary breast cancer.
measure: Distant metastasis
timeFrame: up to 10 years
measure: Short time adverse effects
timeFrame: 3 months since radiation treatment start
measure: Long time adverse effects
timeFrame: up to 10 years
Other outcomes:
Locations:
city: Jiangxi
country: China
facility: Department of Breast Surgery, Jiangxi Provincial Cancer Hospital
state: Jiangxi
city: Shanghai
country: China
facility: Department of Breast Surgery, Obestrics and Gynecology Hospital of Fudan University
state: Shanghai
city: Hangzhou
country: China
facility: Department of Breast Surgery, Cancer Hospital of University of Chinese Academy of Sciences
state: Zhejiang
city: Hangzhou
country: China
facility: Department of Breast Surgery, the First Affiliated Hospital, College of Medicine, Zhejiang University
state: Zhejiang
city: Hangzhou
country: China
facility: Department of Breast Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine
state: Zhejiang
city: Hangzhou
country: China
facility: Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University
state: Zhejiang
city: Hangzhou
country: China
facility: Department of Oncology, Zhejiang Hospital
state: Zhejiang
city: Singapore
country: Singapore
facility: Department of Breast Surgery, Yong Loo Lin School of Medicine, National University of Singapore
Study officials:
affiliation: Department of Breast Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University
name: Peifen Fu, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University
name: Wenjun Chen, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Breast Surgery, Obsterics and Gynecology Hospital of Fudan University
name: Kejin Wu, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Breast Surgery, Cancer Hospital of University of Chinese Academy of Sciences
name: Xiaowen Ding, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Breast Surgery, Jiangxi Provincial Cancer Hospital
name: Zhengkui Sun
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore
name: Mikael Hartman
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Breast Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine
name: Yiding Chen
role: PRINCIPAL_INVESTIGATOR
affiliation: Departmen of Breast Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine
name: Jiaojiao Zhou
role: PRINCIPAL_INVESTIGATOR
affiliation: Departmen of Breast Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine
name: Kun Zhang
role: PRINCIPAL_INVESTIGATOR
affiliation: Departmen of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine
name: Wenhong Xu
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Oncology, Zhejiang Hospital
name: Zhibing Wu
role: PRINCIPAL_INVESTIGATOR
References: