Recurrent Early-Stage Triple-Negative Breast Cancer

CURRENT CLINICAL PRACTICE

Recurrent Early-Stage Triple-Negative Breast Cancer Christian S. Adonizio, Genorosa Grana, Kanu Sharan, Lewis Rose, Allison Zibelli, Susan Miller-Samuel, and Gloria J. Morris

At times we encounter clinical problems for which there are no directly applicable evidence-based solutions, but we are compelled by circumstances to act. When doing so we rely on related evidence, general principles of best medical practice, and our experience. Each “Current Clinical Practice” feature article in Seminars in Oncology describes such a challenging presentation and offers treatment approaches from selected specialists. We invite readers’ comments and questions, which, with your approval, will be published in subsequent issues of the Journal. It is hoped that sharing our views and experiences will better inform our management decisions when we next encounter similar challenging patients. Please send your comments on the articles, your challenging cases, and your treatment successes to me at [email protected]. I look forward to a lively discussion. Gloria J. Morris, MD, PhD Current Clinical Practice Feature Editor

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riple-negative breast cancer (negative for estrogen receptor [ER], progesterone receptor [PR], and Her-2-neu expression) has emerged as a distinct phenotype of breast cancer that is uniquely sensitive to chemotherapy but has a high recurrence rate. Immunohistochemistry and genomic studies with Address correspondence to Gloria J. Morris, MD, PhD, Editor, Current Clinical Practice, Hematology and Oncology Associates of Northeasern PA, PC, 1100 Meade St, Dunmore, PA 18512. E-mail: dr.morris@hemonc1. com 0270-9295/ - see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2010.09.012

microarrays have further identified this type of breast cancer as similar to basal type breast cancer, with high expressions of p53, ki-67 proliferation index,1 CK5/6, cytokeratins, epidermal growth factor receptor (EGFR),2–4 and p63,5 and new evidence for expression of androgen receptor.6 Studies are underway to determine optimum chemotherapy sensitivities, especially in the neoadjuvant setting. Because of its biologic behavior, concern arises with a diagnosis of triple-negative breast cancer, to try to deliver the most efficient systemic reduction in recurrence. We present here a case of earlystage breast cancer, triple-negative phenotype, which, despite adjuvant therapy 9 years prior, recurred in the ipsilateral breast of a woman now in her sixth decade of life. We pose the following questions: (1) What treatment, if any, would you recommend?, and (2) Would this patient need genetic counseling for a hereditary breast and/or ovarian cancer syndrome?

THE PROBLEM Case Report The patient is a 54-year-old woman with a history of stage IIA (T2N0M0) 2.3-cm invasive ductal carcinoma of the left breast, ER⫺, PR⫺, her-2-neu–negative, p53-negative, ki-67 80%, Elston grade III/III, which occurred 9 years previously at age 45. The breast cancer was previously treated with left lumpectomy and axillary dissection with two sentinel and two axillary lymph nodes negative. She received four cycles of adjuvant chemotherapy in

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the form of doxorubicin and cyclophosphamide, followed by radiation therapy to the breast and axilla. Nine years later, annual routine mammogram showed a new irregular density in the left breast anterior to the surgical scar, measuring 8 ⫻ 10 mm in the CC projection and 8 ⫻ 6 mm in the MLO projection, confirmed by ultrasound to have a low echogenic center surrounded by a highly echogenic halo and shadowing with increased vascularity, and containing tiny calcifications on magnification views. She underwent a vacuum-assisted core biopsy of this area, the pathology of which revealed invasive ductal carcinoma involving several tissue cores, with the largest focus measuring up to 0.5 cm, Nottingham grade 3 out of 3, with extensive ductal carcinomain-situ (DCIS), high nuclear grade, solid type, without comedo-type necrosis. The phenotype again was ER⫺, PR⫺, her-2-neu–negative, p53 90%, ki-67 90%. The patient underwent surgical consultations and decided to pursue bilateral total mastectomy with left breast lymphatic mapping, sentinel lymphadenectomy, and axillary dissection and delayed bilateral breast reconstruction. Pathology of the left breast revealed residual invasive carcinoma with 0.1 and 0.4 cm foci of invasive carcinoma adjacent to the previous biopsy site, without lymphovascular invasion, and clear margins, and no tumor seen in 11 additional dissected lymph nodes. The right breast contained benign breast tissue. The recurrent breast cancer was staged I (T1aN0M0). The pa419

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tient is G6P4A2, with first pregnancy at age 37. The patient’s mother had a history of breast cancer at age 80, and the patient’s cousin had a history of breast cancer in her 50s.

MEDICAL ONCOLOGISTS’ OPINIONS Locoregional recurrence (LRR) after breast conservation surgery (BCS) is a significant predictor of distant recurrence and mortality, although the magnitude of risk depends on the type of LRR—ipsilateral breast tumor recurrence (IBTR) or other LRR (oLRR) including chest wall or regional nodal. The case presented highlights three main questions. First is the frequency of LRR, next is the role of systemic therapy, and lastly is the role of genetic testing in triple-negative breast cancer (ER⫺, PR⫺, and her-2-neu–negative). Data from the National Surgical Adjuvant Breast and Bowel Project (NSABP) has shown that IBTR and oLRR are a significant issue. Wapnir et al reviewed five NSABP node-positive adjuvant breast cancer trials, in which all patients were treated with whole breast irradiation and adjuvant chemotherapy. The cumulative incidence of local recurrence was 15.9% (9.7% IBTR and 6.2% oLRR). Unlike this patient, most LRR was seen within the first 5 years following treatment. Initial patient and tumor characteristics such as age, tumor size, and estrogen receptor status were significantly associated with IBTR. Distant disease-free survival rates and overall survival rates at 5 years were 51.4% and 59.9% for IBTR and 18.8% and 24.1% for oLRR, respectively. Clearly, in this series, LRR was a poor prognostic factor for overall outcome.7 Data from Haffty et al showed a lower rate of LRR (8%) with a median follow-up of 8.2 years.8 Five-year actuarial survival and 5-year disease-free survival for breast recurrences were 59% and 65%, respectively.8 Important parameters for prognosis in the Haffty series were time from diagno-

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sis to IBTR, extent of disease at time of local recurrence, and location within the breast of such recurrence.8 In a series by Voogd et al, patients who had recurrences near the original tumor measuring less than 1 cm, as is the case with this patient, fared significantly better.9 For this patient, recurrence anterior to the original surgical scar measuring less than 1 cm and occurring approximately 9 years post-diagnosis would suggest a better outcome. Traditionally, risk assessment for LRR is based on anatomic and histopathologic features. Genomic profiling is a powerful tool in predicting risk of distant recurrence in earlystage breast cancer. The Oncotype DX assay (Genomic Health, Redwood City, CA) quantifies risk of distant recurrence in node-negative, ER⫹, tamoxifen-treated patients and predicts benefit from chemotherapy. Given the strong association between LRR and distant recurrence, genomic profiles that predict distant recurrence also may predict risk for LRR. Mamounas et al reviewed the association between Oncotype DX recurrence score (RS) and risk of LRR after breast conservation or mastectomy in node-negative, ER⫹ breast cancer from two NSABP trials (B-14 and B-20).10 They reported RS as a significant independent predictor of risk for LRR in tamoxifentreated patients, similar to risk for distant recurrences.10 This association was also seen in placebotreated patients and chemotherapy plus tamoxifen-treated patients. In addition, Voduc et al reported risk of LRR associated with different breast cancer molecular subtypes based on six immunohistochemical (IHC) panels in tissue microarrays.11 This panel included ER, PR, ki-67, her-2, EGFR, and cytokeratin (CK 5/6) which defined luminal A, luminal B, luminal– her-2, her-2– enriched, basal-like, and triple-negative nonbasal as the molecular subtypes of breast cancer. Luminal A tumors (ER⫹ or PR⫹, her-2–negative, ki-67 ⬍14%) had the best prognosis and the lowest rate of LRR.11 For pa-

tients undergoing breast conservation or mastectomy, her-2– enriched and basal subtypes were associated with an increased risk of LRR. Given the low risk of IBTR in luminal subtypes and the anticipated low risk of IBTR in her-2– enriched subtypes treated with anti– her-2 therapy, the more aggressive triple-negative tumors may remain the subtype at highest risk of local relapse after BCS plus radiotherapy. However, this will require further validation with clinical trials and studies to evaluate radiosensitizers, alternative concurrent systemic therapy or alternative locoregional approaches for patients with triple-negative disease. The treatment of IBTR is quite controversial. The standard of care is mastectomy and radiation if negative margins cannot be achieved. The role of chemotherapy or hormone therapy has not been established. Only three randomized trials have been conducted in this setting: observation versus tamoxifen; interferon-alpha versus observation; and irradiation with and without actinomycin-D (the focus here being achievement of local control with actinomycin-D used as a radiation sensitizer).12–14 Interferon therapy had no impact on local or distant relapse,13 while tamoxifen improved 5-year disease-free survival from 36% to 59% but had no significant impact on overall survival.12 Several international and national chemotherapy-focused trials have been initiated looking at the addition of anthracycline-based chemotherapy following resection with or without hormonal therapy based on ER status. However, recruitment has been extremely difficult. The most recent trial spearheaded by NSABP (trial B-37), in conjunction with the International Breast Cancer Study Group (IBCSG) and the Breast International Group (BIG) (clinicaltrials. gov NCT00074152), aimed to assess the impact of systemic therapy following local treatment for LRR (both IBTR as well as post-mastectomy recurrences). For this trial,

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hormone therapy was recommended if ER/PR was positive, and her2-neu–targeted therapy (herceptin or lapatinib) were optional at the discretion of the clinician. Chemotherapy was also at the discretion of the investigator and required only a course of 3 to 6 months of therapy. The trial closed in February 2010 having accrued only 159 patients of the 250 needed in over 7 years. Thus the role of systemic therapy in the setting of LRR remains to be clarified. In the case presented, we favor systemic therapy, due to the patients’ young age and triple-negative histology. A variety of chemotherapy agents could be considered. Although she had four cycles of doxorubicin and cyclophosphamide at the time of initial diagnosis and has the potential to receive additional doxorubicin if needed, the availability of regimens such as docetaxel and cyclophosphamide (TC) or cyclophosphamide, methotrexate, and fluorouracil (CMF) pose other very viable options. A recent review of two IBCSG trials (VIII and IX), in the node-negative setting, demonstrated that the subgroup of patients with triple-negative disease (303 patients or 13% of the group) gained significantly greater benefit from classical CMF than did other tumor subtypes. Trial VIII included premenopausal patients treated with six cycles of CMF versus no CMF, while trial IX included postmenopausal patients treated with three cycles of CMF versus no CMF. In both groups the triple-negative subgroup had a statistically significant benefit from CMF.15 Finally, we will review genetic testing for BRCA-1 and -2. While the patient has had bilateral mastectomies, the results of genetic testing will have implications for management of her ovaries. Testing also will have implications for other family members in terms of risk assessment and potential risk-reducing strategies. BRCA-1 and -2 were identified in 1994 and 1995 respectively. Nine years ago, when this patient was first diagnosed, genetic testing

was relatively new. Today, due to her early age at diagnosis and family history (mother and cousin diagnosed with breast cancer) she will likely meet criteria for testing set by several insurance carriers in the United States. Guidelines for BRCA-1 and -2 mutation testing include early age at onset (before age 50), family history of breast/ovarian cancer in first- or second-degree relatives, bilateral disease, multiple primary tumors, male breast cancer, and a lower threshold for testing in people of Ashkenazi Jewish ancestry.16 While mutation status clearly predicts risk of breast and ovarian cancer, as well as risk of contralateral disease, it remains to be conclusively defined weather mutation status will have an impact on local recurrence in the setting of BCS. Pierce et al looked at this issue in a multi-institutional series that included 302 women treated with breast-conserving treatment (BCT) and 353 treated with mastectomy. With a median follow-up of greater than 8 years in both groups, the authors demonstrated a 15-year local failure as first failure rate of 23.5% in the BCT group versus 5.5% in the mastectomy group (P ⬍.0001). However, no significant differences were seen in distant failure or mortality.17 While many mutation-positive women will elect to undergo bilateral mastectomy as a means of managing their incident cancer, for those who elect BCS, these data may be of value. Triple-negative disease constitutes only 15% of all breast cancers, but it accounts for 70% of cancers occurring in BRCA-1 carriers. Chang et al, in a prospective evaluation of 76 breast cancer patients aged less than 45 years, found that 10.5% of BRCA-1 mutations were detected on the basis of age alone, while the detection rate increased to 25% when ER⫺ and poorly differentiated histology were taken into account in addition to age.18 Whether all breast cancers with a triple-negative phenotype should be screened for BRCA-1 mutation and whether this would improve the rate

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of detection in addition to personal history, family history, and ethnicity, still needs to be answered.19,20 In addition to mutation detection, much interest also revolves around the issue of weather BRCA-1–related cancers, often of basal-like histology, should be treated with different chemotherapeutic agents. The platinum compounds and poly(ADP-ribose) polymerase (PARP) inhibitors are being evaluated actively in this setting. A recent study demonstrated a significant benefit from the use of cisplatin in the neoadjuvant setting in triplenegative disease with 22% of patients treated with four cycles of cisplatin achieving a pathologic complete response (pCR) (and two of the patients achieving pCR were BRCA-1 mutation–positive).21 While provocative, the small size of the study (28 patients) and the lack of long-term follow-up data limit the applicability of this approach at this time. In summary, this case is an excellent example of the complexities of LRR and the implications of this on decision-making for local control, systemic therapy, and incorporation of novel genetic testing paradigms. We support the use of systemic chemotherapy with all of the caveats stated in the foregoing discussion and with full discussion with the patient regarding limitations of available data. Ultimately, enrollment on a clinical trial would be ideal. We support genetic testing to guide both the patient and family in subsequent management. It is perhaps also time to think about incorporating gene expression assays in a manner that includes information about both distant and local recurrence, which may provide a more precise estimate of the potential burdens of breast cancer recurrence in conjunction with clinicopathologic features. Generosa Grana, MD Kanu Sharan, MD UMDNJ Robert Wood Johnson School of Medicine Cooper University Hospital Camden, NJ

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MEDICAL ONCOLOGIST’S OPINION This patient has had two ipsilateral breast cancers, both exhibiting a triple-negative (ER⫺, PR⫺, and her2–negative) phenotype. The interval between the two cancers is 9 years. Based on this, it is almost certain that this is a new event and not recurrence due to the relatively short natural history of recurrence for aggressive triple-negative disease. Most recurrences would be expected to occur within 2 to 3 years with high risk for distant relapse due to the aggressive nature of this particular phenotype. Because of this, it is fairly easy to answer the question of genetic counseling for a hereditary breast and/or ovarian cancer syndrome. The patient fulfills two criteria for testing: (1) initial cancer diagnosed at age 45 or less; and (2) two breast primary tumors with one occurring at age 50 or less. These recommendations are not based on randomized controlled trials but on good retrospective studies for which there is relatively uniform agreement among National Comprehensive Cancer Network (NCCN) experts. She should be tested for the hereditary breast and/or ovarian cancer syndrome. With regard to treatment recommendations, one needs to keep in mind the relatively poor prognosis and lack of therapeutic targets for this subset of 15% of newly diagnosed breast cancers. The triplenegative breast cancers are indeed a heterogeneous population. Investigators are pursuing the understanding of this subset of breast cancers in order to optimize the effect of cytotoxic drugs and to discover new targeted therapies based on an appreciation of the molecular biology of this type of breast cancer. These therapies are initially being used in the setting of measurable metastatic disease and subsequently in the neoadjuvant setting. There are virtually no data on the standard of care for

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treating triple-negative breast cancer in the adjuvant setting. Triple-negative tumors are more common in younger premenopausal women. Although they may be responsive to cytoxic drugs, the responses tend to be transient and the tumors usually recur with a vengeance. Normal factors associated with decreased risk, such as early prima gravida state and multiparity, do not decrease this risk. This type of breast cancer disproportionately affects African American women, with a much high mortality rate among them. There are multiple reasons for this.22,23 Due to these factors and the need to offer a treatment recommendation, I have to get a sense of what might be reasonable from treatment in other clinical scenarios such as metastatic disease and neoadjuvant setting using both agents that are readily available for treatment and those that are still experimental and not standard of care. First, I am cognizant of the fact that triple-negative tumors are far from heterogeneous. The molecular biology is complicated and still not fully understood. They have been characterized by array-comprehensive DNA hybridation and include approximately 80% to 90% basal tumors that are ER⫺, PR⫺, and her-2– negative, and also CK5/6, CK14, CK17, and EGFR immunohistochemically positive. They are of high histologic and nuclear grade, have mutations of p53, and are directly related to the inhibition of normal BRCA-1 function. The majority but not all basal tumors are triplenegative, and the majority but not all triple-negative tumors are basal.24,25 Ten percent to 20% of triple-negative tumors are normal in phenotype. Also there is the rare claudin-low metaplastic cancer that is resistant to all available therapies, which may arise from a stem cell component and represent epithelial to mesenchymal migration. While most breast cancers with BRCA-1 mutations carry a triple-negative basal phenotye, the majority of triple-negative breast

cancers occur at random. I believe that the tumor described here is statistically likely a basal phenotype, which is the one that is associated with homologous repair defects of double-stranded DNA similar to the BRCA gene abnormality.26 Certainly, further immunophenotyping could be done to confirm this. This brings us to the recent report of the results of a randomized phase II trial investigating the efficacy of BSI-201, a PARP1 inhibitor, in combination with gemcitabine/ carboplatin (G/C) in patients with metastatic triple-negative breast cancer.27 This study showed that using a cytotoxic backbone of G/C with a PARP inhibitor, which induces a second defect in DNA repair at the single-strand level on top of a BRCAlike defect in DNA repair at the double-strand level, may induce cell death, causing what is known as synthetic lethality. The clinical benefit rate, median progression-free survival, and median overall survival were all statistically significant. Obviously this must be confirmed in a larger phase III study. Yet it is hypothesis-generating in two ways—that platinums and PARP may be agents which are effective in treating triple-negative disease, and that PARP inhibitors and platinums will likely eventually make their way to the adjuvant setting for treating triple-negative disease.23 Several neoadjuvant studies looking at combinations of cytotoxic drugs with anthracyclines and taxanes have uniformly found higher pathologic complete response rates. Yet despite this initial sensitivity to chemotherapy, survival is uniformly inferior in patients with triple-negative tumors compared to her-2–positive and luminal A tumors. Several other data sets also give us some guidance. The most important is a retrospective review of the adjuvant BCIRG001, a randomized trial of TAC (docetaxel, doxorubicin, cyclophosphamide) versus FAC (fluorouracil, doxorubicin, cyclophosphamide) for operable nodepositive breast cancer, showing

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TAC superiority. This review studied the prognostic and predictive significance of immunophenotyping node-positive early breast cancer in a docetaxel-containing trial.28 Ninety-one percent of the patients (1,350) were retrospectively studied and differentiated by tumor characteristics as (1) triple-negative (ER⫺, PR⫺, her-2–negative), (2) HER2 (her2–positive, ER⫺, PR⫺), (3) luminal B (ER⫹ and/or PR⫹ and either her-2– positive and/or ki-67high), or (4) luminal A (ER⫹ and/or PR⫹ and not her-2–positive or ki-67high), and evaluated for prognosis and chemotherapeutic benefit. The results showed disease-free survival benefits in both luminal B and triple-negative disease but not for luminal A disease for TAC over FAC. Clearly the data are retrospective, but they also give some guidance that a taxane—in this case docetaxel—may overcome some of the problems inherent in treating triple-negative disease. Also, a trial presented at the 31st Annual San Antonio Breast Cancer Symposium showed improved progression-free survival for ixabepilone, an epothilone which inhibits beta-tubulin, plus capecitabine compared to capecitabine alone. This was a pooled group of patients from two trials of ixabepilone in patients with metastatic or local advanced breast cancer resistant to anthracyclines and taxanes. A subset analysis of triple-negative disease showed that the combination of ixabepilone and capecitabine doubled the response from 15% to 31% and increased progression-free survival to 4.2 months from 1.7 months with a nonstatistically significant improvement in overall survival.29,30 This suggests that ixabepilone may have a greater role to play in triple-negative breast cancer. There are also clinical trials currently ongoing in the adjuvant setting where the triple-negative subset is actively studied. These include the TIC-TAC-TOE trial sponsored by the National Surgical Adjuvant Breast and Bowel Project (NSABP), Sarah Cannon and TORI (Tennessee

Oncology Research Institute), and US Oncology, which is a randomized trial of TC ⫻ 6, TAC ⫻ 6, and TC ⫻ 6 plus bevacizumab for nodepositive and high-risk node-negative patients. There is a preplanned subset analysis for triple-negative patients. There is also the BEATRICE trial looking at randomization to standard chemotherapy with anthracycline ⫾ taxane or taxane alone with or without bevacizumab for specifically triple-negative tumors (http://clinical trials.gov/ ct2/show/NCT00528567). These trials are all looking at using bevacizumab as a targeted drug in these tumors. Whether this strategy will be successful or not is not yet known. Another phase III trial, called the TITAN trial, is investigating AC followed by ixabepilone versus AC followed by paclitaxel in earlystage triple-negative breast cancer (http://clinicaltrials.gov/st2/show/ NCT00789581), testing whether ixabepilone would be more efficacious. In the first-line metastatic and locally recurrent setting, trials are looking at ixabepilone plus bevacizumab in two different schedules versus paclitaxel and bevacizumab. Cancer and Leukemia Group B (CALGB)-40502 is looking at bevacizumab with weekly paclitaxel, nanoparticle albumin bound (nab)paclitaxel, or ixabepilone in the first line locally recurrent or metastatic setting. Additionally, there are data in the neoadjuvant setting suggesting increased activity for platinums with or without bevacizumab in triple-negative breast cancer.31,32 Furthermore, a new trial, NSABP B-48, will be looking at the addition of a PARP inhibitor, BSI-201, in the neoadjuvant setting of triple-negative disease with the endpoint being pathologic complete response. All of the data above provide a framework to formulate a decision regarding treatment of a high-grade second primary triple-negative ipsilateral breast cancer in the adjuvant setting. Certainly any recommendation would be based on a level of

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evidence that would be below category 3 and is open to major disagreement. With this as a caveat, I can attempt to offer some treatment recommendations. First and foremost is that the NCCN guidelines support adjuvant chemotherapy in receptornegative disease with tumor ⬎0.5 cm even if node-negative. The tumor in the patient here is in aggregate larger than that, as there are several foci of invasive disease, the largest of which is 0.5 cm. Her total aggregate dose of doxorubicin from 9 years ago with four cycles of AC would have been 240 mg/m2. She is in apparent good health with no other significant comorbidities. Clearly a clinical trial would have been ideal— either TIC-TAC-TOE, BEATRICE, Eastern Cooperative Oncology Group (ECOG) 5103, or TITAN. Unfortunately, she is ineligible for inclusion due to a previous breast cancer. The following would be the preferred order for my treatment recommendations: (1) TAC ⫻ 6; (2) dose-dense AC followed by dosedense paclitaxel or weekly paclitaxel; (3) TC ⫻ 4 based on the US Oncology trial showing superiority of AC to TC33; (4) AC ⫻ 4. My bias would be to treat with TAC ⫻ 6 based on the retrospective data presented from BCIRG001. I would be reluctant to use AC ⫻ 4 as that was used previously. Yet it would be reasonable to use TC ⫻ 4 – 6 based on one’s comfort level regarding duration of therapy, which is being tested in the TICTAC-TOE trial hoping to show equivalency of a non-anthracycline regimen. Also, about the most divergent therapeutic approach would be to offer four cycles of AC followed by four cycles of docetaxel and carboplatin based on data showing greater sensitivity of triplenegative breast cancer to doublestranded DNA-disrupting agents such as the platinums. Obviously, targeted therapy such as anti-vascular endothelial growth factor (antiVEGF), anti-EGFR, and PARP inhibi-

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tor strategies will have to await the results of clinical trials in the metastatic and neoadjuvant setting. If effective there, they can be tested in the adjuvant setting. I believe that this case represents a not unusual clinical quandary where there are preliminary tantalizing therapeutic data in another clinical setting such as metastatic disease or neoadjuvant situations which one intuitively feels eventually will be found to be useful in the adjuvant setting. Unfortunately, the art of oncology and the patient sitting in front of us requires us to make the best decision possible with the data at hand. I hope that this response will stimulate you to think more about this difficult subset of breast cancer patients to whom we must offer the best therapy possible. Lewis J. Rose, MD Division of Regional Cancer Care Kimmel Cancer Center Thomas Jefferson University Hospital Philadelphia, PA

MEDICAL ONCOLOGIST’S OPINION This clinical scenario is uncommon but not rare. After BCT, 5% to 20% of patients will have local recurrance, although the rate is less than 10% in patients who have adjuvant radiation therapy. Restrospective studies have shown that 10-year survival with mastectomy alone is 24% to 64% at 10 years, with systemic recurrence causing the most deaths.34 This would indicate that chemotherapy may offer some benefit. Within this population, recurrence risk varies. Some data suggest that a longer interval between BCT and recurrence confers a lower systemic risk, with some data giving an approximately 22% risk for women recurring later than 5 years.35 The only randomized trial in this setting concerned women who had local recurrence after mastectomy. Women who had tamoxifen added

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to local treatment had no difference in survival at 9 years as compared to women who had resection and radiation therapy only.12 The European Society for Medical Oncology recommends treating isolated local recurrence as a new primary breast cancer.36 However, there currently exists no evidence of a benefit for adjuvant chemotherapy in these patients.37 Because of her long diseasefree interval and the lack of evidence, I would not recommend adjuvant chemotherapy for this patient. However, I would consider enrolling her in a clinical trial such as NSABP B34, which is randomizing patients to chemotherapy versus no chemotherapy after definitive local treatment for locally recurrent breast cancer. If she relapses systemically, we have more guidance on how to proceed. Recent studies suggest that triple-negative breast cancers are much more sensitive to platinums with PARP inhibitors than to other forms of chemotherapy. For example, a recent study presented by Joyce O’Shaughnessy at the 2009 Annual Meeting of the American Society of Clinical Oncology (ASCO) randomized patients with metastatic triple-negative breast cancers to carboplatin and gemcitabine with or without the PARP inhibitor BSI 201. The overall response rate was increased from 16% to 48% by adding the PARP inhibitor, with a hazard ratio of 0.34 for progression.27 Currently, this drug is not commercially available. There is an ongoing phase III clinical trial in this population. If no access to a clincal trial were available, I would advocate a regimen such as carboplatin and paclitaxel, as triple-negative tumors may be especially sensitive to platinums.38 I would definitely advocate genetic testing in this patient. Known risk factors for carrying a BRCA germline mutation include personal history of breast cancer younger than age 50, such as in our patient.39 Other risk factors, although not seen in this patient, include ovarian cancer at any age, family history of male

breast cancer, bilateral breast cancer or breast and ovarian cancer in the same individual, Ashkenazi Jewish heritage, or a known mutation in an affected family member. It is important to emphasize that all patients tested should have access to genetic counseling. If the patient was found to have a mutation, NCCN guidelines suggest intensified screening with breast magnetic resonance imaging, transvaginal ultrasound, and CA-125 yearly, and consideration of risk reduction therapy such as oral contraceptives, tamoxifen, and oophorectomy. Allison Zibelli, MD Division of Regional Cancer Care Kimmel Cancer Center Thomas Jefferson University Hospital Philadelphia, PA

ADVANCED PRACTITIONER IN GENETICS’ OPINION The patient’s family history is significant for her mother being diagnosed with breast cancer at age 80 and a maternal cousin diagnosed with breast cancer in her 50s. The patient denies Ashkenazi background. The patient was initially diagnosed with breast cancer before age 45; therefore, she meets the NCCN Clinical Practice Guidelines in Oncology regarding genetic testing for hereditary breast and/or ovarian cancer syndrome (HBOCS).16 Additionally, two primary cancers in the same woman when the first was diagnosed before age 50 years is another NCCN guideline supporting the option of testing for HBOCS, although in this patient the issue of recurrence versus a new primary tumor cannot be absolutely ascertained. The patient is known to have a history of triple-negative breast cancer. Studies have shown that BRCA1–related breast cancers can present with an unusually aggressive phenotype that tends to be triple-negative, although exceptions are noted.40 – 42

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The patient should be offered the option of participating in a comprehensive genetic consultation with a qualified healthcare professional in order to better understand the issues regarding HBOCS. Risks, benefits, and limitations of genetic testing should be reviewed with the patient at the time of genetic consultation. Issues that would be reviewed at genetic consultation should include increased risk for certain types of cancer for both the patient and her immediate family members. Genetic counseling also should provide the patient and her family with tailored information regarding cancer risk reduction and early detection options through lifestyle changes (eg, elimination or restriction of alcoholic beverages), enhanced screening (eg, breast magnetic resonance imaging), and prophylactic surgery. Chemoprevention options for appropriate female family members should be reviewed at the time of genetic counseling and, if appropriate, further discussed by the individual family member with a board-certified medical oncologist thoroughly familiar with the risks, benefits, and limitations of the chemoprevention options tamoxifen and raloxifene.43 At the time of genetic consultation, insurance coverage for genetic testing should be reviewed. Most commercial insurance carriers cover the cost of BRCA-1 and BRCA-2 genetic testing (Comprehensive BRACAnalysis through Myriad Genetic Laboratories, Salt Lake City, UT) for any woman diagnosed with breast cancer at age ⱕ45 years; this is supported by NCCN guidelines. Of course, there always may be an exception to this insurance coverage guideline and this should be reviewed with the patient. If the patient does not have commercial medical insurance, other funding sources such as those related to a grant or an endowment may be available. We would recommend that a companion test to Comprehensive BRACAnalysis be discussed with the

patient should her BRACAnalysis come back with negative results (with no mutation detected). The BRACAnalysis Rearrangement Test (BART) is an additional testing option provided by Myriad Genetic Laboratories for those with negative Comprehensive BRACAnalysis results. When results from the Comprehensive BRACAnalysis are negative, the BART may provide more complete genetic information by means of large genetic rearrangement testing via polymerase chain reaction (PCR). However, some insurance carriers consider the BART to be investigational and will not cover the cost, which is currently $650.00. It is not completely clear what the exact quantified risk is for BRCA-1 or BRCA-2 mutation carriers to develop breast and or ovarian cancers. However, studies suggest that deleterious mutations in the BRCA-1 or BRCA-2 gene may imply as much as an 87% risk for breast cancer and 44% risk for ovarian cancer by age 70 years.44 With BRCA mutations, risk for a new breast cancer within 5 years of the first is estimated to approach 20%45 (as well as a 10-fold increase in the risk for subsequent ovarian cancer).46 BRCA mutations also may confer an increased risk for male breast, pancreas, colorectal cancer, and melanoma.47 Studies have shown that BRCA-1–related breast cancers can present with an unusually aggressive phenotype along with the “triple-negativity” seen in the patient’s tumor. However, exceptions are noted.40 – 42 Ultimately, genetic consultation should help the patient better understand the difference between hereditary versus nonhereditary cancers, and the personal and family risk factors for certain types of cancer, how genetic test results can affect the patient and her family, and the benefits, risks, and limitations of genetic testing. Genetic counseling should help the patient to make an informed decision about proceeding or not proceeding with genetic test-

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ing. The patient also should obtain a written personalized plan for risk reduction/early detection of certain types of cancers. In summary, we believe that this patient is an appropriate candidate for genetic consultation, including the option of genetic testing for HBOCS after informed consent. Criteria for this recommendation include the young age at diagnosis and the triple-negative phenotype of her breast cancer. The possibility of two primary cancers also exists. The patient has a first- and a third-degree relative diagnosed with breast cancer at age 80 years and in the 50s, respectively. Should the patient proceed with testing and be found to carry a mutation in the BRCA-1 or BRCA-2 gene, she would be encouraged to have further discussions with a board-certified gynecologic oncologist and her regular treating clinicians regarding the risks, benefits, and limitations for prophylactic bilateral salpingo-oophorectomy. If ovarian cancer surgical risk reduction was declined, the patient should be clinically managed by a board-certified gynecologic oncologist and have transvaginal ultrasound (TVU) and CA-125 levels determined every 6 months. However, there are data suggesting that the use of TVU and CA-125 may not be effective for screening high-risk women for ovarian cancer.43 As part of the genetic consultation, a tailored cancer screening/early detection plan should be developed for the patient and her close family members. Close family members would be encouraged to participate in genetic counseling and consider the option of genetic testing for the identified single-site deleterious mutation. If other family members declined genetic testing, they would be managed as though they carry the deleterious mutation until genetic testing proves otherwise. Should the patient proceed with testing and prove negative for a BRCA mutation, we would recommend that her close family members

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still be followed as being at increased risk for breast cancer due to the family history. It is possible for genetic testing to miss a sequence mutation or large rearrangement and therefore is not 100% reliable. Other genes or combinations of genes not yet discovered or fully understood could be the reason for the patient’s breast cancer. Or the cancer could be sporadic and nonhereditary. It sometimes can be difficult to ascertain why a specific person has tested negative for a hereditary cancer syndrome such as HBOCS. Given this, close female family members would be encouraged to see a breast surgeon for twice yearly clinical breast exams and male family members would be encouraged to have their consciousness raised regarding their own risk for breast and prostate cancer. The patient and her close female family members would be encouraged to see a gynecologist thoroughly familiar with the care and management of higher risk women. Pearls for clinical practice are offered in that all clinical management issues for higher risk cancer families are not fully settled and careful clinical interpretation is necessary. Atrisk patients should be referred to a clinical cancer genetics specialist to explore options for genetic testing, cancer risk reduction, and early diagnosis. Clarifying cancer genetics and cancer risk assessment information for the patient, their family, and their collaborating clinicians can be helpful. Genetic consultation plans should be tailored to meet the needs of the individual person and their family while using established clinical guidelines as a template. Susan Miller-Samuel, RN, MSN, APNG Jefferson Breast Care Center Thomas Jefferson University Hospital Philadelphia, PA

CONCLUSION We present here a case of recurrent early-stage breast cancer, of tri-

C.S. Adonizio et al

ple-negative phenotype, which has recurred 9 years after initial presentation, and was removed after mastectomy at a size ⱕ5 mm, with clear margins. The above oncologists make strong proposals for treating this patient with further adjuvant chemotherapy based on the biology of her breast cancer and the application of newly developing treatments for triple-negative breast cancer. After discussion weighing the risks and projected survival benefits of systemic adjuvant chemotherapy for recurrence, this patient was also offered observation per NCCN guidelines, 48 which recommend that despite ER⫺ phenotype, chemotherapy should be considered for tumors 6 mm in size and above. Whether this is a situation heralding a recurrent versus new primary breast cancer is also a point of discussion. Typically, triple-negative breast cancer tends to recur much earlier in its natural history,49 and while a late recurrence in this patient’s case is unusual, it also may speak to the disparate biology of all triple-negative tumors. Emerging evidence has shown that even within triple-negative breast cancer, there tends to be a spectrum of behavior: triple-negative breast cancers encompass a remarkably heterogeneous group of tumors.50 Rahka et al have shown that although the morphologic features of basal-like breast cancer are similar to that of other triple-negative tumors, there are those that do not express defined basal markers, such as CK5/6, CK17, CK14, and EGFR (termed non-basal triple-negative breast cancer subtypes,50 and thus may translate into distinct clinical differences. Basallike triple-negative breast cancers in particular are reported also to show other distinct immunophenotypic patterns, including association with the expression of the hypoxia-associated factor (CA9), neuroendocrine markers, p53, and a difference in the expression of cell cycle–associated proteins.49 In addition, basallike breast cancer is more positively associated with BRCA-1 mutation

status and tends to show a unique pattern of distant metastasis, better response to chemotherapy, and shorter survival, as compared to non-basal but triple-negative breast cancer cells.50 Testing for HBOCS also may be considered for this patient with triple-negative breast cancer. Tumors in women with BRCA-1 germ-line mutations are indeed known to have similarities to basal-like breast cancers.49 Of BRCA-1 and -2 mutation carriers affected by breast cancer, triple-negative phenotype is reported to occur a significant portion of the time,49,51 and in a study of triple-negative breast cancer, BRCA-1 and -2 mutations were detected in approximately 11%.52 In addition, if mutations in BRCA-1 and -2 confer less ability to repair DNA damage, this may contribute to the initial heightened sensitivity of these tumors to chemotherapy. It has been suggested in the literature that women with early-onset triple-negative breast cancer are indeed candidates for genetic testing, even in the absence of a family history of breast or ovarian cancer. This tumor may be possibly classified as basal-like breast cancer with high ki-67 and p53 expression, and thus may be estimated to manifest its natural history, behavior, and chemosensitivity as such. However, the natural history of the breast cancer in this case showed a later recurrence than expected, and therefore, microarray analysis on the tumor may further prove its immunophenotype if necessary. Triple-negative T1N0 patients are known to have a greater recurrence risk in spite of more aggressive therapy, thus prompting need for the development of new treatment modalities specific for this disease.53 According to NCCN guidelines,48 this patient was offered observation based on the size of the recurrent tumor alone. However, if further recurrent in the future, the patient would subsequently be offered systemic chemotherapy, which could also include both a platinum agent, with or

Recurrent early-stage triple-negative breast cancer

without a PARP inhibitor, based on recent data emerging from phase II clinical trials in the metastatic setting.27 In addition, this patient was tested for hereditary mutations in BRCA-1 and -2 genes by comprehensive genomic analysis, and was indeed found to harbor a deleterious mutation in BRCA-1 (5385insC), which results in a stop codon at amino acid position 1829 of the BRCA-1 protein. As corroborated by the authors, the patient’s heritage is being further explored, as it is suggested that if she truly is of Ashkenazi Jewish ancestry, further follow-up testing of at least her firstdegree relatives should also be pursued, for this mutation, as well as some additional mutations which may also co-exist in Ashkenzi families. Further risk reduction measures for hereditary breast and ovarian cancer (ie, oophorectomy) are also offered to this patient. Christian S. Adonizio, MD Gloria J. Morris, MD, PhD Hematology & Oncology Associates of NE PA, PC Dunmore, PA The Commonwealth Medical College Scranton, PA

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