In-breast Event Research Articles

Limitations in the Application of Clinicopathologic Factors Alone in Predicting Radiation Benefit for Women with Low-Risk DCIS after Breast Conserving Surgery: The Impact of a 7-Gene Biosignature Based on 10-Year Ipsilateral Breast Recurrence (IBR) Rates

Most women diagnosed with ductal carcinoma in situ (DCIS) receive radiotherapy (RT) after breast conserving surgery (BCS); however, clinical trials show that over 70% of women with BCS alone will not have a recurrence and therefore not benefit from RT. Traditionally, clinicopathologic (CP) factors have been used to select for whom to de-escalate treatment, but prospective trials have failed to identify a low risk CP group that did not benefit from RT with respect to local control. This study assessed the re-classification of patients with low-risk CP into Risk groups defined by the 7-gene biosignature and compared to 10-yr IBR rates. Women (n = 926) from four international DCIS cohorts treated with BCS had formalin-fixed paraffin embedded tissue samples analyzed at a CLIA lab (Laguna Hills, CA). CP low-risk patients were identified using a) RTOG-9804-like criteria [Nuclear Grade 1 or 2 & Size ≤2.5 cm & non-Palpable & Screen Detected & margin negative (no-ink on tumor)] and b) MSKCC-like criteria [low-risk score<220, determined using nomogram weighted factors (excluding: number of re-excisions and RT treatment), and using no-ink-on-tumor instead of close margin]. The 7-gene DCIS biosignature combined biomarkers with CP factors (age, size, palpability, and margin status) using an algorithm reporting a Decision Score (DS) and Residual Risk subtype (RRt). Women with low-risk CP were classified into biosignature Low Risk (DS≤2.8, no RRt) or High Risk (DS>2.8 +/- RRt) groups. 10yr in-breast event (IBR) rates with and without RT were assessed by Kaplan-Meier rates and Cox proportional hazard analyses. Overall, 37% of all women were classified into the biosignature Low Risk group, while 51% and 34% were classified into CP low-risk groups (RTOG-9804-like, MSKCC-like, respectively). The biosignature Low Risk group (n = 338) had a 10-yr IBR risk of 5.6% after BCS and no significant RT benefit (absolute RT benefit = 0.8%, p = 0.70), 99% negative predictive value (NPV) for RT benefit. CP low-risk groups had 10-yr IBR rates of 12% and 8% after BCS without RT with absolute 6% (p = 0.04) and 4% (p = 0.1) IBR rate reductions with RT. The biosignature reclassified 51% and 63% of CP low-risk patients into the biosignature High Risk group. Importantly, these patients had higher IBR rates without RT (20% and 12%) and significant 13% (p = 0.005) and 8% (p = 0.01) absolute IBR rate reductions from RT. CP low-risk patients with concordant biosignature Low Risk demonstrated no significant RT benefit. The 7-gene predictive biosignature more reliably identified patients with low 10-yr IBR rates and no significant RT benefit than the traditional CP low-risk criteria (RTOG-9804-like, MSKCC-like). Importantly, those CP low-risk patients who were re-classified as biosignature High Risk had increased 10-year IBR rates and significant RT benefit.

Abstract P5-12-06: Non-adherence to endocrine therapy is associated with a significant increased risk of local recurrence in women ≥65 years with stage T1N0 breast cancer treated with adjuvant endocrine therapy alone after breast-conserving surgery

Abstract Purpose: Clinical guidelines recommend that for women ≥65 years with stage T1N0 breast cancer (BC) treated with breast-conserving surgery (BCS) that breast RT may be omitted and treatment with ET alone is acceptable. However, population-based studies report that up to two-thirds of women with T1N0 BC do not complete 5 years of ET. The effect of non-adherence to ET on recurrence risks in women treated with ET alone is unclear. We established a contemporary population-based cohort of women aged ≥65 years with stage T1N0, hormone receptor positive, breast cancer treated with single modality adjuvant ET or RT alone. We examined the effect of non-adherence in those treated with ET alone and compared the outcomes (ipsilateral LR, any breast event and any invasive in-breast event) of women who were non-adherent to those who were adherent to ET or those treated with RT alone. Methods: A population-based cohort of women diagnosed with T1N0 BC from 2010-2016, aged ≥65 years at diagnosis, treated with BCS and single modality adjuvant therapy with RT alone or ET alone was identified from the Ontario Cancer Registry. ER-/PR-, ER unknown/PR unknown, HER2+ cases and those without sentinel node biopsy or axillary dissection were excluded. Treatment and outcomes were ascertained using deterministic linkages of administrative databases. Receipt of adjuvant ET was identified using dispensing records from the Ontario Drug Benefit Claims database. Adherence percentage at any specific time was calculated by dividing the number of days dispensed (up to that time) by the number of days since diagnosis. This was updated every 3 months for each woman receiving ET. Adherence to ET was captured as a 3-level time-varying covariate (RT only, &amp;lt;80% ET adherence, ≥80% ET adherence). Patients were censored at the time of recurrence. Differences in recurrence risks were compared by Chi-square test. Multivariable Cox regression adjusted for age was used to evaluate risks of ipsilateral LR, any in-breast event (ipsilateral or contralateral, DCIS or invasive) and any first invasive in-breast recurrence. Results: The cohort includes 1551 women; 1054 women treated with BCS + adjuvant RT alone and 497 treated with BCS + adjuvant ET alone. The median follow-up time was 5 years. Almost half (45.7%) of cases prescribed ET alone were &amp;lt;80% adherent. For those who were followed for 5 years, 35% of follow-up time was spent non-adherent to ET. The 5-year risk of LR was 5.8% in patients treated with ET alone who spent &amp;lt;80% of time adherent to ET, 0.4% in patients treated with ET alone who were &amp;gt;80% adherent and 0.9% in those treated with RT alone (p&amp;lt;.001). The 5-year risk of any in-breast event was 6.6% in women &amp;lt;80% adherent, 0.7% in those adherent to ET and 3.2% in those treated with RT alone (p=.001). Women treated with ET alone who were &amp;lt;80% adherent during their follow-up time had a 5-fold increased risk of LR (HR=4.93, 95%CI: 2.13, 11.42, p=0.0002), a 1.6 fold increased risk of any breast event (HR=1.65, 95% CI: 0.89, 3.07, p=0.11) and a 1.6 fold increased risk (HR=1.68, 95% CI: 0.87, 3.25, p=0.13) of any invasive in-breast event compared to those treated with either RT alone or compared to those who were &amp;gt;80% adherent to ET. There was no significant difference in outcomes between those treated with ET who were &amp;gt;80% adherent during their follow-up time and those treated with RT alone. Conclusions: Almost half of women older than 65 years with stage T1N0 breast cancer treated with breast-conserving surgery and adjuvant ET alone are &amp;lt;80% adherent to ET. Non-adherence to ET is associated with higher risks of local recurrence compared to those treated with adjuvant RT alone. Adjuvant approaches incorporating RT may be preferable to ET alone. Citation Format: Mira Goldberg, Rinku Sutradhar, Lawrence Paszat, Timothy Whelan, Sumei Gu, Cindy Fong, Eileen Rakovitch. Non-adherence to endocrine therapy is associated with a significant increased risk of local recurrence in women ≥65 years with stage T1N0 breast cancer treated with adjuvant endocrine therapy alone after breast-conserving surgery [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-12-06.

Abstract P2-18-01: Single modality adjuvant therapy with radiation (RT) alone or endocrine therapy (ET) alone in women ≥65 years with early stage, hormone receptor positive breast cancer treated with breast-conserving surgery: A population-based analysis

Abstract Purpose: Current guidelines recommend for women (≥65 years at diagnosis) with early stage (T1N0), hormone receptor (HR+) breast cancer (BC) treated with breast-conserving surgery (BCS) that treatment with 5 years of endocrine therapy (ET) alone with omission of radiation (RT) is acceptable. Population studies however report that many women continue to receive RT. The use of RT may reflect preferences due to the convenience of modern RT and/or concerns of the adverse effects of ET. Adjuvant treatment with RT alone may be an attractive option, but further data on the outcomes and morbidity following mono adjuvant therapy with either RT alone or ET alone is needed. We established a contemporary population-based cohort of women ≥65 years with HR+ T1N0 BC treated by BCS. We report the risk of local recurrence, any secondary breast events and adverse treatment-related effects following single modality adjuvant therapy with RT or ET alone. Methods: We identified all women aged ≥65 years at diagnosis with HR+ T1N0 BC diagnosed in Ontario from 2010-2016, treated with BCS and adjuvant RT alone or ET alone (tamoxifen or aromatase inhibitors (AI)). The administration of ET was ascertained from the Ontario Drug Benefit database. Cases were coded as having received either tamoxifen or AI according to the first prescription. Cases with Her2+ BC or those who did not undergo nodal surgery were excluded. Outcomes were ascertained using deterministic linkages of administrative databases. Propensity-weighted scores (PS) were calculated using baseline factors (diagnosis year, age, Charlson comorbidity score, nodal surgery type, grade, socioeconomic status, HR category). Kaplan Meier curves and PS-adjusted multivariable Cox regression were used to evaluate risks of ipsilateral LR, any in-breast event (ipsilateral or contralateral), and adverse treatment-related outcomes (venous thromboembolism (VTE), osteoporotic fracture, vaginal bleeding requiring hysteroscopy or curettage, ischemic heart events, second malignancy. Results: The cohort includes 1054 that received BCS + adjuvant RT and 497 that received BCS + adjuvant ET alone (N= 201 tamoxifen; N=296 AI). Median follow-up time was 5 years. LR occurred in 0.9% (n=10) after RT alone and 2.8% (n=14) after ET alone (p=0.005). Rates of any in-breast event were 3.2% and 3.4%, respectively (p=0.8). Adjusting for PS, treatment with ET alone was associated with an increased risk of LR (HR= 2.79, 95% CI: 1.20, 6.49, p=0.02), no difference in the risk of any in-breast event (HR=0.96, 95% CI: 0.53, 1.77, p=0.9) and a higher risk of VTE (HR=1.8, 95% CI: 1.0, 3.2, p=.05) compared to those treated with RT alone. Women treated with tamoxifen alone had a 5-fold increased risk of vaginal bleeding (HR=4.7, 95%CI: 2.2, 10.0, p&amp;lt;0.0001) and a 2-fold increased risk of VTE (HR=1.9, 95% CI: 0.97, 3.75, p=0.06) compared to those treated with AI alone or RT alone. There were no significant differences in the risks of any or osteoporotic fracture, ischemic heart events, or second malignancies across treatment groups (Table 1). Conclusions: Women ≥65 years with HR+ EBC treated with single modality adjuvant therapy with RT or ET alone experience low risks of recurrence and morbidity. In this population-based study, RT alone compared to ET alone was associated with a lower risk of LR and less adverse events. Table 1. 5-year rates of adverse eventp-valueAny Fracture0.3• RT only11.9• tamoxifen9.5• aromatase inhibitor13.3Osteoporotic Fracture0.1• RT only5.8• tamoxifen2.8• aromatase inhibitor7.3Hysteroscopy/Curettage&amp;lt;.0001• RT only2.1• tamoxifen7.9• aromatase inhibitor0.5Thrombosis/Pulmonary Embolism0.1• RT only3.2• tamoxifen6.2• aromatase inhibitor3.8Ischemic Heart Disease0.3• RT only4.5• tamoxifen1.4• aromatase inhibitor4.2Other Cancer0.7• RT only6.7• tamoxifen7.7• aromatase inhibitor6.4 Citation Format: Mira Goldberg, Rinku Sutradhar, Lawrence Paszat, Timothy Whelan, Sumei Gu, Cindy Fong, Eileen Rakovitch. Single modality adjuvant therapy with radiation (RT) alone or endocrine therapy (ET) alone in women ≥65 years with early stage, hormone receptor positive breast cancer treated with breast-conserving surgery: A population-based analysis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-18-01.

Patterns of adjuvant care and outcomes of elderly women with stage I breast cancer after breast-conserving surgery: a population-based analysis.

Randomized trials studying endocrine therapy (ET) with and without radiation therapy (RT) following breast-conserving surgery (BCS) have detected differences in local recurrence (LR) but not survival among elderly women with hormone receptor positive stage I breast cancer (BC). We assembled a population-based cohort of such women to examine the use and outcomes associated with or without the administration of adjuvant radiotherapy (RT) or ET. Women aged ≥ 65years with stage I BC treated with BCS in Ontario between 2010 and 2016, their treatments and outcomes were ascertained using deterministic linkages of administrative databases. Multivariable Cox regression models were used to evaluate risks of ipsilateral LR and of any first in-breast event, categorizing women by their treatment. 5076 women were treated with BCS followed by RT + ET (n = 1964), RT alone (n = 1325), ET alone (n = 719), or no adjuvant treatment (n = 1068). Median follow-up was 5years. LR occurred in 0.9% after adjuvant RT + ET, 1.4% after RT alone, 3.1% after ET alone, and 9.4% after BCS alone (p < 0.001). The adjusted risk of LR was increased in those who received no adjuvant therapy (HR = 13.43, CI: 7.89, 22.85), or ET alone (HR = 4.03, CI: 2.14, 7.59). The adjusted risk of any first in-breast event was greatest among those without any adjuvant therapy (HR = 7.61, 95%CI: 5.21, 11.11, p < 0.0001). Absolute and adjusted risks of any first in-breast event were comparable between those with ET alone (HR = 2.09, 95%CI: 1.27, 3.43, p = 0.0038) and those with RT alone (HR = 1.91, 95% CI: 1.25, 2.91, p = 0.0028). Older women with stage I BC who receive no adjuvant therapy have a significant absolute risk of LR and any first in-breast event, whereas the absolute risk of these events among those with either RT alone or ET alone is only slightly higher than among those treated with both.

Utility of Clinical Breast Examinations in Detecting Local-Regional Breast Events After Breast-Conservation in Women with a Personal History of High-Risk Breast Cancer.

Although breast cancer follow-up guidelines emphasize the importance of clinical examinations, prior studies suggest a small fraction of local-regional events occurring after breast conservation are detected by examination alone. Our objective was to examine how local-regional events are detected in a contemporary, national cohort of high-risk breast cancer survivors. A stage-stratified sample of stage II/III breast cancer patients diagnosed in 2006-2007 (n=11,099) were identified from 1217 facilities within the National Cancer Data Base. Additional data on local-regional and distant breast events, method of event detection, imaging received, and mortality were collected. We further limited the cohort to patients with breast conservation (n=4854). Summary statistics describe local-regional event rates and detection method. Local-regional events were detected in 5.5% (n=265) of patients. Eighty-three percent were ipsilateral or contralateral in-breast events, and 17% occurred within ipsilateral lymph nodes. Forty-eight percent of local-regional events were detected on asymptomatic breast imaging, 29% by patients, and 10% on clinical examination. Overall, 0.5% of the 4854 patients had a local-regional event detected on examination. Examinations detected a higher proportion of lymph node events (8/45) compared with in-breast events (18/220). No factors were associated with method of event detection. Clinical examinations, as an adjunct to screening mammography, have a modest effect on local-regional event detection. This contradicts current belief that examinations are a critical adjunct to mammographic screening. These findings can help to streamline follow-up care, potentially improving follow-up efficiency and quality.

Abstract P6-13-06: Tamoxifen acceptance by DCIS patients and effect on subsequent ipsilateral and contralateral breast events

Abstract Introduction: Existing data demonstrate that the use of endocrine therapy decreases the risk of in-breast recurrence and contralateral new primary cancers. However, the acceptance of tamoxifen is relatively low in women with DCIS, with reported acceptance rates ranging from 32% to 67%. We reported 67% tamoxifen acceptance in 2005 (Nakhlis F, JACS, p688); we now re-examine this question to assess the impact of patient and tumor characteristics, and the use of tamoxifen, on new breast events in women with DCIS undergoing breast conserving therapy (BCT) or mastectomy. Methods: We conducted a retrospective review using a prospective database; 695 patients with DCIS were identified between 1998 and 2009. Patient and tumor characteristics included age, tumor grade, tumor size, margin status, re-excision status, use of BCT, adjuvant radiation therapy (RT) and tamoxifen therapy. Women undergoing bilateral mastectomy were excluded for analysis of in-breast events. The demographic data were examined for differences in continuous variables using the Wilcoxon rank sum test, and differences in categorical variables between groups were assessed using Fisher’s exact test. Multivariate odds ratios were obtained using logistic regression. Results: The mean age of the patient population was 61.5 ± 11.4 (median and range: 61 (30-99). 44.9% of patients were over the age of 50. The median follow up time was 60 months. Among the BCT group, 58.5% of 348 women with ER+ DCIS accepted tamoxifen therapy, compared to 50.7% of 71 mastectomy patients with ER+ DCIS. 188 women (27.1%) underwent mastectomy (122 unilateral and 66 bilateral); 507 (72.9%) received BCT. Among all women with complete radiation and tamoxifen data, the number of new events was 88 (16.9%). Of these, 8 (1.5%) were in the mastectomy group, and 80 (17.9%) in the BCT group (p=0.0007). Ipsilateral events occurred in 1/99 (1%) woman undergoing mastectomy. In the BCT group complete radiation and tamoxifen data were available on 448 women, of whom 54 (12%) experienced ipsilateral events (p&amp;lt;0.0001). The multivariate odds ratio (OR) for ipsilateral breast events in the BCT group receiving RT+ surgery, was 0.66 (95%CI 0.25-1.71); among those receiving tamoxifen + surgery it was 0.65 (95% CI 0.20-2.1) and for the combination of RT, tamoxifen, and surgery it was 0.23 (95% CI 0.08-0.65, p=0.006). In a model that included these treatment parameters, patient age, DCIS size and grade were non-significant whereas the presence of free margins was highly significant (OR 0.27, 95%CI 0.10-0.71, p=0.008). Overall, 29% of new breast events were invasive. Contralateral events occurred in 14/467 women (3%) of BCT and mastectomy patients with hormone receptor positive DCIS, but eight of these were non-compliant. Conclusions: The use of optimal DCIS therapy (complete excision, RT, tamoxifen) decreased the odds of ipsilateral breast events by 73%, whereas RT alone or tamoxifen alone in addition to surgery were less effective. Despite relatively high acceptance of tamoxifen, lack of compliance remains an issue and will be further examined. Citation Format: Anna M Higham, Irene B Helenowski, Shruti R Zaveri, Daniel H Schneider, Nora M Hansen, Kevin P Bethke, Seema A Khan. Tamoxifen acceptance by DCIS patients and effect on subsequent ipsilateral and contralateral breast events [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-13-06.

Abstract P1-01-05: Effects of preoperative MRI on rate of ipsilateral and contralateral recurrence of breast cancer

Abstract Introduction: Preoperative MRI of the breast is the most sensitive imaging modality in the detection of multifocal or multicentric breast cancer, as well as simultaneous contralateral breast cancer. The aim of this retrospective review was to evaluate the effect of preoperative MRI on local control for patients with breast cancer. Methods: The Enterprise Data Warehouse of Northwestern Medicine was searched for women who underwent breast conserving surgery for ductal carcinoma in situ (DCIS) or primary invasive breast cancer in the interval of 2004-2010. The use of preoperative MRI, and the clinical and therapeutic details of the patients thus identified were extracted by direct review of the electronic medical record. A breast event was defined as a local recurrence in the treated breast more than six months after completion of treatment (ipsilateral) or a new breast cancer in the untreated breast (contralateral). Differences in the frequency of all events (local and distant), for ipsilateral breast events, and for contralateral breast events was evaluated with Cox proportional hazards model, adjusting for patient age, tumor size, nodal status, the presence of triple negative disease, and the use of radiotherapy and systemic therapy. Results: In our cohort of 1097 patients, 526 had preoperative MRI and 571 had no MRI. The patients who had preoperative MRI were younger (59 vs. 66 years, p&amp;lt;0.0001), were more commonly premenopausal (37.8% vs. 27.3%, p=0.0004), were more likely to present with palpable tumors (34.8% vs. 26.6%, p=0.004), were more likely to have invasive lobular disease (16% vs. 11.6%), and less likely to have DCIS (16.5% vs. 29%, p=0.001 for differences in histologic pattern). Mean tumor size was equivalent in the two groups (17.5 and 17.3 mm), but nodes were more frequently positive in the MRI group (23.9% vs. 19.1%, p=0.045). Triple negative tumors were more frequent in the MRI group (14.1% vs. 7.5%, p=0.0003). Mean follow up was 51.5 months in the MRI group and 59.4 months in the no MRI (p&amp;lt;0.0001). The number of events was 49 in the MRI group and 68 in the no MRI group. The Cox hazard ratio (HR) for all events (adjusted for follow-up duration and factors described in the Methods) was equivalent between the two groups (HR 0.90, 95% CI 0.59-1.36, p=0.61). The HR for ipsilateral (HR 0.93, 95% CI 0.57-1.51, p=0.76) and contralateral events (HR 1.22, 95% CI 0.57-2.62, p=0.61) was equivalent between the two groups. Conclusions: In analyses adjusted for important prognostic features, the use of preoperative breast MRI was not associated with a reduced hazard of any breast cancer event, or of in-breast events (ipsilateral or contralateral). However, the MRI group had a more adverse tumor and patient profiles; a propensity score analysis will be performed, to further adjust for these differences. These findings add weight to the position that routine use of preoperative MRI for all breast cancer patients is not beneficial. Citation Format: Amanda L Amin, Irene B Helenowski, Thomas E Kmiecik, Shruti R Zaveri, Nora M Hansen, Kevin P Bethke, Seema A Khan. Effects of preoperative MRI on rate of ipsilateral and contralateral recurrence of breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-01-05.

Ductal Carcinoma In Situ: A Rose by Any Other Name

Ductal Carcinoma In Situ: A Rose by Any Other Name

Does the Oncotype DCIS score impact treatment decisions?

91 Background: The Oncotype Dx DCIS Score has been developed and validated for risk recurrence in ductal carcinoma in situ. It is a 12 gene assay performed on an individual patient’s tumor. The results give information about the 10 year risk of any in-breast event and the 10 year risk of an invasive breast cancer. The clinical validation study was based on patients enrolled in ECOG 5194. The purpose of our study was to evaluate the impact of the DCIS Score on recommendations for adjuvant radiation therapy. Methods: In this IRB approved study, 27 patients at our institution underwent evaluation with the DCIS Score from April 2012 to February 2013. All patients had specimens submitted for DCIS Scores. 14 patients had margins of 3 mm or greater. 12 patients had margins of 1 mm to 2.5 mm, and 1 patient had margins that were less than 1 mm from the DCIS. The mean age was 56.8 years, with a range of 40-79 years old. The DCIS Score is reported on a scale of 0-100. All patients underwent consultation with radiation oncology. The radiation oncologists formulated their preliminary recommendation prior to reviewing the patients’ DCIS Scores. The final recommendation for radiation treatment was rendered after reviewing the DCIS Score. We then compared the pre-DCIS Score and post-DCIS score treatment recommendations. Results: 21 patients (78%) were advised to have adjuvant radiation therapy. 6 patients (22%) were advised not to undergo adjuvant radiation based on their clinical and pathologic features. Although the DCIS Score did not change treatment recommendations for any patient in this study group, it did confirm initial treatment recommendations. For the patients who were advised not to have radiation, their DCIS Scores were 0-31. Conclusions: The DCIS Score is a validated tool to assess the local risk of recurrence for ductal carcinoma in situ. In our study population, the results of the DCIS Score did not alter treatment in any patient. It is important to note that in the 6 patients who were advised not to have radiation, the low DCIS Score confirmed the radiation oncologist’s perceived low risk of recurrence. In order to increase confidence in results of the DCIS Score, further studies need to be performed.

E10. Issues around hereditary breast cancer and local treatment

Women with inherited germline BRCA1 (familial breast/ ovarian cancer gene 1) or BRCA2 (BRCA1/2) mutations have approximately a 55−85% cumulative risk of developing breast cancer by the age of 70. Knowledge of expected outcomes for BRCA1/2 mutation carriers following various breast cancer treatments is needed for decision-making [1,2]. The treatment goals for a woman with a BRCA-associated breast cancer should be to prevent recurrence of the initial cancer and to prevent second primary breast and ovarian cancers. Riskreduction interventions for BRCA-related breast cancer are relevant not only for clinical decisions in breast cancer patients but also for healthy subjects who are potential candidates for undergoing similar interventions. The literature on the impact of different surgical options and adjuvant systemic approaches aimed towards risk reduction for recurrences of ipsilateral and contralateral breast cancer will be reviewed. Breast-conserving therapy (BCT), defined as surgical excision and radiotherapy (RT), has been shown in multiple trials to result in comparable rates of tumour control and survival as mastectomy in women with sporadic early-stage disease. There are only limited data comparing outcomes following BCT versus mastectomy exclusively in women with known BRCA1/2 mutations. Estimates of local recurrence and contralateral new breast cancers following BCT compared with mastectomy could aid in surgical decision-making in a BRCA1/2 mutation carrier newly diagnosed with breast cancer. Pierce et al. [3] compared the clinical outcomes in women with BRCA1/2 mutations treated with BCT to outcomes in similarly staged BRCA1/2 mutation carriers treated with mastectomy. This study included 655 patients with BRCA1/2 mutations, and had a median follow-up of 8.2 years for BCT and 8.9 years for mastectomy. BRCA1/2 mutation carriers with breast cancer have similar survival rates whether treated with mastectomy or BCT. However, women undergoing BCT have an elevated risk of a second in-breast event that is significantly reduced with chemotherapy. Contralateral breast cancer events are very common. From this study we can conclude that breast-conserving surgery is associated with a higher probability of local recurrence, but is counterbalanced by effectiveness of chemotherapy in reducing this risk. Consistent support for the hypothesis that anti-oestrogens are effective in reducing contralateral breast cancer risks is available from the literature. On the other hand, data on chemoprevention approaches for healthy subjects are too preliminary to draw any conclusions from. Studies including conventional and newer hormonal drugs are needed to demonstrate the benefit of chemoprevention approaches. These may also deepen our knowledge on possible differences in the likelihood of clinical benefit to be expected among BRCA1/2-altered tumours. Assessment of long-term risks of ipsilateral [4] and both ipsilateral and contralateral [5] breast cancer have been studied. These studies led to the conclusion that patients with germline mutations have high risks for second primary tumours, although local recurrence rates were not statistically different. The rate of contralateral breast cancer is significantly higher in mutation carriers, which is why prophylactic surgery of the contralateral breast is a treatment option that needs to be discussed with the patient. Kirova et al. [6,7] investigated, after long-term follow-up, whether mutation status influenced the rate of ipsilateral and contralateral breast cancers after BCT. BRCA1 and BRCA2 genes were screened for germline mutations in 131 patients with a family history of breast and/or ovarian cancer who had undergone

Local therapy in BRCA1 and BRCA2 mutation carriers with operable breast cancer: comparison of breast conservation and mastectomy

Women with BRCA1 and BRCA2 mutations have an elevated risk of breast cancer and ovarian cancer, but also of developing second primary breast cancer. BRCA1/2 mutation carriers with breast cancer must choose between breast conservation (BCT) and mastectomy (M) yet data on outcomes are limited. The purpose of this study is to compare long-term outcome following BCT and M in BRCA1/2 carriers. 655 women with BRCA1/2 mutations diagnosed with breast cancer and treated with BCT (n = 302) or M (n = 353) were identified and underwent follow-up to assess local, regional, and systemic recurrence. Local failure as first failure was significantly more likely in those treated with BCT compared to M, with a cumulative estimated risk of 23.5 vs. 5.5%, respectively, at 15 years (P < 0.0001); 15-year estimates in carriers treated with BCT and chemotherapy was 11.9% (P = 0.08 when compared to M). Most events appeared to be second primary cancers rather than failure to control the primary tumor. The risk of contralateral breast cancer was high in all groups, exceeding 40%, but was not statistically significantly different by use of adjuvant radiotherapy (RT) or not, suggesting no added risk from scatter RT at 10 and 15 years. There were no differences seen in regional or systemic recurrences between the BCT and M groups, and no difference in overall survival. In conclusion, BRCA1/2 mutation carriers with breast cancer have similar survival whether treated with M or BCT. However, women undergoing BCT have an elevated risk of a second in-breast event that is significantly reduced in the presence of chemotherapy. Contralateral breast cancer events are very common.

Isolated ipsilateral in-breast event after breast conservation therapy does not affect survival: An analysis of the NCI randomized trial

Isolated ipsilateral in-breast event after breast conservation therapy does not affect survival: An analysis of the NCI randomized trial

Isolated ipsilateral in-breast event after breast conservation therapy does not affect survival: An analysis of the NCI randomized trial

Materials/Methods: After informed consent, the National Cancer Institute (NCI) randomized 237 evaluable women with early stage breast cancer to undergo modified radical mastectomy (MT) or breast conservation therapy (BCT), which was comprised of lumpectomy, axillary lymph node dissection and radiation therapy. The records of the patients in the BCT arm who experienced an isolated ipsilateral in-breast event were reviewed to determine survival after the event using Kaplan-Meier estimates, log-rank tests and time-dependent covariate Cox models.

Diagnosis and management of ductal carcinoma in situ.

Ductal carcinoma in situ (DCIS) is a preinvasive form of breast cancer that has increased in incidence over the past 25 years, primarily as a result of mammographically detected microcalcifications. Inadequately treated DCIS carries a risk for evolving into the malignant phenotype; however, the magnitude and timeline for this risk are poorly defined. Treatment options include lumpectomy with or without breast irradiation and mastectomy. The overall survival rate is 96% to 98% with any of these strategies, but the risk of local recurrence (LR) is highest after lumpectomy alone. Breast irradiation can reduce this risk from levels in excess of 40% to 10% over a 10-year follow-up period. Approximately 50% of all LR from DCIS are invasive lesions. Therefore, the occurrence of a LR after breast-conserving therapy is a potentially greater threat to the patient with DCIS compared to the patient diagnosed with invasive cancer. In patients diagnosed with invasive cancer, the risk of micrometastatic disease is present from the time of initial diagnosis. In patients with DCIS, the expectation is that a potentially 100% cure rate should be achieved with local therapy alone. Although most DCIS cases complicated by LR will be successfully salvaged with prolonged overall survival, it is critically important to take every precaution that will minimize the risk of locally recurrent disease. Therefore, radiation therapy as an adjunct to lumpectomy is essential. A subset of patients with DCIS with low-volume low-grade disease who can be safely treated by lumpectomy alone has not yet been clearly defined. Prospective studies designed to identify this category are ongoing. Inadequate margin control is the most consistent risk factor for LR that has been reported thus far, but there is no universally accepted definition for what constitutes an optimal negative margin distance. Young age at diagnosis, high nuclear grade, and comedonecrosis are other factors that have been implicated as increasing the risk for LR. Tamoxifen can further decrease the rate of new in-breast events on the affected side and in the contralateral breast. Ongoing trials will also define the role of aromatase inhibitors as a risk-reducing strategy.