Recurrence, new primary and bilateral breast cancer. José Palacios Calvo Servicio de Anatomía Patológica

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1 Recurrence, new primary and bilateral breast cancer José Palacios Calvo Servicio de Anatomía Patológica

2 Ipsilateral Breast Tumor Relapse (IBTR) IBTR can occur in approximately 5 20% of women after breast-conserving therapy. In a retrospective analysis of 5 National Surgical Adjuvant Breast and Bowel Project (NSABP) trials by Wapnir et al, 9.7% of patients experienced IBTR. Patients who sustain an IBTR are at increased risk of distant metastases and decreased survival. The risk of distant metastases does not seem to be uniform.

3 Ipsilateral Breast Tumor Relapse (IBTR) Two distinct entities of IBTR have been described: true recurrence (TR) and new primary (NP) tumors arising in the ipsilateral breast. TR has been suggested to be cases of regrowth of malignant cells not completely removed by surgery or not eradicated by RT. NP tumors arise in the ipsilateral breast away from the original breast tumor, representing de novo cancer arising from residual breast tissue.

4 Ipsilateral Breast Tumor Relapse (IBTR) Clinical and pathologic factors associated with increased risk of IBTR Young age Lymphovascular invasion Estrogen receptor negative Nodal disease Multifocality Positive margins Omission of postoperative radiation therapy

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6 Ipsilateral Breast Tumor Relapse (IBTR)

7 Cancer 2011

8 Panet-Raymond et al; Int. J. Radiation Oncology Biol. Phys., 2011; 81:

9 The mean time to recurrence was shorter in TR patients than in NP patients (48%) (4.8 vs. 6.3 years). Panet-Raymond et al; Int. J. Radiation Oncology Biol. Phys., 2011; 81:

10 Panet-Raymond et al; Int. J. Radiation Oncology Biol. Phys., 2011; 81:

11 Comparison of the LOH mutation pattern using markers of frequently deleted tumor suppressor genes is a wellestablished method for determining the clonality of 2 tumors. N LOH LOH Goldstein et al; Am J Clin Pathol 2005

12 Long-term patterns of in-breast failure in patients with early stage breast cancer treated with breast-conserving therapy: A molecular based clonality evaluation The clonality of IBTRs relative to the initial invasive carcinomas were analyzed in 57 patients treated with BCT. 34 (60%) were clonally related and 23 (40%) were clonally different. Clinical IBTR classification and molecular clonality assay results differed in 44% of all cases. McGrath et al. Am J Clin Oncol 2010

13 Long-term patterns of in-breast failure in patients with early stage breast cancer treated with breast-conserving therapy: A molecular based clonality evaluation Clonally related IBTRs were more frequently - higher grade (70% vs. 32%) - developed sooner (5.1 vs 9.3 years) The proportion of IBTRs that were clonally related at 5, 10, and 15 years after BCT were 82%, 48%, and 33%, respectively Twelve patients subsequently developed distant metastases, of which 9 (75%) had clonally related IBTRs. McGrath et al. Am J Clin Oncol 2010

14 Long-term patterns of in-breast failure in patients with early stage breast cancer treated with breast-conserving therapy: A molecular based clonality evaluation This analysis demonstrates the inaccuracy of clinically establishing the clonality of most IBTRs. Clonally related IBTRs occurred sooner than clonally different IBTRs, were more frequently associated with the development of distant metastases and had a worse prognosis. Molecular clonality assays provide a reliable means of identifying patients who may benefit from aggressive systemic therapy at the time of IBTR and provide an accurate assessment of the efficacy of various forms of local therapy. McGrath et al. Am J Clin Oncol 2010

15 15% 22% 30% 37% 9% 5% 100 breast cancer: 79 ER+ 21 ER-

16 Ipsilateral Breast Tumor Relapse (IBTR) Conclusions Some patients who present with an IBTR after conservative surgery with or without RT may have a new primary tumor as opposed to a true local recurrence. The second breast tumor is defined as a new primary if it is distinctly different from the original tumor with respect to histologic subtype, if it presents in a different location in the breast (???), or if it is of different clonality. The time interval between the original primary and the second tumor is generally considerably greater for new primaries compared with true recurrences.

17 Ipsilateral Breast Tumor Relapse (IBTR) Conclusions 10-year overall survival rates and distant disease-free survival rates tend to be much better for patients with new primaries compared with those with true recurrences. The diagnosis of a new primary as opposed to a true recurrence implies a different natural history and prognosis and has implications for therapeutic management. Unfortunately, most series addressing breast tumor recurrences do not adequately distinguish between the 2 entities.

18 BILATERAL BREAST CANCER Increase of bilateral mastectomy SEER registry: 1.8% in 1998 and 4.5% ( ). New York s Memorial Sloan Kettering Cancer Center: 6.7%-24% ( ). MD Anderson: 8%-14% ( ). Narod; Nat Rev Clin Oncol 2014

19 Hartman et al; J Clin Oncol 2007

20 BILATERAL BREAST CANCER Hormonal treatment Both tamoxifen and aromatase inhibitors substantially reduce the risk of contralateral breast cancer. A standard course (5 years) of tamoxifen is associated with a reduction of approximately 50% in the risk of contralateral breast cancer, and the decrease in risk lasts for at least 15 years. A similar or greater decrease in risk is observed in patients treated with an aromatase inhibitor. Most estimates of the reduction of contralateral risk are based on a standard course of tamoxifen treatment; however, shorter courses (2 years) might still provide adequate protection against a second primary breast cancer.

21 BILATERAL BREAST CANCER AGE Contralateral breast cancer occurs in 4% (2%-15%) of women with primary breast cancer (a risk 2 to 6 times higher than that of first breast cancer in general population). The annual risk of metachronous contralateral breast cancer in unselected breast cancer patients is %. The relative risk of metachronous bilateral breast cancer is particularly high in youngest patients (relative risk goes up from 5 to 23 in patients younger than 45, up to 50 - in those aged and up to in year-old population).

22 BILATERAL BREAST CANCER BRCA status Cumulative risk of contralateral breast cancer at 15 years in BRCA mutation carriers: 36% for women with a BRCA1 mutation 29% for women with a BRCA2 mutation Cumulative risk of contralateral breast cancer at 25 years in BRCA1 mutation carriers: 63% for women younger than 40 years 20% for women older than 50 years of age. Tamoxifen treatment reduces the risk of contralateral breast cancer: BRCA1 (HR: ) BRCA1 (HR: ) Narod; Nat Rev Clin Oncol 2014

23 BILATERAL BREAST CANCER Family history Women diagnosed with a first breast cancer by age 55 years and who had a mother or sister with bilateral breast cancer had a 10-year risk of contralateral breast cancer of 15.6%, about three times higher than expected. Reiner et al. ; J Clin Oncol 2013

24 A total of 11,247 patients diagnosed and treated with operable bilateral breast cancer (BBC) between June 2007 and December 2011: 161 (1.6%) sbbc (< 1 year after the diagnosis of the first BC) 235 (2.3%) mbbc (> 1year after the diagnosis of the first BC) Chen et al; PLoS One 2014

25 All women diagnosed with breast cancer in the Stockholm region patients, of whom 940 suffered CBC. Women with breast cancer had a doubled risk of CBC compared to the risk of breast cancer in the general female population. ER-positive breast cancer predicts an increased risk for CBC in general while an ER-negative first cancer specifically increases the risk for ER-negative CBC. The increased risk compared to the general population is further enhanced for young women and in particular for ER-negative CBC. The protective effect of adjuvant endocrine therapy for the first breast cancer is exclusively seen for the risk of ER-positive CBC, however also these treated women have a significantly higher risk of CBC than the risk of breast cancer for general female population. Sandberg et al.; PLoS One 2012

26 BILATERAL BREAST CANCER Prognosis Mortality from breast cancer after 10 year follow-up: Unilateral breast cancer: 33% Synchronous breast cancer: 45% Metachronous (diagnosed within 5 years): 56%. Metachronous (diagnosed after 10 years): 34%. Hartman et al; J Clin Oncol 2007

27 BILATERAL BREAST CANCER Benefit of bilateral mastectomy Theoretical considerations Assuming that the annual risk of contralateral cancer is 0.5%, and that 20% of women will die from the contralateral cancer within 10 years of its diagnosis, the expected reduction in 10-year mortality resulting from prevention of contralateral cancer is less than 1%. Even in carriers of BRCA1 mutations, in whom the annual risk of contralateral breast cancer is about 2%, the expected risk of contracting and dying of a contralateral cancer at 10 years is only about 2% To demonstrate a clinical benefit, a long follow-up period (20 years) is necessary, which will allow ample time to first develop a contralateral cancer and then to die from it. Narod; Nat Rev Clin Oncol 2014

28 BILATERAL BREAST CANCER Benefit of bilateral mastectomy Most studies reporting a reduction in mortality associated with contralateral mastectomy are limited by one or more biases : Observational studies were not randomized by stage. Contralateral mastectomy was not considered as a time-dependent variable (survivorship bias). Narod; Nat Rev Clin Oncol 2014

29 BILATERAL BREAST CANCER Conclusions The annual risk of contralateral breast cancer is 0.5%. This risk increases in younger women, those with family history of breast cancer, and those carrying BRCA mutations. The only histological feature that is an established risk factor for contralateral cancer is lobular histology, but even this association might be less strong for asynchronous cancers than for synchronous cancers. A statistically significant excess concordance exists for hormone receptor status and for HER2 status. Hormonal treatment reduces the risk of contralateral ER-positive breast cancer.

30 BILATERAL BREAST CANCER Conclusions Synchronous and metachronous (diagnosed within 5 years) bilateral breast cancer have worse prognosis than unilateral breast cancer. The benefit of prophylactic bilateral mastectomy is not well established. Very little is known about the molecular or cellular basis for susceptibility to bilateral cancer and explanations based on current risk factors are inadequate.