Antonio M. Jimenez, MD1
Alicia Growney, MD2
George Behrens, MD3
Carol Corbridge, MD3
Dianne D. Chapman, ND1
Lydia Usha, MD1
1Division of Hematology and Oncology, 2Department of General Surgery, 3Department of Radiology, Rush University Medical Center, Chicago, Illinois
Address correspondence to: Antonio Jimenez, MD, Division of Hematology/Oncology, Department of Medicine, Rush University, 1725 W. Harrison St. # 821, Chicago, IL 60612; Phone: 312-563-2200; Fax: 312-942-3192; E-mail: antonio_m_jimenez@rush.edu.
Case Report
A 40-year-old white woman of Irish descent presented with a 4-week history of a right breast mass associated with edema and enlargement of the breast. Her family history was significant for inflammatory breast cancer (IBC) in her mother, who was diagnosed and died at age 35, as well as for breast cancer in a paternal aunt diagnosed at age 55. On physical examination, she had an enlarged right breast with a palpable 9 cm mass in its inferolateral aspect, with peau d’orange skin changes around the right nipple (Figure 1) and associated ipsilateral axillary lymphadenopathy. Her left breast was unremarkable. Diagnostic ultrasound (Figure 2) showed an irregular 5-cm mass at the 9 o’clock position, bilateral nodular tissue densities seen throughout both breasts, and right axillary adenopathy. Thickened dermis was noticed in the periareolar area and the inferior aspect of the right breast. A core biopsy of the right breast mass revealed a grade III, infiltrating ductal carcinoma with associated high-grade ductal carcinoma in situ (DCIS). The tumor was estrogen receptor (ER)-positive (80%) and negative for progesterone (PR), human epidermal growth factor receptor 2 (HER2), and epidermal growth factor receptor (EGFR). A single-site skin punch biopsy did not show invasion of the dermal lymphatics; however, given the constellation of findings and the typical course, the clinical diagnosis of inflammatory breast cancer was made. A staging positron emission tomography (PET) scan demonstrated increased uptake in the right internal mammary, right paratracheal, and cervical lymph nodes. A biopsy of the paratracheal lymph node confirmed the presence of breast cancer metastasis.
Given the patient’s personal and family history, genetic testing for breast cancer predisposition was recommended. Full sequencing of BRCA1 and BRCA2 genes was positive for a suspected deleterious mutation in the BRCA2 gene, S2670L (8237C>T). This mutation results in the substitution of leucine for serine at amino acid position 2670 of the BRCA2 protein. This genetic alteration in the BRCA2 gene had been previously considered a variant of undetermined significance (VUS). However, numerous observations enabled Myriad Genetic Laboratories to reclassify this mutation as suspected deleterious, based on its strong association with more severe, personal and family history that is typical for individuals with deleterious BRCA2 mutations.1,2 This re-classification agrees with the structure-based prediction previously made by Karchin and associates.3 Because the patient pursued treatment at an outside institution closer to her home, details regarding further diagnostic work-up or treatment are not currently available.
Discussion
IBC is a rare and aggressive form of breast cancer that accounts for 1–3% of all breast cancer diagnoses.4 Although its incidence is low, it is rising, unlike that of non-IBC.5 Clinically, IBC is characterized by rapid progression, aggressive clinical behavior,6 and earlier age at diagnosis. Despite the introduction of primary chemotherapy and multimodality treatment, it is often a lethal disease, primarily because of its strong metastatic potential; its 3-year survival ranges from 32–42%, and the median overall survival (OS) is 3.8 years.7
Because of its rarity, data regarding risk factors for IBC are scant, and it remains unknown if these risk factors are the same as for non-IBC. Currently, there are a few recognized risk factors for IBC; factors with the strongest association include African-American ethnicity, high body mass index (BMI), and younger age at disease onset. In addition, very few studies have evaluated the presence of a familial link for IBC. Traditionally, IBC has been considered a de novo (sporadic) malignancy, rather than a familial or hereditary malignancy, and BRCA testing is not routinely recommended in patients with IBC.
In 2007, Bondy and colleagues8 established a multinational IBC registry to identify risk factors and prognostic features by prospectively collecting epidemiologic, clinical, and imaging data from IBC patients. As of early 2010, 85 patients had been enrolled, with younger age (median, 55 years) and high BMI (50% of patients above 30) being identified as probable risk factors.
Although less than 10% of breast cancer cases are hereditary,9 with only a fraction of those attributable to inherited mutations in BRCA1 or BRCA2 genes,10 a true familial link for IBC has not been evaluated in large, epidemiologic studies. A small case-control study by Aziz and coworkers11 suggested that a family history of breast cancer was more prominent in IBC compared to non-IBC (20% vs 5%, respectively). A recently reported, retrospective study evaluated the incidence of BRCA mutations in women with IBC.12 In this study, which investigated differences in the BRCA mutation rate between IBC and non-IBC patients, 992 patients with non-IBC and 39 patients with IBC underwent genetic testing; epidemiologic, clinical, and pathologic features were reviewed. Although IBC affected patients of slightly younger age (40 years for IBC vs 42 years for non-IBC), there was no statistically significant difference in the rate of BRCA1 and BRCA2 mutations between cohorts (35.9% in IBC patients vs 26.1% in non-IBC patients; P=.169). Therefore, the authors recommended applying standard BRCA testing guidelines to women with IBC.
Although IBC has been reported in conjunction with BRCA1 and BRCA2 mutations and in conjunction with family history of breast cancer, to our knowledge, this is the first reported case of IBC in the same family, and specifically, in a mother and daughter. Our case is not only unique because of the hereditary IBC presentation, it is also linked to a suspected deleterious BRCA2 mutation. Due to the rarity of both IBC and BRCA mutations, it would be difficult to collect data on a larger series to validate any causal relationship. Nonetheless, the small studies cited above and this observation point to a potential common genetic mechanism underlying the development of IBC and non-IBC, with possibly a few additional genetic aberrations in IBC that lead to its unusually rapid and aggressive course.
Acknowledgment
The authors would like to thank Dr. Banu Arun, Dr. Jennifer Litton, Angelica Gutierrez-Barrera, MS (MD Anderson Cancer Center), and Shelly Cummings, MS (Myriad Laboratories) for their valuable input.
References
1. Easton DF, Deffenbaugh AM, Pruss D, et al. A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. Am J Hum Genet. 2007;81:873-883.
2. Goldgar DE, Easton DF, Byrnes GB, et al. Genetic evidence and integration of various data sources for classifying uncertain variants into a single model. Hum Mutat. 2008;29:1265-1272.
3. Karchin R, Agarwal M, Sali A, et al. Classifying variants of undetermined significance in BRCA2 with protein likelihood ratios. Cancer Inform. 2008;6:203-216.
4. Levine PH, Steinhorn SC, Ries LG, et al. Inflammatory breast cancer: the experience of the surveillance, epidemiology, and end results (SEER) program. J Natl Cancer Inst. 1985;74:291-297.
5. Ueno NT, Buzdar AU, Singletary SE, et al. Combined-modality treatment of inflammatory breast carcinoma: twenty years of experience at M. D. Anderson Cancer Center. Cancer Chemother Pharmacol. 1997;40:321-329.
6. Cristofanilli M, Valero V, Buzdar AU, et al. Inflammatory breast cancer (IBC) and patterns of recurrence: understanding the biology of a unique disease. Cancer. 2007;110:1436-1444.
7. Low JA, Berman AW, Steinberg SM, et al. Long-term follow-up for locally advanced and inflammatory breast cancer patients treated with multimodality therapy. J Clin Oncol. 2004;22:4067-4074.
8. Bondy M, Cristofanilli M, El-Zein R, Wiggins S, Lara J, Jackson S. A progress review of the Inflammatory Breast Cancer Registry at the University of Texas MD Anderson Cancer Center. Cancer Research. 2009;69:2073.
9. Pharoah PD, Antoniou A, Bobrow M, et al. Polygenic susceptibility to breast cancer and implications for prevention. Nat Genet. 2002;31:33-36.
10. Peto J, Collins N, Barfoot R, et al. Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. J Natl Cancer Inst. 1999;91:943-949.
11. Aziz SA, Pervez S, Khan S, et al. Case control study of prognostic markers and disease outcome in inflammatory carcinoma breast: a unique clinical experience. Breast J. 2001;7:398-404.
12. Gutierrez-Barrera AM, Turco DL, Alvarez RH, et al. BRCA mutations in women with inflammatory breast cancer. J Clin Oncol (ASCO Breast Cancer Symposium Abstracts). 2010;28: Abstract 192.
Review
Deleterious BRCA2 Mutation in a 40-Year-Old Woman With Inflammatory Breast Cancer and Strong Family History of Maternal Inflammatory Breast Cancer at a Young Age
Gloria J. Morris, MD, PhD
Department of Medicine, Mount Sinai Hospital of Queens, Long Island City, New York
Address correspondence to: Gloria J. Morris, MD, PhD, Department of Medicine, Mount Sinai Hospital of Queens, Long Island City, NY 11106; E-mail: dr.gjmorris@gmail.com.
Introduction
Jimenez and associates present and discuss a very intriguing case of a 40-year-old white woman of Irish heritage who presented with an inflammatory, invasive, estrogen receptor (ER)-positive, progesterone (PR)-negative, human epidermal growth factor receptor 2 (HER2)-negative right breast cancer, and whose mother had succumbed to the disease at age 35.1 Because of this familial significance, which further included a paternal aunt diagnosed with breast cancer at age 55, the proband met the standard criteria for testing for mutations in BRCA1 or BRCA2. Indeed, she was found to harbor a deleterious sequence in BRCA2 of S2670L (8237C>T), reclassified after family studies by the genetic laboratory from a previous characterization of a mere variant of undetermined significance (VUS).
The patient presented with inflammatory features of the breast mass, and was subsequently shown to have developed metastatic disease, with the rapid appearance of her breast mass heralding an aggressive behavior of this cancer. This is an important report of a deleterious BRCA mutation in a woman with inflammatory breast cancer (IBC), itself a rare form of breast cancer. Due to BRCA2-positivity, the patient would be routinely counseled on her simultaneous increase of contralateral breast cancer and ovarian cancer, with appropriate risk reduction strategies considered.2,3 However, considering her presentation with IBC, oncologists should also be made aware of the need to regard this entity as an additional manifestation of hereditary breast cancer.
Discussion
On account of the increasing incidence of BRCA mutations in other types of breast cancer (particularly [preinvasive] ductal carcinoma in situ4 [DCIS] and specific invasive breast cancers, such as the triple-negative phenotype5,6), the standard National Comprehensive Cancer Network (NCCN) Guidelines for offering risk evaluation and testing have expanded to include these among the high-risk criteria.2 Included within the well-described case presentation and review of the current literature by Jimenez and colleagues is a recent abstract by Gutierrez-Barrera and coworkers,7 which raises the question as to whether IBC should also be included in the well-recognized criteria for individuals who could also be at high risk for hereditary breast and ovarian cancer syndrome (HBOC).
This presentation of such an aggressive breast cancer in a young woman at familial high risk brings forth many other questions. The biology of her tumor, while ER-positive, is an intriguing point of study in the quest to define specific chemosensitivity patterns of IBC. Several ongoing studies and clinical trials are trying to identify such patterns, and are looking at specific microRNA and gene array signatures that not only set IBC apart as a distinct entity of breast cancer, but also may even define particular markers as therapeutic drug targets.8-11 Specifically, the p53 tumor suppressor pathway in IBC is being examined as a potential explanation of aggressive behavior in IBC12 and as a potential target for therapeutic intervention.
Conversely, since BRCA deficiency correlates with inhibition of DNA polymerase and defects in DNA repair, and because highly proliferative IBC may be exquisitely chemosensitive, this begs the question as to whether specific inhibitors of DNA repair may provide a higher rate of response and disease control in IBC versus other more prevalent invasive breast cancers. Studies utilizing poly (ADP-ribose) polymerase (PARP) inhibitors to enhance chemotherapy-induced DNA damage in BRCA-mutated breast cancers have done so in the previously treated metastatic setting.13-15 We do know that higher complete response (CR) rates have been achieved in ER-negative, BRCA1-mutated breast cancers treated in the neoadjuvant setting.16 Recently, it has also been shown that while of different histology, BRCA2-mutated ovarian cancers may actually fare better after treatment than non-mutated ovarian tumors.17 It will be important to design clinical trials that further focus on the exquisite sensitivity of IBC to chemotherapy, especially those stratified to BRCA1 or BRCA2 mutation status, and to gauge endpoints of not only CRs with such possible combinations, but also progression-free survival and overall survival.
Conclusion
Participation in center-based family registries will continue to be essential in identifying new mutations responsible for high-risk situations, as well as performing family linkage analysis. Although standard criteria related to age at diagnosis should certainly prompt genetic testing for a patient at high risk for harboring a BRCA mutation by standard prediction models,18-21 the inclusion of IBC in the histology of breast cancers that may harbor BRCA mutations is further illustrated by this very significant case study.
References
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2. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian Cancer. Version 1.2011. http://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf. accessed April 26, 2012.
3. Rebbeck TR, Lynch HT, Neuhausen SL, et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med. 2002;346:1616-1622.
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5. Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med. 2010;363:1938-1948.
6. Comen E, Davids M, Kirchhoff T, Hudis C, Offit K, Robson M. Relative contributions of BRCA1 and BRCA2 mutations to “triple-negative” breast cancer in Ashkenazi women. Breast Cancer Res Treat. 2011;129:185-190.
7. Gutierrez-Barrera AM, Turco DL, Alvarez RH, et al. BRCA mutations in women with inflammatory breast cancer. J Clin Oncol (ASCO Breast Cancer Symposium Abstracts). 2010;28: Abstract 192.
8. Hatzis C, Pusztai L, Valero V, et al. A genomic predictor of response and survival following taxane-anthracycline chemotherapy for invasive breast cancer. JAMA. 2011;305:1873-1881.
9. Bièche I, Lerebours F, Tozlu S, Espie M, Marty M, Lidereau R. Molecular profiling of inflammatory breast cancer: identification of a poor-prognosis gene expression signature. Clin Cancer Res. 2004;10:6789-6795.
10. Ventura AC, Merajver SD. Genetic determinants of aggressive breast cancer. Annu Rev Med. 2008;59:199-212.
11. ClinicalTrials.gov. MIRNA Profiling of Breast Cancer in Patients Undergoing Neoadjuvant or Adjuvant Treatment for Locally Advanced & Inflammatory Breast Cancer. Identifier: NCT01231386. http://clinicaltrials.gov/show/NCT01231386.
12. Yang CH, Cristofanilli M. The role of p53 mutations as a prognostic factor and therapeutic target in inflammatory breast cancer. Future Oncol. 2006;2:247-255.
13. Tutt A, Robson M, Garber JE, et al. Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced breast cancer. J Clin Oncol (ASCO Annual Meeting Abstracts). 2009;27: Abstract CRA501.
14. O’Shaughnessy J, Osborne C, Pippen J, et al. Efficacy of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, in combination with gemcitabine/carboplatin (G/C) in patients with metastatic triple-negative breast cancer (TNBC): results of a randomized phase II trial. J Clin Oncol (ASCO Annual Meeting Abstracts). 2009;27: Abstract 3.
15. O’Shaughnessy J, Osborne C, Pippen J, et al. Final Results of a Randomized Phase II Study Demonstrating Efficacy and Safety of BSI-201, a Poly (ADP-Ribose) Polymerase (PARP) Inhibitor, in Combination with Gemcitabine/Carboplatin (G/C) in Metastatic Triple Negative Breast Cancer (TNBC). Paper presented at the San Antonio Breast Cancer Symposium; December 9-12, 2009; San Antonio, TX. Abstract 3122.
16. Arun B, Bayraktar S, Liu DD, et al. Response to neoadjuvant systemic therapy for breast cancer in BRCA mutation carriers and noncarriers: a single-institution experience. J Clin Oncol. 2011;29:3739-3746.
17. Yang D, Khan S, Sun Y, et al. Association of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer. JAMA. 2011;306:1557-1565.
18. Huo D, Senie RT, Daly M, et al. Prediction of BRCA mutations using the BRACAPro model in clinic-based African American, Hispanic, and other minority families in the United States. J Clin Oncol. 2009;27:1184-1190.
19. Parmigiani G, Chen S, Iversen ES, et al. Validity of models for predicting BRCA1 and BRCA2 mutations. Ann Intern Med. 2007;147:441-450.
20. Frank TS, Deffenbaugh AM, Reid JE, et al. Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. J Clin Oncol. 2002;20:1480-1490.
21. Myriad Genetic Laboratories, Inc. Mutation Prevalence Tables. www.myriad.com/lib/brac/brca-prevalence-tables.pdf. Accessed April 26, 2012.