Management of Young Breast Cancer Patients With de Novo Genetic Mutations

, , , ,
Oncology, Oncology Vol 28 No 10, Volume 28, Issue 10

A 24-year-old woman presents to her primary care provider with a mass in her left breast. Examination confirms a 2.2-cm mass in the upper outer quadrant, with a single mobile axillary node that is firm to palpation.

The Case: A 24-year-old woman presents to her primary care provider with a mass in her left breast. Examination confirms a 2.2-cm mass in the upper outer quadrant, with a single mobile axillary node that is firm to palpation. Diagnostic mammogram (see Figure) confirms a spiculated mass in the setting of dense breast tissue. Ultrasound testing confirms a 2.4 × 1.9 × 1.6-cm mass with an eccentric lymph node in the axilla. Ultrasound-guided core biopsy of the primary site and lymph node are performed, both showing an invasive ductal carcinoma, grade 3, and tumor markers showing estrogen receptor (ER)-, progesterone receptor (PR)-, and human epidermal growth factor receptor 2 (HER2)-negative (0 expression by immunohistochemistry) disease. There is no significant family history. The woman has recently been married and plans to start a family in the next 1 to 2 years.


Breast cancer is the most common cancer in women in the United States. An estimated 232,670 new cases will be diagnosed in 2014, with 25,500 of these occurring in women under 45 years of age. Unique challenges and questions arise in terms of both the management of this young-onset breast cancer population and the ancillary services needed to appropriately address their concerns about fertility and genetics.

The fact that the patient is presenting with invasive breast cancer at an extremely young age suggests a hereditary predisposition, even in the absence of a family history. From a genetic counseling perspective, we would recommend a careful review of that history, both maternal and paternal. Whereas some families are too small to provide useful information, others may have cancer diagnoses suggestive of unusual syndromes that could guide subsequent genetic testing.

Even in families with a clear hereditary pattern of inherited breast cancer, genetic mutations are identified in only about half of cases. The most common mutations that we find with genetic testing occur in the BRCA1 and BRCA2 genes, and in the absence of a family history to guide us, genetic testing for these two genes would be an appropriate first step. Her triple-negative histology would give further support for this strategy, as BRCA mutations (mostly BRCA1) are found in up to 20% of unselected patients with this histology.[1]

Very-early-onset breast cancer can also be indicative of Li-Fraumeni syndrome (LFS), and caused by germline mutations in the tumor suppressor gene p53. LFS is a highly penetrant cancer syndrome inherited as an autosomal dominant condition. Classically the syndrome comprises bone and soft tissue sarcomas; leukemia; brain tumors; adrenocortical cancers; and, less frequently, several other malignancies. The most common cancer in women with LFS is breast cancer; although, unlike this patient, the histology is much more commonly triple-positive (ER+, PR+, and HER2+). In small series, as many as 20% of women with breast cancer diagnosed before age 30 harbor a p53 mutation, and a negative family history is somewhat common. In this very young group, p53 mutations may be more common than BRCA mutations. If BRCA testing is negative in the patient described in this case, then she should be counseled about p53 mutation testing. New options for genetic testing have been developed in the past year, with the advent of several panels of genes that can be assessed simultaneously. The cost is significant, and many panels include genes for which we have little knowledge about risk or management. Many experts in this area believe these panels should be used in the setting of clinical trials only, but simultaneous BRCA and p53 testing could be offered via this tool.[1]

In the setting of a p53 mutation, the patient’s cancer therapy options must be carefully considered. The loss of the tumor suppressor p53 has been associated with a higher incidence of radiation-related malignancies. These patients are typically offered mastectomy and axial lymph node dissection in an attempt to minimize the need for radiation. In a young, node-positive patient with a p53 mutation, one faces the difficult choice of balancing the desire for breast cancer control against the risk of future malignancies that could arise following higher-dose radiation therapy. One other option with a complete nodal response to neoadjuvant systemic therapy is consideration of no radiation, an approach that is now being investigated in the National Surgical Adjuvant Breast and Bowel Project B-51 trial. In this favorable subset of biological responders, the benefit of radiation is not likely to outweigh the risk of future radiation-related malignancies.[2]

Given the patient’s young age and desire to start a family, consult with an oncofertility team is warranted, and in our program, is offered to young patients regardless of their current family plans. Young women diagnosed with early breast cancer represent a group especially appropriate for oocyte and embryo cryopreservation, the established methods for female fertility preservation. There is often a 4-week interval between breast surgery and chemotherapy or radiation, which offers an optimal window for ovarian stimulation, oocyte retrieval, and cryopreservation. Banking of both embryos and oocytes requires women to administer daily hormonal injections to stimulate the ovaries to produce multiple mature oocytes over the course of 1 to 2 weeks. This process is closely monitored by serial blood tests to assess estradiol levels and pelvic ultrasounds to evaluate ovarian response. During ovarian stimulation, an aromatase inhibitor can be used to maintain modest levels of estradiol.[3] Oocyte retrieval is performed using a transvaginal ultrasound guidance with needle aspiration to collect the oocytes. At this point, either unfertilized mature oocytes can be cryopreserved or oocytes can be fertilized with sperm to create embryos for banking.[3]

Women who are not candidates for oocyte or embryo banking may consider ovarian tissue cryopreservation. Ovarian tissue banking is an investigational procedure by which the outer layer of the ovary, containing immature oocytes, is surgically removed, frozen, and stored. This tissue can be thawed and transplanted back to the woman to restore fertility, or individual oocytes can be matured in vitro.[3]

One question that arises in patients found to have a germline mutation is how this may affect offspring, and whether genetic mutations can be detected. Preimplantation genetic diagnosis (PGD) is a technique used to identify genetic mutation in embryos created through in vitro fertilization before pregnancy. By day 5 to 6, a few trophectoderm cells are removed while the inner cell mass is left undisturbed. These cells can be analyzed for germline mutations, with a small rate (~5%) of false-positive and false-negative results. Therefore, chorionic villus sampling or genetic amniocentesis during pregnancy is recommended to confirm PGD findings.[3]


The management of this young woman’s breast cancer includes the important multidisciplinary coordination of surgical, medical, and radiation oncologists, but it also necessitates the participation and input of additional specialists, including experts in genetics and oncofertility. To best inform decision-making, genetic testing should be initiated at the time of diagnosis. Careful planning is needed to ensure optimal outcomes, not only of the current tumor but also with the goal of minimizing the risk of future malignancies via appropriate local therapy. Planning for future fertility, and even testing of embryos prior to implantation, are all possible and play critical roles in optimizing the future quality of life for young women with breast cancer.

Outcome of This Case

Genetic testing revealed a de novo p53 mutation in our patient, seen without the typical family history. Following an oncofertility consult, the patient chose to freeze fertilized embryos created with her husband. PGD testing will be performed.

Neoadjuvant chemotherapy was given using dose-dense AC-T (doxorubicin, cyclophosphamide, paclitaxel). After a thorough discussion of treatment options with the patient, she chose to undergo bilateral mastectomy for treatment as well as risk reduction, with ipsilateral axillary node dissection and contralateral sentinel lymph node biopsy. This showed a complete response to systemic therapy in the nodes, and minimal residual disease in the breast. Given the risks associated with radiation in the setting of loss of p53, radiation was discussed but held at this time given the patient’s pathologic response.

Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.


1. National Cancer Institute. High penetrance breast and/or ovarian cancer susceptibility genes. Available from: Updated July 11, 2014. Accessed on September 17, 2014.

2. Heymann S, Delaloge S, Rahal A, et al. Radio-induced malignancies after breast cancer postoperative radiotherapy in patients with Li-Fraumeni syndrome. Radiat Oncol. 2010;5:104.

3. Loren AW, Mangu PB, Beck LN, et al. Fertility preservation for patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2013;31:2500-10.