Key Points
- The integration of genomics into the care of oncology patients has led to an increasing population of breast cancer patients identified with germline (i.e., inherited) mutations in breast cancer susceptibility genes, requiring physicians to integrate this information into treatment decision-making.
- Pathogenic or likely pathogenic variants (commonly referred to as mutations) in high-penetrance breast cancer susceptibility genes increase the risk of breast cancer more than 4-fold.
- Germline mutations in BRCA1 or BRCA2 (BRCA1/2) are found in 3–4% of all women with breast cancer, including 10–20% of those with triple negative breast cancer and 10–15% of Jewish women with breast cancer.
- The lifetime risk of breast cancer for a BRCA mutation carrier varies from 50–90% based on populations studied, gene, study design and method of analysis.
- Other high-penetrance breast cancer susceptibility genes include PTEN (Cowden's Syndrome), TP53 (Li-Fraumeni Syndrome), STK11 (Peutz-Jeghers Syndrome), and CDH1 (Hereditary Invasive Lobular Breast-Diffuse Gastric Cancer).
- Mutations in more moderate-penetrance genes such as PALB2, CHEK2, and ATM occur in 4–6% of breast cancer patients with lifetime risk of 35%–60% (PALB2) and 25%–30% (ATM and CHEK2).
- Providers caring for breast cancer patients with germline BRCA1/2 mutations should discuss treatment options related to the index cancer and the increased risk of contralateral breast and new ipsilateral breast cancer.
Management
Recommendation 1.1
- Germline BRCA status should not preclude a patient with newly diagnosed breast cancer otherwise eligible for breast conserving therapy (BCT) from receiving BCT. (Moderate recommendation; FC-I)
Recommendation 1.2
- Surgical management of the index malignancy (BCT vs. ipsilateral therapeutic and contralateral risk-reducing mastectomy) in BRCA1/2 mutation carriers should be discussed considering the increased risk of contralateral breast cancer and possible increased risk of an ipsilateral new primary breast cancer compared to non-carriers. (Strong recommendation; FC-I)
Recommendation 1.3
- The following factors should be considered for assessing risk of contralateral breast cancer (CBC) and role of risk-reducing mastectomy in BRCA1/2 mutation carriers: age of diagnosis (the strongest predictor of future contralateral breast cancer; family history of breast cancer, overall prognosis from this or other cancers (e.g., ovarian), ability of patient to undergo appropriate breast surveillance (MRI), comorbidities, and life expectancy. (Moderate recommendation; FC-L)
Recommendation 1.4
- BRCA1/2 mutation carriers who do not have bilateral mastectomy should undergo high-risk breast screening of remaining breast tissue with annual mammogram and MRI. (Moderate recommendation; FC-L)
Recommendation 2.1
- For women with newly diagnosed breast cancer who have a mutation in a moderate-penetrance breast cancer susceptibility gene, mutation status alone should not determine local therapy decisions for the index tumor or contralateral risk-reducing mastectomy. (Moderate recommendation; FC-L)
Recommendation 2.2
- In breast cancer patients with a mutation in a moderate-penetrance breast cancer susceptibility gene, BCT should be offered to patients for whom BCT is an appropriate treatment option. (Moderate recommendation; FC-L)
Note: There is a lack of data regarding ipsilateral breast cancer events after BCT among patients with moderate-risk mutations.
Recommendation 2.3
- The evidence regarding contralateral breast cancer risk is limited for mutations in moderate-penetrance breast cancer genes, aside from some data for CHEK2 1100delC. (Moderate recommendation; FC-L)
Note: Information about the specific gene and what is known about the risk of contralateral breast cancer should be discussed in the context of shared decision-making.
Recommendation 2.4
- Patients with mutations in moderate-penetrance genes who do not have bilateral mastectomy should undergo high-risk breast screening of remaining breast tissue with annual mammogram and MRI. (Moderate recommendation; FC-L)
Recommendation 3.1
- For women with newly diagnosed breast cancer undergoing mastectomy who have a deleterious mutation in BRCA 1 or 2, nipple-sparing mastectomy is a reasonable oncologic approach to consider in appropriately selected patients. (Moderate recommendation; FC-I)
Recommendation 3.2
- For women with newly diagnosed breast cancer undergoing mastectomy who have a deleterious mutation in moderate-penetrance genes, nipple-sparing mastectomy is a reasonable oncologic approach to consider in appropriately selected patients. (Moderate recommendation; FC-L)
Recommendation 4.1
- For women with breast cancer who have a BRCA1/2 mutation and who have been treated or are being treated with unilateral mastectomy, contralateral risk-reducing mastectomy (CRRM) should be offered. CRRM is associated with a decreased risk of contralateral breast cancer; there is insufficient evidence for improved survival. (Moderate recommendation; FC-I)
Note: The following factors should be considered for assessing risk of CBC and role of risk-reducing mastectomy: age of diagnosis (the strongest predictor of future contralateral breast cancer), family history of breast cancer, overall prognosis from this or other cancers (e.g., ovarian), ability of patient to undergo appropriate breast surveillance (MRI), comorbidities, and life expectancy.
Recommendation 4.2
- For women with breast cancer who have a mutation in a moderate-penetrance breast cancer predisposition gene and who have been treated or are being treated with unilateral mastectomy, the decision regarding CRRM should not be based predominantly on the mutation status. (Moderate recommendation; FC-L)
Note: Additional factors that predict CBC such as age at diagnosis and family history should be considered, as they are in all cases. The impact of CRRM on decreasing risk of CBC is dependent on the risk of CBC for each individual gene. Data regarding the risk of CBC due to moderate-penetrance genes are limited.
Recommendation 5.1
- For breast cancer patients with a deleterious germline BRCA1/2 mutation interested in a contralateral risk-reducing mastectomy, physicians should discuss the option of nipple-sparing mastectomy as a reasonable oncologic option. (Strong recommendation; FC-I)
Recommendation 5.2
- For breast cancer patients with a mutation in a moderate-penetrance gene who are interested in a contralateral risk-reducing mastectomy, physicians should discuss the option of nipple sparing mastectomy as a reasonable oncologic option. (Moderate recommendation; FC-L)
Recommendation 6.1
- For women with breast cancer who are treated with BCT or with mastectomy for whom post-mastectomy radiotherapy is considered, radiation therapy should not be withheld due to mutation status, except for mutations in TP53 (see Recommendation 6.3). (Strong recommendation; FC-I)
Note: There is no evidence of a significant increase in toxicity or contralateral breast cancers (CBC) related to radiation exposure among patients with a mutation in a BRCA1/2 or a moderate-penetrance gene.
Recommendation 6.2
- For women with breast cancer who are carriers of an ATM mutation, radiation therapy should be offered when clinically indicated. Data regarding rates of toxicity between ATM mutation carriers and non-carriers are limited and inconsistent. Potential absolute risks appear to be small. However, more research is needed. (Moderate recommendation; FC-L)
Note: Discussion with ATM carriers interested in BCT is encouraged.
Recommendation 6.3
- For women with breast cancer who are carriers of a germline TP53 mutation, radiotherapy of the intact breast is contraindicated. Mastectomy is the recommended therapeutic option. Postmastectomy radiation therapy should only be considered in patients with significant risk of locoregional recurrence. (Moderate recommendation; FC-L)
Recommendation 7
- When offering chemotherapy for germline BRCA mutation carriers with metastatic breast cancer, platinum chemotherapy is preferred to taxane therapy for patients who have not previously received platinum. There are no data to address platinum efficacy in other germline mutation carriers. (Moderate recommendation; EB-I)
Recommendation 8
- For germline BRCA mutation carriers with breast cancer treated with (neo)adjuvant therapy, data do not support the routine addition of platinum to anthracycline and taxane-based chemotherapy. While single-agent platinum has demonstrated activity in the neoadjuvant setting, there are no data yet comparing it to standard chemotherapy. There are no data to address platinum efficacy in other germline mutation carriers. (Moderate recommendation; EB-I)
Recommendation 9.1
- For BRCA1/2 mutation carriers with metastatic HER2-negative breast cancer, olaparib or talazoparib should be offered as an alternative to chemotherapy in the 1st-3rd line setting. For BRCA1/2 mutation carriers with metastatic HER2-negative breast cancer, there are no data directly comparing efficacy of PARP inhibitor to platinum chemotherapy. (Strong recommendation; EB-H)
Recommendation 9.2
- For breast cancer patients with mutations in moderate-penetrance genes, there are currently no robust data to support the use of PARP inhibitors. (Moderate recommendation; IC-Ins)
Recommendation 10 – ASCO Recommendation Update June 2021
- For patients with early-stage, HER2–negative breast cancer with high risk of recurrence and germline BRCA1 or BRCA2 pathogenic or likely pathogenic variants, one year of adjuvant olaparib should be offered after completion of (neo)adjuvant chemotherapy and local treatment, including radiation.
- For those who had surgery first, one year of adjuvant olaparib should be offered for patients with triple negative breast cancer (TNBC) and tumor size >2 cm or any involved axillary nodes.
- For those with hormone receptor-positive disease, one year of adjuvant olaparib should be offered to those with at least four involved axillary lymph nodes.
- For patients who had neoadjuvant chemotherapy, one year of adjuvant olaparib should be offered to patients with TNBC and any residual cancer; for patients with hormone receptor-positive disease, one year of adjuvant olaparib should be offered to patients with residual disease and a clinical stage, pathologic stage, estrogen receptor status, and tumor grade (CSP+EG) score ≥3.
Table 1. Management of Hereditary Breast Cancer in BRCA1/2 vs. Moderate Penetrance Genes
| Women with Breast Cancer Who Have a BRCA1or BRCA2Mutation |
|---|
| Local Therapy Recommendations |
| Index/Current Cancer |
| Germline BRCA status should not preclude a patient with newly diagnosed breast cancer otherwise eligible for breast conserving therapy (BCT) from receiving BCT. |
| Surgical management of the index malignancy (BCT vs. ipsilateral therapeutic and contralateral risk-reducing mastectomy) in BRCA1/2 mutation carriers should be discussed, considering the increased risk of contralateral breast cancer and possible increased risk of an ipsilateral new primary breast cancer compared to non-carriers. |
| For women with newly diagnosed breast cancer undergoing mastectomy who have a deleterious mutation in BRCA1 or 2, or moderate-penetrance genes, nipple-sparing mastectomy is a reasonable oncologic approach to consider in appropriately selected patients. |
| For women with breast cancer who are treated with BCT or with mastectomy for whom post-mastectomy radiotherapy is considered, radiation therapy should not be withheld due to mutation status, except for mutations in TP53 (see Recommendation 6.3 that states that radiotherapy of the intact breast is contraindicated in TP53 carriers). There is no evidence of a significant increase in toxicity or contralateral breast cancers (CBC) related to radiation exposure among patients with a mutation in a BRCA1/2 or a moderate-penetrance gene. |
| Risk-Reduction/Second cancer |
| The following factors should be considered for assessing risk of contralateral breast cancer (CBC) and role of risk-reducing mastectomy in BRCA1/2 mutation carriers: age of diagnosis (the strongest predictor of future contralateral breast cancer; family history of breast cancer, overall prognosis from this or other cancers (e.g., ovarian), ability of patient to undergo appropriate breast surveillance (MRI), comorbidities, and life expectancy. |
| For women with breast cancer who have a BRCA1/2 mutation and who have been treated or are being treated with unilateral mastectomy, contralateral risk-reducing mastectomy (CRRM) should be offered. CRRM is associated with a decreased risk of contralateral breast cancer; there is insufficient evidence for improved survival. The following factors should be considered for assessing risk of CBC and role of risk-reducing mastectomy: age of diagnosis (the strongest predictor of future contralateral breast cancer), family history of breast cancer, overall prognosis from this or other cancers (e.g., ovarian), ability of patient to undergo appropriate breast surveillance (MRI), comorbidities, and life expectancy. |
| For breast cancer patients with a deleterious germline BRCA1/2 mutation interested in risk-reducing mastectomy, physicians should discuss the option of nipple-sparing mastectomy as a reasonable oncologic option. |
| BRCA1/2 mutation carriers who do not have bilateral mastectomy should undergo high-risk breast screening of remaining breast tissue with annual mammogram and MRI. |
| Systemic Therapy Recommendations |
| When offering chemotherapy for germline BRCA mutation carriers with metastatic breast cancer, platinum chemotherapy is preferred to taxane therapy for patients who have not previously received platinum. There are no data to address platinum efficacy in other germline mutation carriers. |
| For germline BRCA mutation carriers with breast cancer treated with (neo)adjuvant therapy, data do not support the routine addition of platinum to anthracycline and taxane-based chemotherapy. While single-agent platinum has demonstrated activity in the neoadjuvant setting, there are no data yet comparing it to standard chemotherapy. There are no data to address platinum efficacy in other germline mutation carriers. |
| For BRCA1/2 mutation carriers with metastatic HER2-negative breast cancer, olaparib or talazoparib should be offered as an alternative to chemotherapy in the 1st-3rd line setting. For BRCA1/2 mutation carriers with metastatic HER2-negative breast cancer, there are no data directly comparing efficacy of PARP inhibitor to platinum chemotherapy. |
| For patients with early-stage, HER2–negative breast cancer with high risk of recurrence and germline BRCA1 or BRCA2 pathogenic or likely pathogenic variants, one year of adjuvant olaparib should be offered after completion of (neo)adjuvant chemotherapy and local treatment, including radiation. For those who had surgery first, one year of adjuvant olaparib should be offered for patients with triple negative breast cancer (TNBC) and tumor size >2 cm or any involved axillary nodes. For those with hormone receptor-positive disease, one year of adjuvant olaparib should be offered to those with at least four involved axillary lymph nodes. For patients who had neoadjuvant chemotherapy, one year of adjuvant olaparib should be offered to patients with TNBC and any residual cancer; for patients with hormone receptor-positive disease, one year of adjuvant olaparib should be offered to patients with residual disease and a clinical stage, pathologic stage, estrogen receptor status, and tumor grade (CSP+EG) score ≥3. |
| Women with Breast Cancer Who Have a Mutation in a Moderate-Penetrance Gene |
| Local Therapy Recommendations |
| Index/Current Cancer |
| For women with newly diagnosed breast cancer who have a mutation in a moderate-penetrance breast cancer susceptibility gene, mutation status alone should not determine local therapy decisions for the index tumor or contralateral risk-reducing mastectomy. |
| In breast cancer patients with a mutation in a moderate-penetrance breast cancer susceptibility gene, BCT should be offered to patients for whom BCT is an appropriate treatment option. There is a lack of data regarding ipsilateral breast cancer events after BCT among patients with moderate-risk mutations. |
| For women with newly diagnosed breast cancer undergoing mastectomy who have a deleterious mutation in moderate-penetrance genes, nipple-sparing mastectomy is a reasonable oncologic approach to consider in appropriately selected patients. |
| For women with breast cancer who are carriers of an ATM mutation, radiation therapy should be offered when clinically indicated. Data regarding rates of toxicity between ATM mutation carriers and non-carriers are limited and inconsistent. Potential absolute risks appear to be small; however, more research is needed. Discussion with ATM carriers interested in BCT is encouraged. |
| Risk-Reduction/Second Cancer |
| For women with breast cancer who have a mutation in a moderate-penetrance breast cancer predisposition gene and who have been treated or are being treated with unilateral mastectomy, the decision regarding CRRM should not be based predominantly on the mutation status. Additional factors that predict CBC such as age at diagnosis and family history should be considered, as they are in all cases. The impact of CRRM on decreasing risk of CBC is dependent on the risk of CBC for each individual gene. Data regarding the risk of CBC due to moderate-penetrance genes are limited. |
| The evidence regarding contralateral breast cancer risk is limited for mutations in moderate-penetrance breast cancer genes, aside from some data for CHEK2 1100delC. Information about the specific gene and what is known about the risk of contralateral breast cancer should be discussed in the context of shared decision-making. |
| For breast cancer patients with a mutation in a moderate-penetrance gene who are interested in risk-reducing mastectomy, physicians should discuss the option of nipple sparing mastectomy as a reasonable oncologic option. |
| Patients with mutations in moderate-penetrance genes who do not have bilateral mastectomy should undergo high-risk breast screening of remaining breast tissue with annual mammogram and MRI. |
| Systemic Therapy Recommendations |
| For breast cancer patients with mutations in moderate-penetrance genes, there are currently no robust data to support the use of PARP inhibitors. |
Table 2. Clinical Stage + Pathologic Stage + ER status + Nuclear grade (CPS&EG score) Calculation instructions: Add the points for Clinical Stage + Pathologic Stage + ER status + Nuclear grade to derive a sum (CPS&EG score) between 0 and 6.
| Stage/feature | Points | |
|---|---|---|
| Clinical Stage (AJCC staging1) | I | 0 |
| IIA | 0 | |
| IIB | 1 | |
| IIIA | 1 | |
| IIIB | 2 | |
| IIIC | 2 | |
| Pathologic Stage (AJCC staging1) | 0 | 0 |
| I | 0 | |
| IIA | 1 | |
| IIB | 1 | |
| IIIA | 1 | |
| IIIB | 1 | |
| IIIC | 2 | |
| Receptor status | ER negative2 | 1 |
| Nuclear grade3 | Nuclear grade3 | 1 |
1 AJCC: American Joint Committee on Cancer (https://cancerstaging.org/Pages/default.aspx)
2 ER: Estrogen receptor; definitions for ER negativity see eligibility criteria section 4.1.4.a
3 In the unlikely situation nuclear grade cannot be determined, regular histologic grade should be used; if only Nottingham overall grade is reported, the Nottingham overall grade must be 9 to be scored as 1 point in the CPS&EG score (http://pathology.jhu.edu/breast/grade.php).
From The New England Journal of Medicine, Tutt ANJ et al, Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer, 384, 2394-2405. Copyright ©2021 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
