Volume 82, Issue 2 , Pages 505-507, 1 February 2012
Oncology Scan – February 1, 2012
Article Outline
Some of the most important articles relevant to the clinical practice of breast cancer have been published by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) based at Oxford University in the United Kingdom. They collaborate with phase III trial investigators to compile complete datasets and perform meta-analyses. The group has been successful in obtaining the raw data from nearly every phase III local-regional trial and adjuvant systemic treatment trial. The group has planned updates of their analyses every five years. The first article we will review is an October 2011 Lancet publication of the EBCTCG meta-analysis investigating the role of radiation in the management of patients with invasive breast cancer treated with breast conservative surgery. This article is the EBCTCG’s first publication on local-regional treatment outcome since their important 2005 Lancet publication. (1)
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet. 2011 Oct 19. [Epub ahead of print] (2)
Summary: In this article, the authors performed a meta-analysis of the data from 10,801 treated in 17 phase III trials that randomized patients with invasive breast cancer treated with breast conserving surgery to adjuvant whole breast radiation versus no radiation treatments. More than 70% of the patients included in the study had pathologically negative lymph nodes.
In this analysis, the authors chose not to focus on local-regional control or on the risk of subsequent mastectomy but instead reported the risk of overall recurrence (either a local-regional or distant recurrence). The reason for selection of this endpoint was their previous publications had shown an interaction between local-regional treatments and distant metastasis, and so overall recurrences were felt to be the most important endpoint. The results confirmed that radiation is highly effective. The patients treated with radiation had an overall recurrence risk of 19.3%, which was significantly lower than the 35% risk in the patients randomized to no radiation (2p<0.00001). Equally important, radiation decreased the 15-year risk of death from breast cancer from 25.2% to 21.4% (2p=0.00005). There was also a statistically significant improvement in overall survival.
The benefits of radiation were present in all stage groups. For patients with lymph node negative disease, radiation decreased the risk of overall recurrence by one-half (31.0% to 15.6%, 2p<0.00001). In the 1,050 patients with pathologically positive lymph nodes, radiation reduced the 10-year recurrence risk from 63.7% to 42.5% (2p<0.00001). In both of these subgroups, radiation use was associated with a statistically significant reduction in the risk of breast cancer death.
Finally, this analysis also provided important data concerning the benefits of radiation according to breast cancer biological subtype. Specifically, the authors reported the proportional benefits of radiation in reducing breast cancer recurrence differed according to estrogen receptor (ER) status. The respective proportional reductions in recurrences were 62% for patients with ER-positive who received tamoxifen, 59% for ER-positive, no tamoxifen, and 35% for patients with ER-negative disease.
Comment: I had an opportunity to write an accompanying invited commentary, which was published with the EBCTCG article (3), in which I wrote that this recent publication confirms that radiation plays a critically important role in the management of patients treated with a breast conserving surgery for an invasive breast cancer. The nearly 50% proportional reduction in overall recurrence is higher than the proportional reduction in recurrence achieved by either chemotherapy or adjuvant hormonal therapy. (4) Importantly however, the reduction in recurrences with radiation and systemic treatments are complementary, as evidence by the fact that the greatest proportional reduction in recurrence was noted in patients who also were treated with tamoxifen.
The very exciting finding of this article is that radiation use is also associated with a decrease risk of breast cancer death and an improvement in overall survival. For many years, some investigators believed that radiation benefits were strictly local; that its use could help avoid mastectomy but could not decrease distant metastases and thereby could not improve long-term survival outcome. These data conclusively refute this once commonly held belief. It is clear from this update that radiation use eradicates local foci of residual disease that, if left untreated, have the potential to metastasize and cause death. This process takes time, such that the local benefits of radiation may be evident within five years but the survival benefits associated with radiation become manifest only between five to 15 years after treatment.
The final discussion point concerns the data on the effect of ER status on the benefits of radiation. The finding that patients with ER-negative disease had the lowest proportional benefit from radiation is consistent with a similar finding noted for the patients treated in the Danish 82b/c postmastectomy radiation trials. (5) In addition, investigators from Dana Farber, M. D. Anderson, and British Columbia have independently demonstrated that patients with triple negative (ER-negative, progesterone receptor(PR)-negative, and HER2/neu-negative) breast cancer have a higher risk of breast recurrence after surgery and breast radiation than patients with ER+ disease. 6, 7, 8 Together, such data suggest that ER-negativity may be associated with a more radio-resistant phenotype or may be associated with a greater postsurgical microscopic disease burden. Such data raise the question whether patients with triple negative disease should be offered mastectomy rather than breast conservation. A recent publication directly relevant to this question was selected as the second of the three articles to review.
Abdulkarim BS, Cuartero J, Hanson J, Deschênes J, Lesniak D, Sabri S. Increased risk of locoregional recurrence for women with T1-2N0 triple-negative breast cancer treated with modified radical mastectomy without adjuvant radiation therapy compared with breast-conserving therapy. J Clin Oncol. 2011 Jul 20;29(21):2852-8. Epub 2011 Jun 13. (9)
Summary: In this article, the authors reviewed the outcome of 768 patients with non-metastatic invasive triple-negative breast cancer treated in a single institution with either breast conservation with radiation, or mastectomy with or without radiation. After a median follow-up of 7.2 years, the overall rate of disease progression was 20% and the local-regional recurrence rate was 10%.
The authors then analyzed local-regional outcome according to treatment. Given this was a retrospective institutional study, there were obvious clinical and patient factors that contributed to the selection of breast conservation and whether those who were treated with mastectomy received radiation. A Cox regression analysis was performed to adjust for the identified confounding factors. This analysis showed that patients treated with mastectomy without radiation had a hazard ratio of 3.44 (P<0.001) compared to those treated with breast conserving surgery and radiation. In contrast, those treated with mastectomy plus radiation did not have a significant difference in local-regional recurrence relative to those treated with breast conservation (P=0.34). Chemotherapy use also correlated with a reduced hazard for local-regional recurrence (0.39, P<0.001).
To further control for stage bias, the authors then investigated the local-regional treatment outcome in the subset of 468 patients treated for a T1-2N0 triple negative breast cancer. They found a 5 year local control rate of 96% for those treated with breast conservation versus a rate of 90% for those treated with mastectomy without radiation (P=0.02). In a Cox regression limited to this subset, mastectomy without radiation was the only independent factor associated with increased local-regional recurrence (hazard ration 2.53, P = 0.0264).
Comment: This article provides interesting data regarding local-regional treatment outcomes for patients with triple negative breast cancer and suggests that radiation may play an important role in management of such patients. Unlike the previous article, this article did not compare whether ER-negativity increases local-regional recurrences in patients who receive radiation. Instead it compared the outcome of an irradiated cohort versus no radiation cohort. Looking at the outcome only in irradiated patients determines whether ER-negativity is a negative predictive factor for radiation control, whereas the comparing radiation to no radiation cohorts addresses whether ER-negativity is a prognostic factor for local-regional recurrence. Taken this study and the EBCTCG together, one conclusion that can be reached is that ER-negativity is both a predictive and prognostic factor.
The article suggests that patients with triple negative breast cancer who have negative lymph nodes do well with breast conservation (the 4% recurrence rate at 5 years is certainly acceptable). In the study, positive lymph node status was independently associated with local-regional recurrence and therefore it would have been interesting to see the outcome of patients with T1-2N1 disease treated with breast conservation, but this was not provided. The article does provide assurance that patients with T1-2N0 should not be recommended to have mastectomy on the basis of having a triple negative subtype. Taken another way, while other data suggest that patients with triple negative disease may have higher risks of recurrence than those with ER-positive breast cancer, mastectomy does not appear to be a more favorable alternative.
The article also questions whether some cohorts of patients with lymph node-negative breast cancer should receive postmastectomy radiation. Despite finding a higher risk of recurrence in lymph node-negative patients treated with mastectomy with no radiation, the overall risk was only 10%, which in my opinion does not warrant the added toxicity of radiation. Triple negative disease that recurs tends to do so within the first five years of follow-up, and so it is not likely that this risk will dramatically increase with further follow-up to this study. Also, a limitation of this study is the low use of chemotherapy in patients with triple negative breast cancer with negative lymph nodes. Chemotherapy use was associated with a lower risk of local-regional recurrence and is now usually a recommended component of therapy for most patients with triple negative disease.
A second reason to be less enthusiastic about postmasectomy radiation for this lymph node-negative population is that the data from the Danish postmastectomy trial suggests that the proportional benefit of postmastectomy radiation is less in ER-negative disease. (5) M. D. Anderson has also published similar data. In a recursive partition analysis of predictive factors for local-regional recurrence in patients treated with mastectomy and postmastectomy radiation, ER-negativity proved to be the most important variable. (10)
Goss PE, Ingle JN, Alés-Martínez JE, Cheung AM, Chlebowski RT, Wactawski-Wende J, McTiernan A, Robbins J, Johnson KC, Martin LW, Winquist E, Sarto GE, Garber JE, Fabian CJ, Pujol P, Maunsell E, Farmer P, Gelmon KA, Tu D, Richardson H; NCIC CTG MAP.3 Study Investigators. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med. 2011 Jun 23;364(25):2381-91. Epub 2011 Jun 4. Erratum in: N Engl J Med. 2011 Oct 6;365(14):1361. (11)
Summary: This phase III double-blind trial randomized 4,560 postmenopausal women with no cancer history to a chemoprevention treatment with exemestane or placebo. Women had to have Gail risk score >1.66%. The medication compliance rate was 85%. After a median follow-up of 35 months, there were 32 invasive breast cancers that developed in the placebo group compared to only 11 in the exemestane group. The annual incidence of invasive breast cancer was 0.55% for the placebo group compared to only 0.19% in the exemestane group (a reduction in the relative incidence of breast cancer by 65%). Development of musculo-skeletal complaints (grade 2 – 6.5% vs. 4.0%) and hot flashes (grade 2 – 18.3% versus 11.9%) were higher in the exemestane group
Comment: This is a well-conducted and potentially practice changing trial, in that postmenopausal women now have an appropriate alternative to tamoxifen and raloxifene for chemoprevention of breast cancer. In this study, the benefits of the exemestane were consistent across all risk cohorts and precursor lesions. The tolerance of the medication was acceptable. This trial is important because the widespread acceptance of tamoxifen and/or raloxifene as chemopreventive treatments has been poor, due in part to concerns of potential rare but serious side effects.
For premenopausal patients seeking chemoprevention strategies, tamoxifen remains the standard of care.
References
- . Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005 Dec 17;366(9503):2087–2106
- Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10 801 women in 17 randomised trials. Lancet. Oct 19.
- Buchholz TA. Radiotherapy and survival in breast cancer. Lancet. Oct 19.
- . Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005 May 14-20;365(9472):1687–1717
- . Estrogen receptor, progesterone receptor, HER-2, and response to postmastectomy radiotherapy in high-risk breast cancer: the Danish Breast Cancer Cooperative Group. J Clin Oncol. 2008 Mar 20;26(9):1419–1426
- Albert JM, Gonzalez-Angulo AM, Guray M, Sahin A, Strom EA, Tereffe W, et al. Estrogen/progesterone receptor negativity and HER2 positivity predict locoregional recurrence in patients with T1a, bN0 breast cancer. Int J Radiat Oncol Biol Phys. Aug 1;77(5):1296–302.
- Breast cancer subtype approximated by estrogen receptor, progesterone receptor, and HER-2 is associated with local and distant recurrence after breast-conserving therapy. J Clin Oncol. 2008 May 10;26(14):2373–2378
- Voduc KD, Cheang MC, Tyldesley S, Gelmon K, Nielsen TO, Kennecke H. Breast cancer subtypes and the risk of local and regional relapse. J Clin Oncol. Apr 1;28(10):1684–91.
- Abdulkarim BS, Cuartero J, Hanson J, Deschenes J, Lesniak D, Sabri S. Increased risk of locoregional recurrence for women with T1-2N0 triple-negative breast cancer treated with modified radical mastectomy without adjuvant radiation therapy compared with breast-conserving therapy. J Clin Oncol. Jul 20;29(21):2852–8.
- Locoregional recurrence after doxorubicin-based chemotherapy and postmastectomy: Implications for breast cancer patients with early-stage disease and predictors for recurrence after postmastectomy radiation. Int J Radiat Oncol Biol Phys. 2003 Oct 1;57(2):336–344
- Goss PE, Ingle JN, Ales-Martinez JE, Cheung AM, Chlebowski RT, Wactawski-Wende J, et al. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med. Jun 23;364(25):2381–91.
PII: S0360-3016(11)03688-1
doi:10.1016/S0360-3016(11)03688-1
Volume 82, Issue 2 , Pages 505-507, 1 February 2012
