Family history of breast cancer matters—even and especially when genetic test results are negative.


Earlier this month, the results of a study published online, ahead of the print edition of the American Journal of Clinical Oncology, underscored the significance of family history of breast cancer for guiding surgical management.

If you’ve recently been diagnosed with breast cancer, you’ve probably become more familiar than you ever hoped you’d need to be with a lot of terms—lumpectomy, mastectomy, sentinel node biopsy, ER/PR/HER2 . . . and the list goes on.

Depending on the stage and specifics of your breast cancer, your surgeon may discuss with you the option of a lumpectomy, single mastectomy, or double mastectomy. Some of this is guided by cancer stage, some by other medical issues or personal preferences and risk tolerance— some by your estimated risk of recurrence or of a second primary breast cancer.


Genetic testing results can help to guide surgical management. Women diagnosed with breast cancer under the age of 45 meet NCCN guidelines for testing even in the absence of any family history of cancer. Women diagnosed with breast cancer at any age who have two or more close relatives on the same side of the family with breast cancer also meet NCCN guidelines for testing . . . and this is just the start of a long list of who meets NCCN guidelines for genetic testing. A family history of ovarian, pancreatic, or prostate cancer may also be significant. Collection of cancer family history is critical for identifying who meets NCCN guidelines for testing, and insurance coverage for those who meet NCCN guidelines is generally quite good.  

Positive genetic testing results indicating a mutation (pathogenic variant) in any one of a number of different genes should prompt a different conversation about your chances of developing a second primary breast cancer or possibly other cancers. Referrals to other relevant specialists are often made, and targeted genetic testing for other family members is possible, helping sort out who is high risk and who may be low risk— in spite of the family history of cancer. This is a big part of the promise of personalized medicine that has been at our fingertips for the past 20 years. 


But what about when genetic testing results are negative? More often than not, even with a striking family history of cancer, and even when a large panel of genes is ordered, genetic testing results are negative. +/- a Variant of Uncertain Significance. Then what? In some ways, negative genetic testing results are good news. Much of medicine involves ruling out certain possibilities, and ruling out identifiable mutations in a number of different clinically relevant genes is incredibly worthwhile. But what’s the next step for a surgeon and a patient? 

The Women’s Environmental Cancer and Radiation Epidemiology (WECARE) study looked at women diagnosed with invasive breast cancer under the age of 55. The study was a population-based case-control study that compared 1,521 contralateral breast cancer (CBC) cases with 2,212 individually matched unilateral breast cancer (UBC) controls. What did the study find?

  • Women under the age of 55 who had a diagnosis of invasive breast cancer and who also had a first-degree relative (ex. mother or sister) with breast cancer had an 8% risk of developing breast cancer in the opposite breast. 
    • If the relative was diagnosed with breast cancer under the age of 40, the risk of developing breast cancer in the opposite breast went up to 13.5%.
    • If the relative with breast cancer was diagnosed with a second primary breast cancer herself, the risk went up to 14%. 
  • A subset of women was tested for mutations in the most common high-risk breast cancer genes (BRCA1/2PALB2CHEK2ATM). Even for those with negative genetic testing results, estimates were unchanged. 

The authors concluded, “Breast cancer family history confers a high CBC risk, even after excluding women with deleterious mutations. Clinicians are urged to use detailed family histories to guide treatment and future screening decisions for young women with breast cancer.”  


Consideration of family history is a crucial part of a personalized plan of care

Collection of cancer family history is an important starting point for determining who meets NCCN criteria for genetic testing. But the value of family history goes beyond just access to genetic testing. Cancer family history is also an important part of an individual’s risk assessment and provides important albeit murky insight into the >20,000 genes that were not included on a large gene panel. Family history should be used in combination with any genetic testing results (positive or negative) to guide discussions about surgical management options and which options make the most sense for a particular patient.


For Patients

  • It’s not only genetic testing results that can influence the options your surgeon discusses with you—your family history matters too!  
  • Ask relatives about your family history of cancer if at all possible. Your doctor only has the information you give to go on!
    • Many physicians offices send out intake forms in advance of an appointment that includes family history questions. Use this sheet as a guide (or an excuse) to ask relatives about your family history of cancer.
  • Take the time to think through diagnoses of cancer in your family and ages at diagnosis in your family before your appointment.
    • Many of us recall how old we were when someone in the family was diagnosed with cancer or how old someone was when they passed away from cancer. But for family history evaluation and risk assessment, the age at which someone was diagnosed is what counts. If you have already calculated your best estimates of ages at diagnosis in the family before you arrive at your appointment, you will be able to spend more of your appointment discussing the significance of your family history and less of your appointment trying to do quick math in your head.
  • Ask your surgeon about a referral to genetic counseling.
    • A genetic counselor can evaluate your personal and family history of breast or other cancers, discuss with you which hereditary cancer syndromes should be considered and why, and talk with you about the implications of any test results not only for your own healthcare but also for your family members.
    • Genetic counselors often work as part of a multidisciplinary team with surgeons and oncologists, weighing in on the impact of cancer family history to a patient’s proposed plan of care. Even if you don’t meet with a genetic counselor, your surgeon may discuss your case with a genetic counselor in a tumor board. 

For basic background information on cancer genetics and hereditary cancer, check out this page. If you’re wondering if you meet criteria for genetic testing, you can take this quiz. If you choose to share your results with us, we’ll follow up with you!


For Surgeons & Other Healthcare Providers

  • Careful review of cancer family history matters—not only in determining which patients meet NCCN guidelines for testing, not only for reviewing positive results in the context of a personal and family history, but also when genetic testing results are negative and don’t provide clear direction for surgical management. 
  • When delivering negative genetic testing results to a patient, take an extra moment to confirm the family history your patient initially reported to you. Your patient may have learned new or different information about her family history since you ordered genetic testing. Reported types of cancer diagnosed and ages at diagnosis may change significantly. 
  • Unless you return to a review of your patient’s family history when giving negative genetic testing results, your patient may wrongly assume that her family history is moot now that you have test results in hand.

Have questions about a particular case? Email me. I’d be happy to discuss.


Do you meet genetic testing criteria for hereditary breast cancer risk?