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Cancer Therapy: Clinical |
Authors' Affiliations: 1 Institute of Cancer Research and Royal Marsden NHS Foundation Trust; 2 Department of Medical Genetics and 3 Oncology Unit, Guy's and St. Thomas NHS Foundation Trust; 4 St. George's Hospital Medical School and St. George's Hospital; 5 Gray Cancer Institute, Northwood, London, United Kingdom; 6 Division of Genetic Medicine, Vanderbilt University, Nashville, Tennessee; 7 Birmingham Oncology Centre, University Hospitals NHS Trust, Birmingham, United Kingdom; 8 Academic Unit of Medical Genetics and Regional Genetics Services, St. Mary's Hospital; 9 Christie Hospital, Withington, Manchester, United Kingdom; 10 Princess Anne Hospital, Wessex Regional Genetics Centre; 11 Department of Surgery, Royal South Hants Hospital, Southampton, United Kingdom; 12 Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan; and 13 Strangeways Research Laboratory, Worts Causeway, Cambridge, United Kingdom
Requests for reprints: Susan Shanley, Cancer Genetics Unit, Royal Marsden NHS Foundation Trust, Downs Road, Sutton SM2 5PT, United Kingdom. Phone: 44-208-661-3375; Fax: 44-208-770-1489; E-mail: shanleysusan{at}hotmail.com.
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Abstract |
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Experimental Design: All participants were interviewed by one of two researchers using standardized questionnaires, and their medical records were reviewed by one research nurse. The two main regimens received were cyclophosphamide, methotrexate, and fluorouracil and fluorouracil, epirubicin, and cyclophosphamide. The proportion of cases and controls receiving anthracycline-based treatment was equivalent, but fewer BRCA1 cases received this treatment than did BRCA2 mutation carriers. Toxicity was documented using the Eastern Cooperative Oncology Group Common Toxicity Criteria for hematologic, infective, and gastrointestinal toxicities. No increase in toxicity was seen in BRCA1/2 mutation carriers.
Results: The only significant difference was that neutropenia was less evident in BRCA2 mutation carriers than in either BRCA1 mutation carriers or controls. As a result, there was no requirement for dose reduction among BRCA2 mutation carriers, in contrast to 10 of 39 BRCA1 carriers and 16 of 62 controls (P = 0.02).
Conclusions: This result has implications for therapy and indicates that women with mutations in BRCA1 and BRCA2 may be given the same doses of chemotherapy as noncarriers.
Chemotherapeutic drugs are divided by their mechanisms of action, but most include the production of DNA double-strand breaks in their repertoire, often after the induction of interstrand cross-links. As the BRCA genes are known to function in the homologous repair of DNA double-strand breaks, is there evidence that tumor and/or the normal tissues in BRCA heterozygotes have increased sensitivity to specific chemotherapeutic agents?
In vitro data are limited. Studies using brca1-homozygous null murine ES cells have shown increased cell death induced by the alkylating agent, mitomycin C, platinum, and the topoisomerase inhibitors including doxorubicin (which is also an anthracycline) and mitoxantrone compared with wild-type cells (2–4), but there were no differences for cells treated with antimetabolites. A study of a BRCA2 heterozygous mutant ovarian cancer cell line has shown heightened sensitivity to cisplatin compared with paclitaxel, but this study did not have a wild-type cell line control (5).
Clinical data are suggestive of enhanced chemosensitivity in homozygous tumor tissues in BRCA mutation carriers, but no prospective data are available. Chappuis et al. (3) and Delaloge et al. (6) both found increased clinical response rates in BRCA carriers compared with controls, when treated for breast cancer with anthracyclines and cyclophosphamide. A larger study by Goffin et al. (7) supported a greater survival benefit for chemotherapeutic effect for breast cancer treatment in BRCA1 mutation carriers than in controls. Improved clinical response rates and survival have also been shown for BRCA mutation carriers versus controls in treatment for ovarian cancer with cisplatin (8). The basis for this sensitivity seems to be the disruption of cell signaling pathways involving Fanconi anemia genes, one of which, FANCD1, is now known to be BRCA2 (9). This has generated interest in the use of cisplatin in the treatment of BRCA-related cancers and an international trial of carboplatin versus docetaxel in advanced breast cancer in BRCA carriers is under way (known as the BRCA Trial, see http://www.breakthroughcentre.org.uk/).
Chemotherapeutic regimens for breast cancer in the United Kingdom, during the time that this study was conducted, included the use of several combinations, predominantly cyclophosphamide, methotrexate, and fluorouracil (CMF), fluorouracil, epirubicin, and cyclophosphamide (FEC), and mitoxantrone and methotrexate (MM). Current treatment guidelines suggest that known carriers are offered standard adjuvant chemotherapy for early breast cancer, but there is great interest in the prospect of new therapies. In particular, there are exciting prospects for the use of novel agents [poly(ADP-ribose) polymerase inhibitors], following the demonstration that BRCA homozygous cell lines are exquisitely sensitive to these inhibitors of nonhomologous repair pathways without inflicting detectable damage on heterozygous cells (10, 11). In the interim, there is a need to determine if conventional chemotherapeutic regimens need to be modified, hence, this study.
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Materials and Methods |
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Control participants were recruited from the Breast Units of four centers. Matching was done as described in the accompanying report for the following variables: age ±12 years, tumor size, nodal status, receipt of radiation treatment, and duration of follow up from the end of treatment. Type of chemotherapeutic regimen (anthracycline-based or not) was not a matching criterion, as this proved too restrictive. Exclusion criteria were the presence of any family history of premenopausal breast cancer or ovarian cancer or Jewish ancestry, to limit the likelihood of undetected BRCA mutations in the control group. Matching proved challenging due to the paucity of age-appropriate controls, the presence of occult family history, and differences in treatment regimens.
Acute chemotoxicity was assessed by interview using standardized questionnaires based on Eastern Cooperative Oncology Group Common Toxicity criteria (12) and review of medical records. The questionnaires were administered by one of two researchers—either the coordinating clinician or the research nurse. Mucosal, gastrointestinal, hematologic, and infective toxicities were scored according to the Eastern Cooperative Oncology Group scale of Common Toxicity. Records reviewed included chemotherapy prescription sheets and chemotherapy regime; the dosage and timing of treatment were recorded. Laboratory reports of white cell counts, dose reductions, and delays (and the reason for the delay) were reviewed.
Statistical considerations. Nonparametric methods were employed for analysis. Although individual matching was undertaken, matched pairs analysis was not employed, as missing or unknown data items would require that patients be omitted from the analysis. The Kruskal-Wallis test was used for ordinal data when comparing more than two groups with a P < 0.05. If this overall test was significant, the Mann-Whitney test was then used to compare pairs of groups. The 
2 test was used to compare nominal data, and Fishers exact test was used for 2 x 2 tables. No correction for multiple testing was employed (13), and P values must be interpreted with caution in view of the large number of significance tests done. P values >0.10 have been shown as nonsignificant. P values between 0.10 and 0.051 are suggestive of significance and have therefore been displayed. Missing or inapplicable responses were excluded when calculating P values. Unless otherwise indicated, P values in the tables refer to the comparison of all BRCA1 and BRCA2 carriers with control participants. Typical detectable differences (80% or greater power, 5% two-sided significance level) with 62 patients in each group (comparing binomial end points) were: 5% versus 25%, 10% versus 35%, 20% versus 45%, 30% versus 60%, 40% versus 70%, and 50% versus 80%.
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Results |
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Tumor size. Although matching was undertaken as closely as possible for tumor size (T stage), it was not possible to obtain exact T stage matches in all cases. One T stage difference was therefore accepted, providing that nodal status matched. This resulted in a nonsignificant excess of nine T1 tumors among case participants which were matched with nine controls who had T2 tumors. Two T3 tumors in the cases were matched with T2 control tumors and two T4 case tumors were matched with T3 controls.
Nodal status. Nodal status was matched in addition to T stage as closely as possible. Where nodal status was unknown (when nodes were not dissected or where nodes were found to be clear following neoadjuvant chemotherapy), a match was accepted with a participant who had a node-positive, node-negative, or node-unknown tumor. There is an excess of node-positive tumors among controls but this difference was tolerated due to the fact that this study was examining acute toxicity from chemotherapy and not long-term cancer outcomes.
Overall staging. In keeping with the differences in tumor size matching, there is an excess of case participants with stage I tumors matched to stage II controls. There are also four stage III cases, three of whom were matched to stage II controls. Two stage IV cases were matched to stage III controls.
Surgery. Thirty-six of 62 cases in each group underwent mastectomy. Nine of these in each group also had radiotherapy postoperatively. Twenty-four cases had wide local excision and radiotherapy, and two cases had no surgery but underwent primary treatment with radiation and chemotherapy. These 26 cases were matched with an equivalent number of controls that received conservative surgery and local radiation treatment. Contralateral mastectomies were undertaken in 22 cases but in only 2 controls. Due to this significant difference in surgical treatments, it was not appropriate to examine tumor outcomes such as contralateral tumor rates in this study.
Chemotherapy regimens. Although the type of regimen used was not matched, the proportion of participants receiving anthracycline-based regimens (FEC predominantly) was equivalent in both arms of the study when considering BRCA1 and BRCA2 cases together versus controls. If BRCA1 cases are considered separately from BRCA2 carriers, there is an excess of non–anthracycline-based regimens (CMF) among BRCA1 cases compared with BRCA2 cases (P = 0.03) or controls (P = 0.014).
Endocrine treatments. Thirty of 51 case participants underwent oophorectomy compared with 2 controls. Of these 30, 7 BRCA1 and 8 BRCA2 mutation carriers received tamoxifen in addition. A further 6 received tamoxifen alone. In total, therefore, 36 of 51 cases underwent some form of endocrine manipulation, as compared with 38 of 51 controls receiving tamoxifen (which included the 2 individuals who had oophorectomy).
Toxicities. BRCA2 mutation carriers experienced fewer episodes of neutropenia, and as a result, no alterations in dose, compared with a need for dose reductions in 10 of 39 BRCA1 mutation carriers and 16 of 62 controls (P = 0.02). There were no significant differences in the intervals of dosing required or the proportion of individuals experiencing severe mucosal, infective, or gastrointestinal toxicities in cases versus controls (Table 2 ).
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Discussion |
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Follow up was significantly shorter for the case group than controls. This may have had the potential to bias the recall of the cases towards more severe events due to the shorter time interval between the event and the recollection. We accept that acute toxicity is difficult to assess retrospectively based on recall alone, but our review of medical notes meant that we could assess basic data such as full blood counts and chemotherapy records, indicating scheduling (to assess the most clinically significant outcome of treatment delays), which were available in 95% of cases across the time interval of the study.
Matching constraints also meant that case participants were younger than controls (Table 1). Given that toxicity may be affected by age, it is possible that these differences may have biased the study towards reduced toxicity in the BRCA mutation carriers, although it is questionable whether a difference of 4 years in median age would account for the differences between BRCA2 mutation carriers and controls. It is also notable that the median ages of cases and controls who required dose alterations due to toxicity were not significantly different (P = 0.05).
Although it was not feasible to match for the type of regimen, the distribution of anthracycline versus non–anthracycline regimens was equivalent in the cases and controls. One-third of women in the case and control arms received anthracyclines, although this was more common in BRCA2 carriers than in BRCA1 carriers.
The main finding of this study is that acute toxicity from chemotherapy was not increased in BRCA1/2 mutation carriers, and that in BRCA2 carriers, hematologic toxicity was less than that seen in controls. It is not likely that the difference in need for dose alterations in BRCA2 mutation carriers reflected a difference in chemotherapeutic regimen compared with controls as the distribution of regimens between these two groups was similar. BRCA1 mutation carriers received less anthracycline-based chemotherapy than either BRCA2 mutation carriers or controls, and it is possible that this could have had an effect on their rate of toxicity, perhaps masking a phenotype similar to that seen in BRCA2 carriers. This possibility is supported by findings from the recent National Epirubicin Adjuvant Trial (16), in which toxicity was seen to be greater in patients receiving CMF compared with those receiving initial anthracyclines. It is not possible to comment on outcomes from other regimens such as platinum-based agents because too few participants received these agents.
It would be useful to examine other factors in the treatment regimens of BRCA1/2 mutation carriers for possible confounding factors such as renal function variables, which affect the excretion of some chemotherapeutic agents and thus alter toxicity. Given the age range of the patients, however, it is unlikely that significant renal impairment would be prevalent in this population.
This study is the first to evaluate the acute effects of chemotherapy in BRCA1/2 carriers in the United Kingdom, and indeed, in the world. Although regimen usage will change as more is understood of how best to target BRCA homozygous tumor cells; thus far, treatment does not seem to have been at the expense of heightened toxicity to the heterozygous tissues such as bone marrow, gastrointestinal, and mucosal tissues. This report has provided evidence that there is no increased toxicity from the studied adjuvant regimens for breast cancer in BRCA1/2 mutation carriers. This is reassuring, particularly for BRCA1, because tumors are more often high-grade and estrogen receptor–negative than are sporadic tumors, and in both BRCA1 and BRCA2, breast cancer is more likely to occur at younger ages. These are all indications for adjuvant chemotherapy and this study has provided the first data to indicate that such treatment may be given in a standard dose to such patients.
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Footnotes |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 5/23/06; revised 8/ 4/06; accepted 9/15/06.
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  M. Santarosa, L. Del Col, E. Tonin, A. Caragnano, A. Viel, and R. Maestro Premature senescence is a major response to DNA cross-linking agents in BRCA1-defective cells: implication for tailored treatments of BRCA1 mutation carriers Mol. Cancer Ther., April 1, 2009; 8(4): 844 - 854. [Abstract] [Full Text] [PDF]
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