National Surgical Adjuvant Breast Research Articles

Estrogen Receptor (ESR1) mRNA Expression and Benefit From Tamoxifen in the Treatment and Prevention of Estrogen Receptor–Positive Breast Cancer

Several mechanisms have been proposed to explain tamoxifen resistance of estrogen receptor (ER) -positive tumors, but a clinically useful explanation for such resistance has not been described. Because the ER is the treatment target for tamoxifen, a linear association between ER expression levels and the degree of benefit from tamoxifen might be expected. However, such an association has never been demonstrated with conventional clinical ER assays, and the ER is currently used clinically as a dichotomous marker. We used gene expression profiling and ER protein assays to help elucidate molecular mechanism(s) responsible for tamoxifen resistance in breast tumors. We performed gene expression profiling of paraffin-embedded tumors from National Surgical Adjuvant Breast and Bowel Project (NSABP) trials that tested the worth of tamoxifen as an adjuvant systemic therapy (B-14) and as a preventive agent (P-1). This was a retrospective subset analysis based on available materials. In B-14, ESR1 was the strongest linear predictor of tamoxifen benefit among 16 genes examined, including PGR and ERBB2. On the basis of these data, we hypothesized that, in the P-1 trial, a lower level of ESR1 mRNA in the tamoxifen arm was the main difference between the two study arms. Only ESR1 was downregulated by more than two-fold in ER-positive cancer events in the tamoxifen arm (P < .001). Tamoxifen did not prevent ER-positive tumors with low levels of ESR1 expression. These data suggest that low-level expression of ESR1 is a determinant of tamoxifen resistance in ER-positive breast cancer. Strategies should be developed to identify, treat, and prevent such tumors.

Impact of Lymph Node Status on Clinical Outcomes After Accelerated Partial Breast Irradiation

To compare outcomes after accelerated partial breast irradiation (APBI) between node-negative and node-positive patients. A total of 534 patients with early-stage breast cancer received APBI including 39 node-positive (N+) cases. Clinical, pathologic, and treatment-related factors were compared between node-negative (N-) and N+ cohorts. Local recurrence (LR), regional recurrence (RR), axillary failure (AF), distant metastases (DM), disease-free survival (DFS), cause-specific survival (CSS), and overall survival (OS) were analyzed. N+ patients were younger (p = 0.04), had larger tumors (p < 0.001), and were more likely to receive chemotherapy (p < 0.001). Mean follow-up was 7.8 years for N+ patients and 6.3 years for N- patients (p = 0.06). No differences were seen in 5-year actuarial rates of LR (2.2% vs. 2.6%, p = 0.86), AF (0% vs. 0%, p = 0.69), DFS (90.0% vs. 88.0%, p = 0.79), or OS (91.0 vs. 84.0%, p = 0.65) between the two groups, whereas higher rates of RR (0% vs. 6.1%, p < 0.001) and DM (2.2% vs. 8.9%, p = 0.005) were noted in N+ patients. A trend for improved CSS (p = 0.06), was seen in N- patients. Age, tumor size, receptor status, T-stage, chemotherapy, APBI technique, and nodal status (p = 0.86) were not associated with LR, while a trend for an association with LR was noted with close/positive margins, (p = 0.07), and failure to receive adjuvant hormonal therapy (p = 0.06). No differences were seen in the rates of LR or AF between N- and N+ patients after APBI. These results support the continued enrollment of node-positive patients in Phase III trials evaluating the efficacy of APBI including the National Surgical Adjuvant Breast and Bowel Project-B39/Radiation Therapy Oncology Group 0413.

Cigarette Smoking, Obesity, Physical Activity, and Alcohol Use As Predictors of Chemoprevention Adherence in the National Surgical Adjuvant Breast and Bowel Project P-1 Breast Cancer Prevention Trial

The double-blind, prospective, National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial (BCPT) showed a 50% reduction in the risk of breast cancer for tamoxifen versus placebo, yet many women at risk of breast cancer do not adhere to the 5-year course. This first report of the rich BCPT drug adherence data examines predictors of adherence. Between June, 1992 and September, 1997 13,338 women at high risk of breast cancer were randomly assigned to 20 mg/d tamoxifen versus placebo; we analyzed the 11,064 enrolled more than 3 years before trial unblinding. Primary endpoint was full drug adherence (100% of assigned pills per staff report, excluding protocol-required discontinuation) at 1 and 36 months; secondary was adequate adherence (76%-100%). Protocol-specified multivariable logistic regression tested lifestyle factors, controlling for demographic and medical predictors. About 13% were current smokers; 60% were overweight/obese; 46% had moderate/heavy physical activity; 21%, 66%, 13% drank 0, 0-1, 1+ drinks per day, respectively; 91% were adequately adherent at 1 month; and 79% were at 3 years. Alcohol use was associated with reduced full adherence at 1 month (P = 0.016; OR = 0.79 1+ vs. 0), as was college education (P <0.001; OR = 0.78 vs. high school); age (P < 0.001; OR = 1.4 age 60+) and per capita household annual income (P < 0.001; OR = 1.2 per $30,000) with increased adherence. Current smoking (P = 0.003; OR = 0.75), age (P = 0.024, OR = 1.1), college education (P = 0.037; OR = 1.4), tamoxifen assignment (P = 0.031; OR = 0.84), and breast cancer risk (P <.001; OR = 1.5 high vs. low) predicted adequate adherence at 36 months. There were no significant associations with obesity or physical activity. Alcohol use and smoking might indicate a need for greater adherence support.

Four-Year Follow-Up of Trastuzumab Plus Adjuvant Chemotherapy for Operable Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: Joint Analysis of Data From NCCTG N9831 and NSABP B-31

Trastuzumab is a humanized monoclonal antibody against the human epidermal growth factor receptor 2 (HER2). The clinical benefits of adjuvant trastuzumab have been demonstrated in interim analyses of four large trials. Initial data of the combined analysis of the North Central Cancer Treatment Group (NCCTG) N9831 Intergroup trial and National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial were reported in 2005. Long-term follow-up results on disease-free survival (DFS) and overall survival (OS) have been awaited. Patients with HER2-positive operable breast cancer were randomly assigned to doxorubicin plus cyclophosphamide followed by paclitaxel with or without trastuzumab in the NCCTG N9831 and NSABP B-31 trials. The similar design of both trials allowed data from the control and trastuzumab-containing arms to be combined in a joint analysis. At 3.9 years of median follow-up, there continues to be a highly statistically significant reduction in DFS event rate in favor of the trastuzumab-containing arm (P < .001). Similarly, there continues to be a statistically significant 39% reduction in death rate in favor of the trastuzumab-containing arm (P < .001). These data demonstrate consistent DFS and OS advantages of adjuvant trastuzumab over time, with the longest follow-up reported to date. The clinical benefits continue to outweigh the risks of adverse effects.

Do All Patients with Breast Cancer Require Systemic Adjuvant Therapy?

Do All Patients with Breast Cancer Require Systemic Adjuvant Therapy?

Oxaliplatin As Adjuvant Therapy for Colon Cancer: Updated Results of NSABP C-07 Trial, Including Survival and Subset Analyses

The National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 trial demonstrated that the addition of oxaliplatin to fluorouracil plus leucovorin (FULV) improved disease-free survival (DFS) in patients with stage II or III colon cancer. This analysis is the first publication of overall survival (OS) for the NSABP C-07 study. We updated DFS and examined both end points in clinically relevant patient subsets. Other studies have identified patients age 70 or older and those with stage II disease as patient subsets in which oxaliplatin may not be effective. We investigated toxicity as a driver of divergent outcomes in these subsets. In all, 2,409 eligible patients with follow-up were randomly assigned to either FULV (FU 500 mg/m(2) by intravenous [IV] bolus weekly for 6 weeks; leucovorin 500 mg/m(2) IV weekly for 6 weeks of each 8-week cycle for three cycles) or FLOX (FULV plus oxaliplatin 85 mg/m(2) IV on days 1, 15, and 29 of each cycle). With 8 years median follow-up, OS was similar between treatment groups (hazard ratio [HR], 0.88; 95% CI, 0.75 to 1.02; P = .08). FLOX remained superior for DFS (HR, 0.82; 95% CI, 0.72 to 0.93; P = .002). The effect of oxaliplatin on OS did not differ by stage of disease (interaction P = .38 for OS; interaction P = 0.37 for DFS) but did vary by age for OS (younger than age 70 v 70+ interaction P = .039). There was a similar trend for DFS (interaction P = .073). Oxaliplatin significantly improved OS in patients younger than age 70 (HR, 0.80; 95% CI, 0.68 to 0.95; P = .013), but no positive effect was evident in older patients. Overall, the addition of oxaliplatin to FULV has not been proven to extend OS in this trial, but the DFS effect remained strong. Unplanned subset analyses suggest a significant OS effect of oxaliplatin in patients younger than age 70.

Radiation Therapy Oncology Group 0247: A Randomized Phase II Study of Neoadjuvant Capecitabine and Irinotecan or Capecitabine and Oxaliplatin With Concurrent Radiotherapy for Patients With Locally Advanced Rectal Cancer

To evaluate the rate of pathologic complete response (pCR) and the toxicity of two neoadjuvant chemoradiotherapy (chemoRT) regimens for Stage T3-T4 rectal cancer in a randomized Phase II study. Patients with Stage T3 or T4 rectal cancer of <12 cm from the anal verge were randomized to preoperative RT (50.4 Gy in 1.8-Gy fractions) with concurrent capecitabine (1,200 mg/m(2)/d Mondays through Friday) and irinotecan (50 mg/m(2) weekly in four doses) (Arm 1) or concurrent capecitabine (1,650 mg/m(2)/d Monday through Friday) and oxaliplatin (50 mg/m(2) weekly in five doses) (Arm 2). Surgery was performed 4-8 weeks after chemoRT, and adjuvant chemotherapy 4-6 weeks after surgery. The primary endpoint was the pCR rate, requiring 48 evaluable patients per arm. A total of 146 patients were enrolled. The protocol chemotherapy was modified because of excessive gastrointestinal toxicity after treatment of 35 patients; 96 were assessed for the primary endpoint-the final regimen described above. The patient characteristics were similar for both arms. After chemoRT, the rate of tumor downstaging was 52% and 60% and the rate of nodal downstaging (excluding N0 patients) was 46% and 40%, for Arms 1 and 2, respectively. The pCR rate for Arm 1 was 10% and for Arm 2 was 21%. For Arm 1 and 2, the preoperative chemoRT rate of Grade 3-4 hematologic toxicity was 9% and 4% and the rate of Grade 3-4 nonhematologic toxicity was 26% and 27%, respectively. Preoperative chemoRT with capecitabine plus oxaliplatin for distal rectal cancer has significant clinical activity (10 of 48 pCRs) and acceptable toxicity. This regimen is currently being evaluated in a Phase III randomized trial (National Surgical Adjuvant Breast and Bowel Project R04).

Adjuvant Chemotherapy in Colon Cancer: Ageism or Appropriate Care?

Adjuvant Chemotherapy in Colon Cancer: Ageism or Appropriate Care?

Role of Science in the Treatment of Breast Cancer When Tumor Multicentricity is Present

During the past 100 years, there have been two major controversies with regard to the treatment of primary breast cancer. The first controversy, which occurred approximately 35 years ago, questioned the performance of radical mastectomy, as originally proposed by Halsted in the 1890s. That controversy was resolved by the use of laboratory and clinical research, hypothesis formulation, and evaluation of the efficacy of the latter through the conduct of randomized clinical trials. A second major controversy arose when magnetic resonance imaging began to detect the presence of tumor multicentricity in many breast cancer patients, resulting in a resurgence in mastectomy in women who could have been treated with breast-preserving surgery. Because the use of science resolved the first controversy, I investigated whether there was scientific evidence to justify the current reversion to mastectomy. Extensive examination of the vast amount of recent medical literature related to that subject, that is, individual articles, review articles, and reports from the use of clinical trials, demonstrated that many physicians are not familiar with the scientific method, and thus, were unable to present, in those articles, credible evidence to support mastectomy in the presence of tumor cell multicentricity. Aside from the randomized clinical trial conducted by the National Surgical Adjuvant Breast and Bowel Project begun in 1976, which demonstrated no statistically significant difference in disease-free survival, distant disease-free survival, and overall survival between mastectomy and lumpectomy with or without radiation therapy, there has been no information in any of the few recently conducted studies involving multicentricity to justify the current resurgence in mastectomy.

Counterpoint: Both Immunohistochemistry and Fluorescence In Situ Hybridization Play Important Roles for HER2 Evaluation

Trastuzumab is a humanized monoclonal antibody that is approved for the treatment of breast and gastric cancers that overexpress human growth factor receptor 2 (HER2)3. Since its approval, controversy has existed over whether immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) is the best method for assessing HER2 status. Proponents of IHC point out that trastuzumab targets the HER2 protein molecule, which is assessed directly by IHC, and that the original “clinical trial assay” [and the basis of US Food and Drug Administration (FDA) clearance for the drug] was IHC. Proponents of FISH argue that IHC is more prone to technical issues (fixation, subjective interpretation, lack of proper controls on the actual procedure) and that evaluation by FISH is more objective. Although it is clear that most cases of invasive breast cancer show a direct correlation between amplification of the ERBB2 gene [v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian); also known as HER2 ] and overexpression of HER2 protein, IHC and FISH are complementary tests and examine different aspects of the biology of HER2-driven cancer. The accuracy of HER2 testing has generated substantial interest, especially given the poor concordance of HER2 testing results in clinical trials (1, 2). For example, 2 of the adjuvant clinical trials for HER2-positive breast cancer [NCCTG (North Central Cancer Treatment Group) N9831 and NSABP (National Surgical Adjuvant Breast and Bowel Project) B31] enrolled patients on the basis of a positive HER2 test result from a local laboratory, but retesting by the central laboratory revealed a negative result by both IHC and FISH in approximately 20% of the patients. These patients were still enrolled in the adjuvant trials and surprisingly demonstrated hazard ratios similar to those of patients tested as positive by IHC and FISH in the central …

Avoiding Mastectomy: Accelerated Partial Breast Irradiation for Breast Cancer Patients with Pacemakers or Defibrillators

The objective of this study was to evaluate the safety, toxicity, and planning concerns involved in accelerated partial breast irradiation (APBI) for patients with breast cancer who have a pacemaker or an automatic implantable cardioverter-defibrillator (AICD) and who desire breast conservation. We performed a review of prospectively obtained data for patients with early-stage breast cancer with a pacemaker or AICD treated between April 2007 and July 2010. Patients were treated with either 3D conformal external beam irradiation (3D-CRT) or high-dose rate balloon brachytherapy (HDRBB) as performed in the National Surgical Adjuvant Breast and Nowel Project (NSABP) B-39/Radiation Therapy Oncology Group (RTOG) 0413 protocol. Device interrogation was performed after the first and last radiation treatment, with comparative cardiac monitoring performed before and after the first three treatments. Eight patients were treated and have a mean follow-up of 6months. Three patients received HDRBB delivering 34Gy in 10 fractions. Mean planning target volume for evaluation (PTV_EVAL) coverage was 93.6%. The maximum radiation dose delivered to any device was 1.03Gy, with a mean pacemaker distance to lumpectomy cavity (DLC) of 9.1cm. Five patients received 3D-CRT consisting of 38.5Gy in 10 fractions. The mean 90% PTV_EVAL coverage was 97.3%. Maximum dose delivered to any device was 1.68Gy at a DLC of 9cm. Local toxicity did not exceed grade 1, and no adverse device events were noted. APBI in patients with pacemakers or AICDs who desire breast preservation seems to be a technically safe and reasonable application of targeted radiation therapy.

Cigarette smoking, fitness, and alcohol use as predictors of cancer outcomes among women in the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial (BCPT).

1505 Background: The double-blind, prospective, BCPT demonstrated a 50% reduction in the risk of breast cancer for tamoxifen (T) v placebo (P). We present the risk of cancer at the most common sites, based on the participants’ baseline self-reported cigarette smoking, alcohol use, and leisure-time physical activity. Methods: 13,338 women at high risk of bc. Were randomly assigned 6/92-9/97 to 20 mg/day T v P; we analyzed the 11,064 enrolled more than 3 years (yrs) before the trial unblinding 3/98. Endpoints invasive cancer of the breast (ibc), endometrium (ec), lung (lc), and colon (cc) were analyzed with Cox proportional hazards regression. Covariates were baseline estimated breast cancer risk, treatment assignment, race, age, and co-morbidities. Hazards ratios (HR) are given with 95% bracketed confidence intervals. Results: At baseline, 45.7% had moderate/heavy physical activity. 20.5%, 65.8%, 13.3% drank 0, 0-1, 1+ alcoholic drinks/day. 12.8% were current smokers. At median 8.7 years potential follow-u...

Multigene predictors developed on breast cancer cell lines to predict patient chemotherapy response: A validation study on the NSABP B-27 trial.

1029 Background: We developed multigene predictors (MGPs) of chemotherapy sensitivity based on breast cancer cell lines exposed to combination chemotherapy regimens. Performance was assessed by the prediction of pathological complete response (pCR) in National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-27 clinical trial breast cancer patients. Methods: B-27 was a phase III trial of women with operable primary breast cancer assigned to receive 4 cycles of preoperative doxorubicin and cyclophosphamide (AC) (Grp 1) or 4 cycles of AC followed by 4 cycles of docetaxel (either preop [Grp 2] or post-op [Grp 3]). MGPs associated with AC and ACT sensitivity were separately developed based on the in vitro drug response and publicly available microarray genomic profiles of 40 breast cancer cell lines. Validations of the two genomic predictors were conducted blindly by NSABP statisticians to assess accuracy in predicting breast cancer patient pCR to preoperative therapy. Results: 219 patients treated with AC and 102 with ACT were included in this study. For the AC therapy, the MGP score was significantly associated with pCR from univariate analysis (p=0.0002) and multivariate analysis adjusted (p=0.015), and MGP remained the most important factor in predicting chemotherapy response compared to other clinical and biologic variables; prediction accuracy was 79%, sensitivity was 72%, and specificity was 80%; the area under the ROC curve was 0.75 [95% confidence interval: 0.64, 0.86]. For ACT therapy, the prediction accuracy, sensitivity, and specificity were 69.6%, 60%, and 73%, respectively; the area under the ROC curve was 0.64 [0.51, 0.77]. The association between MGP and pCR was statistically significant from univariate analysis, but less significant from multivariate analysis adjusted for covariates. Conclusions: Cell line-derived multigene predictors show promise in the prediction of chemotherapy response in breast cancer patients treated with neoadjuvant chemotherapy.The B-27 study was funded by NCI PHS grants U10-CA−37377, U10-CA−69974, U10-CA−12027, U10-CA−69651, and U24-CA−114732, and with additional support from sanofi-aventis.

Evaluation of two intracavitary high-dose-rate brachytherapy devices for irradiating additional and irregularly shaped volumes of breast tissue

The SAVI and Contura breast brachytherapy applicators represent 2 recent advancements in brachytherapy technology that have expanded the number of women eligible for accelerated partial breast irradiation in the treatment of early-stage breast cancer. Early clinical experience with these 2 single-entry, multichannel high-dose-rate brachytherapy devices confirms their ease of use and dosimetric versatility. However, current clinical guidelines for SAVI and Contura brachytherapy may result in a smaller or less optimal volume of treated tissue compared with traditional interstitial brachytherapy. This study evaluates the feasibility of using the SAVI and Contura to irradiate larger and irregularly shaped target volumes, approaching what is treatable with the interstitial technique. To investigate whether additional tissue can be treated, 17 patients treated with the SAVI and 3 with the Contura were selected. For each patient, the planning target volume (PTV) was modified to extend 1.1 cm, 1.3 cm, and 1.5 cm beyond the tumor bed cavity. To evaluate dose conformance to an irregularly shaped target volume, 9 patients treated with the SAVI and 3 with the Contura were selected from the original 20 patients. The following asymmetric PTV margin combinations were assessed for each patient: 1.5/0.3, 1.3/0.3, and 1.1/0.3 cm. For all patients, treatment planning was performed, adopting the National Surgical Adjuvant Breast and Bowel Project guidelines, and dosimetric comparisons were made. The 6–1 and 8–1 SAVI devices can theoretically treat a maximal tissue margin of 1.5 cm and an asymmetric PTV with margins ranging from 0.3 to 1.5 cm. The 10–1 SAVI and Contura can treat a maximal margin of 1.3 cm and 1.1 cm, respectively, and asymmetric PTV with margins ranging from 0.3–1.3 cm. Compared with the Contura, the SAVI demonstrated greater dosimetric flexibility. Risk of developing excessive hot spots increased with the size of the SAVI device. Both the SAVI and Contura appear capable of treating >1.0-cm margins and irregularly shaped PTVs. The 6–1 SAVI device demonstrated the greatest versatility in targeting PTVs approaching what is treatable using the interstitial technique.

Long-Term Follow-Up of Women in Trials of Adjuvant Therapy for Breast Cancer: Is It Still Important?

Long-Term Follow-Up of Women in Trials of Adjuvant Therapy for Breast Cancer: Is It Still Important?

Menstrual History and Quality-of-Life Outcomes in Women With Node-Positive Breast Cancer Treated With Adjuvant Therapy on the NSABP B-30 Trial

Premenopausal women with breast cancer receiving adjuvant chemotherapy are at risk for amenorrhea. The National Surgical Adjuvant Breast and Bowel Project B-30 trial included menstrual history (MH) and quality-of-life (QOL) studies to compare treatments on these outcomes. Patients were randomly assigned to sequential doxorubicin (A) and cyclophosphamide (C) followed by docetaxel (T; AC→T), concurrent TAC, or AT, which varied in duration (24, 12, 12 weeks, respectively), and use of C. Endocrine therapy was prescribed for women with hormone receptor-positive tumors. MH and QOL were assessed with standardized questionnaires at baseline; cycle 4, day 1; and every 6 months through 24 months. Prespecified analyses examined rates of amenorrhea by treatment arm, the relationship between amenorrhea and QOL, and QOL by treatment arm. Amenorrhea 12 months after random assignment was significantly different between treatment groups: 69.8% for AC→T, 57.7% for TAC, and 37.9% for AT (P < .001). The AT group without tamoxifen had the lowest rate of amenorrhea. QOL was poorer for patients receiving AC→T at 6 months but similar to others by 12 months. Post-treatment symptoms were increased above baseline for all treatments. Multivariable repeated measures modeling demonstrated that treatment arm, time point, age, and tamoxifen use were significantly associated with symptom severity (all P values < .002). Amenorrhea rates differed significantly by treatment arm, with the AT arm having the lowest rate. Patients treated with longer duration therapy (AC→T) had greater symptom severity and poorer QOL at 6 months, but did not differ from shorter duration treatments at 12 months.

Long-Term Outcomes of Invasive Ipsilateral Breast Tumor Recurrences After Lumpectomy in NSABP B-17 and B-24 Randomized Clinical Trials for DCIS

Ipsilateral breast tumor recurrence (IBTR) is the most common failure event after lumpectomy for ductal carcinoma in situ (DCIS). We evaluated invasive IBTR (I-IBTR) and its influence on survival among participants in two National Surgical Adjuvant Breast and Bowel Project (NSABP) randomized trials for DCIS. In the NSABP B-17 trial (accrual period: October 1, 1985, to December 31, 1990), patients with localized DCIS were randomly assigned to the lumpectomy only (LO, n = 403) group or to the lumpectomy followed by radiotherapy (LRT, n = 410) group. In the NSABP B-24 double-blinded, placebo-controlled trial (accrual period: May 9, 1991, to April 13, 1994), all accrued patients were randomly assigned to LRT+ placebo, (n=900) or LRT + tamoxifen (LRT + TAM, n = 899). Endpoints included I-IBTR, DCIS-IBTR, contralateral breast cancers (CBC), overall and breast cancer-specific survival, and survival after I-IBTR. Median follow-up was 207 months for the B-17 trial (N = 813 patients) and 163 months for the B-24 trial (N = 1799 patients). Of 490 IBTR events, 263 (53.7%) were invasive. Radiation reduced I-IBTR by 52% in the LRT group compared with LO (B-17, hazard ratio [HR] of risk of I-IBTR = 0.48, 95% confidence interval [CI] = 0.33 to 0.69, P < .001). LRT + TAM reduced I-IBTR by 32% compared with LRT + placebo (B-24, HR of risk of I-IBTR = 0.68, 95% CI = 0.49 to 0.95, P = .025). The 15-year cumulative incidence of I-IBTR was 19.4% for LO, 8.9% for LRT (B-17), 10.0% for LRT + placebo (B-24), and 8.5% for LRT + TAM. The 15-year cumulative incidence of all contralateral breast cancers was 10.3% for LO, 10.2% for LRT (B-17), 10.8% for LRT + placebo (B-24), and 7.3% for LRT + TAM. I-IBTR was associated with increased mortality risk (HR of death = 1.75, 95% CI = 1.45 to 2.96, P < .001), whereas recurrence of DCIS was not. Twenty-two of 39 deaths after I-IBTR were attributed to breast cancer. Among all patients (with or without I-IBTR), the 15-year cumulative incidence of breast cancer death was 3.1% for LO, 4.7% for LRT (B-17), 2.7% for LRT + placebo (B-24), and 2.3% for LRT + TAM. Although I-IBTR increased the risk for breast cancer-related death, radiation therapy and tamoxifen reduced I-IBTR, and long-term prognosis remained excellent after breast-conserving surgery for DCIS.

C-MYC Alterations and Association With Patient Outcome in Early-Stage HER2-Positive Breast Cancer From the North Central Cancer Treatment Group N9831 Adjuvant Trastuzumab Trial

Findings from the human epidermal growth factor receptor 2 (HER2) -positive National Surgical Adjuvant Breast and Bowel Project (NSABP) B31 trial suggested that MYC/HER2 coamplification (> 5.0 copies/nucleus) was associated with additional benefit from adjuvant trastuzumab in patients with early-stage breast cancer. To further explore this relationship, we investigated associations between MYC amplification and disease-free survival (DFS) in a similar adjuvant trastuzumab HER2-positive breast cancer trial-North Central Cancer Treatment Group (NCCTG) N9831. This analysis included 799 patients randomly assigned to receive chemotherapy alone or with concurrent trastuzumab on N9831. Fluorescence in situ hybridization (FISH) was performed by using a dual-probe mixture for MYC and centromere 8 (MYC:CEP8) on tissue microarrays. MYC amplification was prespecified as MYC:CEP8 ratio > 2.2 or average MYC copies/nucleus > 5.0. Exploratory variables included polysomy 8. In comparing DFS (median follow-up, 4.0 years) between treatments, patients with MYC:CEP8 ratio ≤ 2.2 (n = 618; 77%) and > 2.2 (n = 181; 23%) had hazard ratios (HRs) of 0.46 (P < .001) and 0.67 (P = .33), respectively (interaction P = .38). Patients with MYC copies/nucleus ≤ 5.0 (n = 534; 67%) and > 5.0 (n = 265; 33%) had HRs of 0.52 (P = .002) and 0.48 (P = .02), respectively (interaction P = .94). Patients with MYC:CEP8 ratio < 1.3 with normal chromosome 8 copy number (n = 141; 18%) and ≥ 1.3 or < 1.3 with polysomy 8 (n = 658; 82%) had HRs of 0.66 (P = .28) and 0.44 (P < .001), respectively (interaction P = .23). Patients with MYC copies/nucleus < 2.5 (n = 130; 16%) and ≥ 2.5 (n = 669; 84%) had HRs of 1.07 (P = .87) and 0.42 (P < .001), respectively (interaction P = .05). We did not confirm the B31 association between MYC amplification and additional trastuzumab benefit. Exploratory analyses revealed potential associations between alternative MYC/chromosome 8 copy number alterations and differential benefit of adjuvant trastuzumab.

Accelerated Partial Breast Irradiation: Using the CyberKnife as the Radiation Delivery Platform in the Treatment of Early Breast Cancer.

We evaluate the CyberKnife (Accuray Incorporated, Sunnyvale, CA, USA) for non-invasive delivery of accelerated partial breast irradiation (APBI) in early breast cancer patients. Between 6/2009 and 5/2011, nine patients were treated with CyberKnife APBI. Normal tissue constraints were imposed as outlined in the National Surgical Adjuvant Breast and Bowel Project B-39/Radiation Therapy Oncology Group 0413 (NSABP/RTOG) Protocol (Vicini and White, 2007). Patients received a total dose of 30 Gy in five fractions (group 1, n = 2) or 34 Gy in 10 fractions (group 2, n = 7) delivered to the planning treatment volume (PTV) defined as the clinical target volume (CTV) +2 mm. The CTV was defined as either the lumpectomy cavity plus 10 mm (n = 2) or 15 mm (n = 7). The cavity was defined by a T2-weighted non-contrast breast MRI fused to a planning non-contrast thoracic CT. The CyberKnife Synchrony system tracked gold fiducials sutured into the cavity wall during lumpectomy. Treatments started 4–5 weeks after lumpectomy. The mean PTV was 100 cm3 (range, 92–108 cm3) and 105 cm3 (range, 49–241 cm3) and the mean PTV isodose prescription line was 70% for groups 1 and 2, respectively. The mean percent of whole breast reference volume receiving 100 and 50% of the dose (V100 and V50) for group 1 was 11% (range, 8–13%) and 23% (range, 16–30%) and for group 2 was 11% (range, 7–14%) and 26% (range, 21–35.0%), respectively. At a median 7 months follow-up (range, 4–26 months), no acute toxicities were seen. Acute cosmetic outcomes were excellent or good in all patients; for those patients with more than 12 months follow-up the late cosmesis outcomes were excellent or good. In conclusion, the lack of observable acute side effects and current excellent/good cosmetic outcomes is promising. We believe this suggests the CyberKnife is a suitable non-invasive radiation platform for delivering APBI with achievable normal tissue constraints.

Do selective estrogen receptor modulators treat cervical precancer and cancer? Time to pool data from relevant trials

Based on the nearly absolute etiologic link between carcinogenic human papillomavirus (HPV) and cervical cancer, two new approaches for the prevention of cervical cancer have emerged: (1) HPV vaccination for primary HPV prevention in younger women and (2) carcinogenic HPV detection for secondary prevention via identifying and treating cervical precancer and early cancers. Both have demonstrated high degrees of efficacy with maximum effectiveness guided by an understanding of the causal model and application of these technologies in an age appropriate manner.1 Despite the advent of these promising prevention tools, there is a real need to develop nonsurgical methods for treating cervical precancerous lesions and even early cancer for three reasons. First, current HPV vaccines are prophylactic and do not treat pre-existing HPV infections.1 Second, surgical excision of screen-detected precancerous lesions, while a highly efficacious (90–95%) treatment1 increases the risk of preterm delivery and infant morbidity and mortality.2 Third, most women who screen positive by a Pap and/or HPV do not have clinically actionable disease, yet these women are at risk of cervical precancer and cancer in the future and must be followed up intensively. In addition, in the low-resource settings, surgical methods are not commonly available and cryotherapy, while moderately efficacious when its use is limited to smaller lesions, causes significant watery discharge and requires sexual abstinence for several weeks to permit healing of treated epithelium. Despite the knowledge that HPV infection is the obligate cause of cervical cancer, targeted immunological approaches for therapy such as therapeutic vaccines have been unsuccessful.3 Chung and Lambert4 present a novel approach of using estrogen receptor antagonists (selective estrogen receptor modulators or SERMs) to treat cervical precancer and cancer. As noted by the authors, there are strongly supportive laboratory5 and epidemiological data6, 7 that estrogen plays contributing role in cervical carcinogenesis. In this study, Chung and Lambert4 successfully treated 7 E6/E7 transgenic mice that spontaneously manifested cervical cancer with Raloxifene, an estrogen receptor antagonist that reduces the risk of breast cancer. To investigate whether Raloxifene might reduce the incidence of cervical cancer and its immediate precursor, carcinoma in situ (CIS), previously unpublished data on these outcomes from two randomized clinical trials to evaluate two SERMs, tamoxifen and raloxifene, for breast cancer risk reduction were analyzed. The NSABP (National Surgical Adjuvant Breast and Bowel Project), an NCI funded Cooperative Group, has designed and conducted the two large breast cancer prevention trials, Breast Cancer Prevention Trial P-1 (BCPT-P1)8 and Study of Tamoxifen vs. Raloxifene (STAR).9 While both tamoxifen and raloxifene are estrogen receptor antagonists in breast tissue, raloxifene is an estrogen receptor antagonist whereas tamoxifen is an agonist in the human reproductive tract (e.g., Tamoxifen increases the risk of endometrial cancer while raloxifene does not.).4, 10, 11 However, as shown in the Table 1, despite small numbers, there was no evidence that long-term raloxifene use reduces, or long-term tamoxifen use increases, the risk of cervical CIS and cancer (n.b., results were combined because SERMS were reported to treat both in the mouse models, and CIS has a high risk of invading if left untreated12) (BCPT P-1: Placebo vs. Tamoxifen, p = 1.0, two-sided Fisher's exact; STAR: Tamoxifen vs. Raloxifene, p = 1.0, two-sided Fisher's exact). This post-hoc analysis was limited by small numbers. Data from other clinical trials of SERMs13, 14 should be pooled to examine the impact of SERMs on outcomes of cervical precancer and cancer. Until evidence is forthcoming on the positive effects of SERMs on cervical precancer and cancer in humans, extreme caution in interpreting data from mouse models is warranted. Despite the probable role of estrogens in cervical carcinogenesis, the protective effects of SERMs against cervical cancer cannot be inferred based on mouse models. Importantly, the therapeutic effectiveness of SERMs would need to be exceeding high to be acceptable, given the efficacy of current methods of treatment for cervical intraepithelial neoplasia15 and early cervical cancer.16 Dr. Castle acknowledges Dr. Joseph Costantino (University of Pittsburgh, Pittsburgh, PA, USA) for providing data from Breast Cancer Prevention Trial P-1 (BCPT-P1) and the Study of Tamoxifen vs. Raloxifene (STAR). Dr. Castle was supported by the Intramural Research Program of the NIH, National Cancer Institute and he reports no conflicts of interest. Yours sincerely, Philip E. Castle