This clinical practice guideline addresses 10 clinical questions: What is the appropriate surgical management of the index malignancy for women with newly diagnosed nonmetastatic breast cancer who have a BRCA1/2 mutation? What is the appropriate surgical management of the index malignancy for women with newly diagnosed nonmetastatic breast cancer who have a selected moderate-penetrance mutation? Among women with breast cancer who have a BRCA1/2 germline mutation or selected moderate-penetrance non-BRCA1/2 germline mutation who are undergoing therapeutic mastectomy, what is the role of nipple-sparing mastectomy? What is the role of contralateral prophylactic mastectomy for women with breast cancer who have a BRCA1/2 mutation or a selected moderate-penetrance gene mutation? Among women with breast cancer who have a BRCA1/2 germline mutation or selected moderate-penetrance mutation who are undergoing contralateral risk-reducing mastectomy (CRRM), what is the role of nipple-sparing mastectomy? What is the role of RT in women with breast cancer who have a BRCA1/2 germline mutation or selected moderate-penetrance non-BRCA1/2 germline mutation? What is the role of platinum chemotherapy in women who have a BRCA1/2 mutation or selected moderate-penetrance germline mutation and advanced breast cancer? What is the role of (neo)adjuvant platinum chemotherapy in women who have a BRCA1/2 mutation or selected moderate-penetrance germline mutation and breast cancer? What is the role of poly (ADP-ribose) polymerase (PARP) inhibitors in women who have a BRCA1/2 mutation or selected moderate-penetrance germline mutation and advanced breast cancer? What is the role of PARP inhibitors in women who have a BRCA1/2 mutation or selected moderate-penetrance mutation and nonmetastatic breast cancer?

The recommendations for the local therapy clinical questions were developed by using a systematic review of the literature and clinical experience. The literature review involved searches of PubMed for the period from January 1, 2010, through September 26, 2019 (surgery search), or January 1, 1999, through September 26, 2019 (RT search). The searches were broad and included a combination of treatment, genetic mutation, and breast cancer search terms (see Data Supplement [online only] 1 for more details of the literature search). Articles from the search were included if they reported data on outcomes of local therapy (therapeutic or prophylactic mastectomy, nipple-sparing mastectomy, RT) among women with newly diagnosed nonmetastatic or advanced breast cancer and a high- or moderate-penetrance germline mutation. Disease outcomes considered in the studies included in the literature were ipsilateral events, including true recurrences and new primary tumors, survival, cosmesis, contralateral breast cancer (CBC), and treatment toxicity/complications. An article was excluded from the local therapy literature review if (1) it was a narrative (v systematic) review of the literature, (2) it reported on a single case, (3) it reported on a study with a variant that was not pathogenic or likely pathogenic (eg, single-nucleotide polymorphisms or variant overexpression in the tumor), (4) it was a meeting abstract not subsequently published in peer-reviewed journal, or (5) it reported exclusively on a study of a group of women who received postmastectomy RT versus breast-conserving surgery (BCS) plus RT.

Upon approval of the Protocol, a systematic review of the medical literature is conducted. ASCO staff use the information entered into the Protocol, including the clinical questions, inclusion/exclusion criteria for qualified studies, search terms/phrases, and range of study dates, to perform the systematic review. Literature searches of selected databases, including The Cochrane Library and Medline (via PubMed) are performed. Working with the Expert Panel, ASCO staff complete screening of the abstracts and full text articles to determine eligibility for inclusion in the systematic review of the evidence. Unpublished data from meeting abstracts are not generally used as part of normal ASCO guideline development (“Meeting Data”). However, abstract data from reputable scientific meetings and congresses may be included on a case‐by‐case basis after review by the CPGC leadership. Expert Panels should present a rationale to support integration of abstract data into a guideline. The CPGC leadership will consider the following inclusion criteria for the unpublished scientific meeting data: 1) whether the data were independently peer reviewed in connection with a reputable scientific meeting or congress; 2) the potential clinical impact of the unpublished data; 3) the methodological quality and validity of the associated study; 3) the potential harms of not including the data; and 4) the availability of other published data to inform the guideline recommendations.

Literature search results were reviewed and deemed appropriate for full text review by two ASCO staff reviewers in consultation with the Expert Panel Co-Chairs. Data were extracted by two staff reviewers and subsequently checked for accuracy through an audit of the data by another ASCO staff member. Disagreements were resolved through discussion and consultation with the Co-Chairs if necessary. Evidence tables are provided in the manuscript and/or in Data Supplement.

ASCO guideline recommendations are crafted, in part, using the GuideLines Into DEcision Support (GLIDES) methodology. ASCO adopted a five‐step approach to carry out quality appraisal, strength of evidence ratings and strength of recommendations ratings. The ASCO approach was primarily adapted from those developed by the AHRQ,, USPSTF, and GRADE, however with the validation of the GRADE methodology, the sole use of GRADE is being evaluated by the Clinical Practice Guidelines Committee.