Prophylactic Irradiation to the Contralateral Breast for BCAs Patients

Study Overview
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Brief Summary
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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
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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.

Official Title
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Phase II Multicenter Clinical Trial of Prophylactic Irradiation to the Contralateral Breast for Breast Cancer Patients With BRCA1, BRCA2 and PALB2 Deleterious Mutation

Conditions
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Breast Cancer

Intervention / Treatment
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* Radiation: Prophylactic contralateral breast irradiation


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Standard group<br>Standard loco-regional treatment without prophylactic contralateral breast irradiation | |
| Experimental: Prophylactic irradiation group<br>Standard loco-regional treatment with prophylactic contralateral breast irradiation | Radiation: Prophylactic contralateral breast irradiation<br>* The whole contralateral breast will be irradiated once daily, 5 days a week, for 5-6 weeks, using 1.8-2 Gy/fx to a total dose of 45-50 Gy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Contralateral breast cancer | The recurrence rate of contralateral breast cancer | up to 10 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overal survival | The length of time from either the date of diagnosis or the start of lumpectomy or mastectomy for primary breast cancer with or without prophylactic irradiation to the contralateral breast | up to 10 years | 
| Ipsilateral loco-regional recurrence | Reappearance of cancer in the ipsilateral preserved breast, chest wall, axillary or supraclavicular lymph nodes. | Every 3-6 months. Follow up will be continued until 10 years after lumpectomy or mastectomy for primary breast cancer. | 
| Distant metastasis | Breast cancer that has spread from the original (primary) breast cancer to distant organs or distant lymph nodes. | up to 10 years | 
| Short time adverse effects | Any short term adverse effects that related to prophylactic irradiation | 3 months since radiation treatment start | 
| Long time adverse effects | Any long term adverse effects that related to prophylactic irradiation | up to 10 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BRCA1, BRCA2, PALB2, Deleterious mutation, Prophylactic irradiation, Contralateral breast cancer risk