Interrupting Endocrine Therapy to Attempt Pregnancy after Breast Cancer.

BACKGROUND: Prospective data on the risk of recurrence among women with hormone receptor-positive early breast cancer who temporarily discontinue endocrine therapy to attempt pregnancy are lacking. METHODS: We conducted a single-group trial in which we evaluated the temporary interruption of adjuvant endocrine therapy to attempt pregnancy in young women with previous breast cancer. Eligible women were 42 years of age or younger; had had stage I, II, or III disease; had received adjuvant endocrine therapy for 18 to 30 months; and desired pregnancy. The primary end point was the number of breast cancer events (defined as local, regional, or distant recurrence of invasive breast cancer or new contralateral invasive breast cancer) during follow-up. The primary analysis was planned to be performed after 1600 patient-years of follow-up. The prespecified safety threshold was the occurrence of 46 breast cancer events during this period. Breast cancer outcomes in this treatment-interruption group were compared with those in an external control cohort consisting of women who would have met the entry criteria for the current trial. RESULTS: Among 516 women, the median age was 37 years, the median time from breast cancer diagnosis to enrollment was 29 months, and 93.4% had stage I or II disease. Among 497 women who were followed for pregnancy status, 368 (74.0%) had at least one pregnancy and 317 (63.8%) had at least one live birth. In total, 365 babies were born. At 1638 patient-years of follow-up (median follow-up, 41 months), 44 patients had a breast cancer event, a result that did not exceed the safety threshold. The 3-year incidence of breast cancer events was 8.9% (95% confidence interval [CI], 6.3 to 11.6) in the treatment-interruption group and 9.2% (95% CI, 7.6 to 10.8) in the control cohort. CONCLUSIONS: Among select women with previous hormone receptor-positive early breast cancer, temporary interruption of endocrine therapy to attempt pregnancy did not confer a greater short-term risk of breast cancer events, including distant recurrence, than that in the external control cohort. Further follow-up is critical to inform longer-term safety. (Funded by ETOP IBCSG Partners Foundation and others; POSITIVE ClinicalTrials.gov number, NCT02308085.).

Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma.

BACKGROUND: Whether pembrolizumab given both before surgery (neoadjuvant therapy) and after surgery (adjuvant therapy), as compared with pembrolizumab given as adjuvant therapy alone, would increase event-free survival among patients with resectable stage III or IV melanoma is unknown. METHODS: In a phase 2 trial, we randomly assigned patients with clinically detectable, measurable stage IIIB to IVC melanoma that was amenable to surgical resection to three doses of neoadjuvant pembrolizumab, surgery, and 15 doses of adjuvant pembrolizumab (neoadjuvant-adjuvant group) or to surgery followed by pembrolizumab (200 mg intravenously every 3 weeks for a total of 18 doses) for approximately 1 year or until disease recurred or unacceptable toxic effects developed (adjuvant-only group). The primary end point was event-free survival in the intention-to-treat population. Events were defined as disease progression or toxic effects that precluded surgery; the inability to resect all gross disease; disease progression, surgical complications, or toxic effects of treatment that precluded the initiation of adjuvant therapy within 84 days after surgery; recurrence of melanoma after surgery; or death from any cause. Safety was also evaluated. RESULTS: At a median follow-up of 14.7 months, the neoadjuvant-adjuvant group (154 patients) had significantly longer event-free survival than the adjuvant-only group (159 patients) (P = 0.004 by the log-rank test). In a landmark analysis, event-free survival at 2 years was 72% (95% confidence interval [CI], 64 to 80) in the neoadjuvant-adjuvant group and 49% (95% CI, 41 to 59) in the adjuvant-only group. The percentage of patients with treatment-related adverse events of grades 3 or higher during therapy was 12% in the neoadjuvant-adjuvant group and 14% in the adjuvant-only group. CONCLUSIONS: Among patients with resectable stage III or IV melanoma, event-free survival was significantly longer among those who received pembrolizumab both before and after surgery than among those who received adjuvant pembrolizumab alone. No new toxic effects were identified. (Funded by the National Cancer Institute and Merck Sharp and Dohme; S1801 ClinicalTrials.gov number, NCT03698019.).

Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer.

BACKGROUND: Poly(adenosine diphosphate-ribose) polymerase inhibitors target cancers with defects in homologous recombination repair by synthetic lethality. New therapies are needed to reduce recurrence in patients with BRCA1 or BRCA2 germline mutation-associated early breast cancer. METHODS: We conducted a phase 3, double-blind, randomized trial involving patients with human epidermal growth factor receptor 2 (HER2)-negative early breast cancer with BRCA1 or BRCA2 germline pathogenic or likely pathogenic variants and high-risk clinicopathological factors who had received local treatment and neoadjuvant or adjuvant chemotherapy. Patients were randomly assigned (in a 1:1 ratio) to 1 year of oral olaparib or placebo. The primary end point was invasive disease-free survival. RESULTS: A total of 1836 patients underwent randomization. At a prespecified event-driven interim analysis with a median follow-up of 2.5 years, the 3-year invasive disease-free survival was 85.9% in the olaparib group and 77.1% in the placebo group (difference, 8.8 percentage points; 95% confidence interval [CI], 4.5 to 13.0; hazard ratio for invasive disease or death, 0.58; 99.5% CI, 0.41 to 0.82; P<0.001). The 3-year distant disease-free survival was 87.5% in the olaparib group and 80.4% in the placebo group (difference, 7.1 percentage points; 95% CI, 3.0 to 11.1; hazard ratio for distant disease or death, 0.57; 99.5% CI, 0.39 to 0.83; P<0.001). Olaparib was associated with fewer deaths than placebo (59 and 86, respectively) (hazard ratio, 0.68; 99% CI, 0.44 to 1.05; P = 0.02); however, the between-group difference was not significant at an interim-analysis boundary of a P value of less than 0.01. Safety data were consistent with known side effects of olaparib, with no excess serious adverse events or adverse events of special interest. CONCLUSIONS: Among patients with high-risk, HER2-negative early breast cancer and germline BRCA1 or BRCA2 pathogenic or likely pathogenic variants, adjuvant olaparib after completion of local treatment and neoadjuvant or adjuvant chemotherapy was associated with significantly longer survival free of invasive or distant disease than was placebo. Olaparib had limited effects on global patient-reported quality of life. (Funded by the National Cancer Institute and AstraZeneca; OlympiA ClinicalTrials.gov number, NCT02032823.).

Outcomes of patients with small and node-negative HER2-positive early breast cancer treated with adjuvant chemotherapy and anti-HER2 therapy-a sub-analysis of the ALTTO study.

BACKGROUND: Patients with small node-negative HER2-positive breast cancer are commonly treated with paclitaxel and 1 year of adjuvant trastuzumab. We performed a sub-analysis of the ALTTO trial to explore the long-term outcomes of patients with small node-negative tumours. METHODS: The ALTTO trial randomised 8381 patients with early HER2-positive BC treated with adjuvant chemotherapy (anthracycline/taxane- or taxane/carboplatin-based), to trastuzumab (T), lapatinib (L), their sequence (T → L) or their combination (L + T). Patients with tumours ≤3 cm and node-negative were included in this sub-analysis. RESULTS: A total of 2821 patients were analysed (median follow-up of 7 years). The median age was 52 years, and most patients had tumours ≤2 cm (64.3%). The 7-year disease-free survival (DFS) was 88.1% (95% CI: 86.7-89.3%). DFS was similar for arms T, T + L and T⟶L and significantly lower for arm L (stratified log-rank P = 0.031). The 7-year overall survival rate was 95.9% (95% CI: [95.0-96.6%) and the 7-year time-to-distant recurrence was 93.4% (95% CI: 92.3-94.4%). CONCLUSION: With most patients treated with anthracycline-based regimens, ALTTO shows that patients with small tumours treated with trastuzumab and concomitant chemotherapy have excellent long-term outcomes, similar to those of the APT trial. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT00490139.

Expanding the Staging Criteria for T1-2N0 Hormone-Receptor Positive Breast Cancer Patients Enrolled in TAILORx.

BACKGROUND: The American Joint Committee on Cancer (AJCC) 8th edition pathologic prognostic staging (PPS) incorporates anatomic and biologic factors. The OncotypeDX Breast Recurrence Score (RS) was included based on the initial report of the TAILORx trial, with T1-2N0 hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer patients who had a RS < 11 staged as PPS 1A. This study examined whether the RS criteria for PPS 1A can be further expanded using patients enrolled in the TAILORx trial. METHODS: The TAILORx trial enrolled 10,273 HR+HER2- T1-2N0 patients. Those with incomplete HR-status/grade and T3 disease were excluded for analysis. The recurrence-free interval (RFI) was compared between the patients who did and those who did not fall into the current PPS 1A category using the Kaplan-Meier method. RESULTS: The study enrolled 9535 patients for analysis. The RS was < 11 in 16.1%, 11-17 in 35.9%, 18-25 in 32.4%, and > 25 in 15.6% of the patients. The majority (91.2%) of the patients (including all the T1N0 patients regardless of RS) were PPS 1A, and 8.8% were not-PPS 1A. The median follow-up time was 95 months. The PPS 1A patients had an 8-year RFI of 94.2%, which was similar to that of the patients with a RS of 11-17 who were not-PPS 1A (91.7%; p = 0.07) and better than that of the patients with a RS ≥ 18 who were not-PPS 1A (85.4% for a RS of 18-25, 76.0% for a RS > 25; both p < 0.01). Similar RFI trends were seen in patients who received endocrine therapy or chemotherapy followed by endocrine therapy. CONCLUSIONS: Patients with T1-2N0 HR+HER2- breast cancer and a RS < 18 have an RFI similar to that of patients staged as PPS 1A by the current AJCC staging system, regardless of treatment, suggesting that the criteria for PPS 1A can be expanded to include a RS < 18.

Tolerability and toxicity of trastuzumab or trastuzumab + lapatinib in older patients: a sub-analysis of the ALTTO trial (BIG 2-06; NCCTG (Alliance) N063D).

PURPOSE: Little is known about the use of trastuzumab or trastuzumab + lapatinib in older patients. We have performed a sub-analysis of the Adjuvant Lapatinib And/Or Trastuzumab Treatment Optimisation (ALTTO) trial focused on toxicity and treatment completion of both regimens in older patients (≥ 65 years old) METHODS: The ALTTO trial randomised 8381 patients with early HER2-positive BC in 4 arms. Eligible patients for this study were those having received at least one dose of assigned treatment in either the trastuzumab or trastuzumab + lapatinib arms. Treatment completion was evaluated through the rate of temporary treatment interruptions, permanent treatment discontinuations and lapatinib dose reductions. Toxicity was evaluated via a selected subset of adverse events of interest (AEI). Risk factors for both treatment completion outcomes and toxicity were investigated, including comorbidities and use of 5 or more co-medications at randomization. RESULTS: A total of 430 patients ≥ 65 year were eligible. Median age was 68 (range 65-80). In comparison with the younger cohort, older patients had a significantly higher number of comorbidities at randomization (p < 0.001). Treatment completion outcomes were worse, particularly in the trastuzumab + lapatinib arm. Adverse events of interest were likewise more common in the trastuzumab + lapatinib arm with higher AEI rates (63.4% in younger vs 78.0% in older, p < 0.001). Concomitant chemotherapy was associated with worse treatment completion outcomes among older patients. CONCLUSION: Trastuzumab plus lapatinib was significantly more toxic among older patients and had worse treatment completion. Trastuzumab was generally well tolerated.

Body Mass Index and Weight Change in Patients With HER2-Positive Early Breast Cancer: Exploratory Analysis of the ALTTO BIG 2-06 Trial.

BACKGROUND: The association between obesity and prognosis in HER2-positive early breast cancer remains unclear, with limited data available. This study aimed to determine the impact of body mass index (BMI) at baseline and weight change after 2 years on outcomes of patients with HER2-positive early breast cancer. METHODS: ALTTO was a randomized phase III trial in patients with HER2-positive early breast cancer. BMI was collected at randomization and 2 years after. WHO BMI categories were used: underweight, <18.5 kg/m2; normal weight, 18.5 to <25 kg/m2; overweight, ≥25 to <30 kg/m2; and obese ≥30 kg/m2. A weight change from baseline of ≥5.0% and ≤5.0% was categorized as weight gain and weight loss. The impact of BMI at randomization and of weight change on disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) were investigated with multivariate analyses, adjusting for baseline patients and tumor characteristics. RESULTS: A total of 8,381 patients were included: 187 (2.2%), 3,797 (45.3%), 2,690 (32.1%), and 1,707 (20.4%) were underweight, normal weight, overweight, and obese at baseline, respectively. Compared with normal weight, being obese at randomization was associated with a significantly worse DDFS (adjusted hazard ratio [aHR], 1.25; 95% CI, 1.04-1.50) and OS (aHR, 1.27; 95% CI, 1.01-1.60), but no significant difference in DFS (aHR, 1.14; 95% CI, 0.97-1.32). Weight loss ≥5.0% at 2 years after randomization was associated with significantly poorer DFS (aHR, 1.34; 95% CI, 1.05-1.71), DDFS (aHR, 1.46; 95% CI, 1.07-1.98), and OS (aHR, 1.83; 95% CI, 1.18-2.84). Hormone receptor and menopausal status but not anti-HER2 treatment type influenced outcomes. Toxicities were more frequent in obese patients. CONCLUSIONS: In patients with HER2-positive early breast cancer, obesity at baseline is a poor prognostic factor. Weight loss during treatment and follow-up negatively impacts clinical outcomes. Dietary counseling should be part of survivorship care programs.

Pregnancies during and after trastuzumab and/or lapatinib in patients with human epidermal growth factor receptor 2-positive early breast cancer: Analysis from the NeoALTTO (BIG 1-06) and ALTTO (BIG 2-06) trials.

BACKGROUND: Limited data exist on the safety of using anti-human epidermal growth factor receptor 2 (HER2) targeted agents during pregnancy. To date, only retrospective studies have assessed the prognosis of patients with a pregnancy after prior early breast cancer, with no data in HER2-positive patients. METHODS: The Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization (NeoALTTO) trial and the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization (ALTTO) trial were randomized phase 3 trials for patients with HER2-positive early breast cancer. In both trials, pregnancy information was prospectively collected. Pregnancy outcomes were compared between patients unintentionally exposed to trastuzumab and/or lapatinib during gestation (the exposed group) and those who became pregnant after trastuzumab and/or lapatinib completion (the unexposed group). In the ALTTO trial, disease-free survival (DFS) was compared between pregnant patients and those aged 40 years or younger without a subsequent pregnancy via an extended Cox model with time-varying covariates to account for a guarantee-time bias. RESULTS: Ninety-two patients (12 in the exposed group and 80 in the unexposed group) had a pregnancy: 7 in the NeoALTTO trial and 85 in the ALTTO trial. Seven patients (58.3%) in the exposed group and 10 patients (12.5%) in the unexposed group opted for an induced abortion; in the unexposed group, 10 patients (12.5%) had a spontaneous abortion. No pregnancy/delivery complications were reported for the remaining cases, who successfully completed their pregnancy, with the exception of 1 fetus with trisomy 21 (Down syndrome). No significant difference in DFS (adjusted hazard ratio, 1.12; 95% confidence interval, 0.52-2.42) was observed between young patients with a pregnancy (n = 85) and young patients without a pregnancy (n = 1307). CONCLUSIONS: For patients with HER2-positive early breast cancer, having a pregnancy after treatment completion appears to be safe without compromising fetal outcome or maternal prognosis.

Dissecting the effect of hormone receptor status in patients with HER2-positive early breast cancer: exploratory analysis from the ALTTO (BIG 2-06) randomized clinical trial.

PURPOSE: Limited evidence exists on the impact of hormone receptor (HR) status to counsel HER2-positive early breast cancer patients receiving adjuvant anti-HER2 therapy. METHODS: ALTTO (BIG 2-06) was an international, intergroup, open-label, randomized phase III trial in HER2-positive early breast cancer patients randomized to receive 1 year of trastuzumab and/or lapatinib. HER2, estrogen and progesterone receptors were centrally tested for all patients. We investigated the impact of HR status on prognosis, risk of disease-free survival (DFS) events over time, patterns of first DFS events, and factors associated with risk of DFS events overall, in years 0-5 and 6-8. RESULTS: Out of 6273 patients included in this analysis, 3603 (57.4%) had HR-positive tumors. Median follow-up was 6.93 years. Five-year and 8-year DFS were 86% and 80% in patients with HR-positive disease, and 83% and 79% in those with HR-negative tumors, respectively. Mean annual hazards of recurrence in years 0-5 were 3% in patients with HR-positive disease and 4% in those with HR-negative tumors, while in years 6-8 they were 3% and 2%, respectively. Distribution of first DFS event in years 6-8 (P = 0.005) and type of first distant recurrence (P < 0.001) were significantly different between the two groups. Risk factors for DFS events overall, in years 0-5, and 6-8 were different in patients with HR-positive and HR-negative tumors. CONCLUSIONS: HER2-positive early breast cancer is characterized by the presence of two diseases with distinct natural history based on HR status requiring the development of different follow-up strategies and future de-escalation and escalation clinical trials.

Ductal Carcinoma in Situ: Quantitative Preoperative Breast MR Imaging Features Associated with Recurrence after Treatment.

Purpose To investigate whether specific imaging features on breast magnetic resonance (MR) images are associated with ductal carcinoma in situ (DCIS) recurrence risk after definitive treatment. Materials and Methods Patients with DCIS who underwent preoperative dynamic contrast material-enhanced (DCE) MR imaging between 2004 and 2014 with ipsilateral recurrence more than 6 months after definitive surgical treatment were retrospectively identified. For each patient, a control subject with DCIS that did not recur was identified and matched on the basis of clinical, histopathologic, and treatment features known to affect recurrence risk. On DCE MR images, lesion characteristics (longest diameter, functional tumor volume [FTV], peak percentage enhancement [PE], peak signal enhancement ratio [SER], and washout fraction) and normal tissue features (background parenchymal enhancement [BPE] volume, mean BPE) were quantitatively measured. MR imaging features were compared between patients and control subjects by using the Wilcoxon signed-rank test, with adjustment for multiple comparisons. Results Of 415 subjects with DCIS who underwent preoperative MR imaging, 14 experienced recurrence and 11 had an identifiable matching control subject (final cohort, 11 patients and 11 control subjects). Median time to recurrence was 14 months, and median follow-up for control subjects was 102 months. When compared with matched control subjects, patients with DCIS recurrence exhibited significantly greater FTV (median, 9.3 cm3 vs 1.3 cm3, P = .01), lesion peak SER (median, 1.7 vs 1.2; P = .03), and mean BPE (median, 58.3% vs 41.1%; P = .02). Conclusion Quantitative lesion and normal breast tissue characteristics at preoperative MR imaging in women with newly diagnosed DCIS show promise for association with breast cancer recurrence after treatment. © RSNA, 2017.

Repletion of vitamin D associated with deterioration of sleep quality among postmenopausal women.

Reduced health-related quality of life (HRQOL), depressive symptoms and poor sleep quality are important health issues among postmenopausal women and may be associated with low vitamin D status. Overweight postmenopausal women, with serum 25-hydroxyvitamin D [25(OH)D] 10-32ng/m, were recruited in Seattle, WA (2010-2012) and randomly assigned to 12months of weight loss +2000IU oral vitamin D3/day or weight loss+daily placebo. The weight-loss program included a reduced-calorie diet and 225min/week of moderate-to-vigorous aerobic activity. Eight subscales of HRQOL were assessed by the MOS 36-Item Short-Form Health Survey. Depressive symptoms were assessed using the Brief Symptom Inventory-18, and sleep quality was assessed using the Pittsburg Sleep Quality Index (PSQI). Mean 12-month changes in HRQOL, depressive symptoms and sleep quality were compared between groups (intent-to-treat) using generalized estimating equations. Compared to placebo, women receiving vitamin D did not experience any significant change in depressive symptoms (p=0.78), HRQOL subscales (all p>0.05), or overall sleep quality (p=0.21). However, a greater magnitude of change in serum 25(OH)D was associated with an increased need to take medications to sleep (ptrend=0.01) and overall worse sleep quality (ptrend<0.01). Women who became vitamin D replete (≥32ng/mL) also showed a deterioration in total PSQI sleep quality score compared to women who remained <32ng/mL despite supplementation, even after adjusting for relevant covariates (Non-Replete: -5.7% vs. Replete: +6.2%, p<0.01). Vitamin D supplementation of 2000IU/d may result in overall worse sleep quality for postmenopausal women with low circulating vitamin D undergoing weight loss.

Testicular germ cell tumor susceptibility associated with the UCK2 locus on chromosome 1q23.

Genome-wide association studies (GWASs) have identified multiple common genetic variants associated with an increased risk of testicular germ cell tumors (TGCTs). A previous GWAS reported a possible TGCT susceptibility locus on chromosome 1q23 in the UCK2 gene, but failed to reach genome-wide significance following replication. We interrogated this region by conducting a meta-analysis of two independent GWASs including a total of 940 TGCT cases and 1559 controls for 122 single-nucleotide polymorphisms (SNPs) on chromosome 1q23 and followed up the most significant SNPs in an additional 2202 TGCT cases and 2386 controls from four case-control studies. We observed genome-wide significant associations for several UCK2 markers, the most significant of which was for rs3790665 (PCombined = 6.0 × 10(-9)). Additional support is provided from an independent familial study of TGCT where a significant over-transmission for rs3790665 with TGCT risk was observed (PFBAT = 2.3 × 10(-3)). Here, we provide substantial evidence for the association between UCK2 genetic variation and TGCT risk.

Are Qualitative Assessments of Background Parenchymal Enhancement, Amount of Fibroglandular Tissue on MR Images, and Mammographic Density Associated with Breast Cancer Risk?

PURPOSE: To investigate whether qualitative magnetic resonance (MR) imaging assessments of background parenchymal enhancement (BPE), amount of fibroglandular tissue (FGT), and mammographic density are associated with risk of developing breast cancer in women who are at high risk. MATERIALS AND METHODS: In this institutional review board-approved HIPAA-compliant retrospective study, all screening breast MR images obtained from January 2006 to December 2011 in women aged 18 years or older and at high risk for but without a history of breast cancer were identified. Women in whom breast cancer was diagnosed after index MR imaging comprised the cancer cohort, and one-to-one matching (age and BRCA status) of each woman with breast cancer to a control subject was performed by using MR images obtained in women who did not develop breast cancer with follow-up time maximized. Amount of BPE, BPE pattern (peripheral vs central), amount of FGT at MR imaging, and mammographic density were assessed on index images. Imaging features were compared between cancer and control cohorts by using conditional logistic regression. RESULTS: Twenty-three women at high risk (mean age, 47 years ± 10 [standard deviation]; six women had BRCA mutations) with no history of breast cancer underwent screening breast MR imaging; in these women, a diagnosis of breast cancer (invasive, n = 12; in situ, n = 11) was made during the follow-up interval. Women with mild, moderate, or marked BPE were nine times more likely to receive a diagnosis of breast cancer during the follow-up interval than were those with minimal BPE (P = .007; odds ratio = 9.0; 95% confidence interval: 1.1, 71.0). BPE pattern, MR imaging amount of FGT, and mammographic density were not significantly different between the cohorts (P = .5, P = .5, and P = .4, respectively). CONCLUSION: Greater BPE was associated with a higher probability of developing breast cancer in women at high risk for cancer and warrants further study.

Breast Cancer Risk Reduction, Version 2.2015.

Breast cancer is the most frequently diagnosed malignancy in women in the United States and is second only to lung cancer as a cause of cancer death. To assist women who are at increased risk of developing breast cancer and their physicians in the application of individualized strategies to reduce breast cancer risk, NCCN has developed these guidelines for breast cancer risk reduction.

Predictors and outcomes of completion axillary node dissection among older breast cancer patients.

BACKGROUND: The role of completion axillary lymph node dissection (ALND) for older women who had sentinel lymph node-positive (SLN+) invasive breast cancer is unclear. We examined factors predictive of ALND and the association between ALND, adjuvant chemotherapy administration, and survival. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, we reviewed records of women age >65 diagnosed with stage I/II breast cancer from 1998-2005. Adjusted Cox proportional hazards and multivariate logistic regression were used to identify patient and disease variables associated with ALND, and assess association between ALND and all-cause and breast cancer-specific survival. RESULTS: Among SLN+ patients, 88 % underwent ALND. Earlier diagnosis year, greater nodal involvement, younger age, registry location, and larger tumor size were all associated with a significantly higher likelihood of ALND. The ALND in SLN+ patients was not significantly associated with 5-year breast cancer-specific survival (hazard ratio [HR] 1.22, 95 % confidence interval [CI] 0.76-1.96). The SLN+ patients who underwent ALND were more likely to receive adjuvant chemotherapy (odds ratio [OR] 1.8, 95 % CI 1.45-2.24). However, younger age (OR 18.0, 95 % CI 14.4-23.9), estrogen receptor-negative (ER-) status (OR 4.2, 95 % CI 3.4-5.3), and fewer comorbidities (OR 2.6, 95 % CI 1.7-4.0) were all more strongly linked to receipt of chemotherapy. CONCLUSIONS: ALND for older patients with SLN+ breast cancer is not associated with improved 5-year all-cause or breast cancer-specific survival. Younger age, fewer comorbidities, and estrogen receptor-negative (ER-) status were more strongly associated with receipt of chemotherapy than ALND. Consideration should be given to omitting ALND in older patients, particularly if findings of ALND will not influence adjuvant therapy decisions.

Familial testicular germ cell tumor: no associated syndromic pattern identified.

BACKGROUND: Testicular germ cell tumor (TGCT) is the most common malignancy in young men. Familial clustering, epidemiologic evidence of increased risk with family or personal history, and the association of TGCT with genitourinary (GU) tract anomalies have suggested an underlying genetic predisposition. Linkage data have not identified a rare, highly-penetrant, single gene in familial TGCT (FTGCT) cases. Based on its association with congenital GU tract anomalies and suggestions that there is an intrauterine origin to TGCT, we hypothesized the existence of unrecognized dysmorphic features in FTGCT. METHODS: We evaluated 38 FTGCT individuals and 41 first-degree relatives from 22 multiple-case families with detailed dysmorphology examinations, physician-based medical history and physical examination, laboratory testing, and genitourinary imaging studies. RESULTS: The prevalence of major abnormalities and minor variants did not significantly differ between either FTGCT individuals or their first-degree relatives when compared with normal population controls, except for tall stature, macrocephaly, flat midface, and retro-/micrognathia. However, these four traits were not manifest as a constellation of features in any one individual or family. We did detect an excess prevalence of the genitourinary anomalies cryptorchidism and congenital inguinal hernia in our population, as previously described in sporadic TGCT, but no congenital renal, retroperitoneal or mediastinal anomalies were detected. CONCLUSIONS: Overall, our study did not identify a constellation of dysmorphic features in FTGCT individuals, which is consistent with results of genetic studies suggesting that multiple low-penetrance genes are likely responsible for FTGCT susceptibility.

Fertility Preservation and Assisted Reproduction in Patients With Breast Cancer Interrupting Adjuvant Endocrine Therapy to Attempt Pregnancy.

PURPOSE: We investigated time to pregnancy, efficacy and safety of fertility preservation, and assisted reproductive technologies (ARTs) in women with early hormone receptor-positive breast cancer (BC) desiring future pregnancy. PATIENTS AND METHODS: POSITIVE is an international, single-arm, prospective trial, in which 518 women temporarily interrupted adjuvant endocrine therapy to attempt pregnancy. We evaluated menstruation recovery and factors associated with time to pregnancy and investigated if ART use was associated with achieving pregnancy. The cumulative incidence of BC-free interval (BCFI) events was estimated according to the use of ovarian stimulation at diagnosis. The median follow-up was 41 months. RESULTS: Two hundred seventy-three patients (53%) reported amenorrhea at enrollment, of whom 94% resumed menses within 12 months. Among 497 patients evaluable for pregnancy, 368 (74%) reported at least one pregnancy. Young age was the main factor associated with shorter time to pregnancy with cumulative incidences of pregnancy by 1 year of 63.5%, 54.3%, and 37.7% for patients age <35, 35-39, and 40-42 years, respectively. One hundred and seventy-nine patients (36%) had embryo/oocyte cryopreservation at diagnosis, of whom 68 reported embryo transfer after enrollment. Cryopreserved embryo transfer was the only ART associated with higher chance of pregnancy (odds ratio, 2.41 [95% CI, 1.75 to 4.95]). The cumulative incidence of BCFI events at 3 years was similar for women who underwent ovarian stimulation for cryopreservation at diagnosis, 9.7% (95% CI, 6.0 to 15.4), compared with those who did not, 8.7% (95% CI, 6.0 to 12.5). CONCLUSION: In POSITIVE, fertility preservation using ovarian stimulation was not associated with short-term detrimental impact on cancer prognosis. Pregnancy rates were highest among those who underwent embryo/oocyte cryopreservation followed by embryo transfer.

Timing and Reporting of Secondary Overall Survival End Points for Phase III Trials in Advanced/Metastatic Disease.

Recent therapeutic advances have led to improved patient survival in many cancer settings. Although prolongation of survival remains the ultimate goal of cancer treatment, the availability of effective salvage therapies could make definitive phase III trials with primary overall survival (OS) end points difficult to complete in a timely manner. Therefore, to accelerate development of new therapies, many phase III trials of new cancer therapies are now designed with intermediate primary end points (eg, progression-free survival in the metastatic setting) with OS designated as a secondary end point. We review recently published phase III trials and assess contemporary practices for designing and reporting OS as a secondary end point. We then provide design and reporting recommendations for trials with OS as a secondary end point to safeguard OS data integrity and optimize access to the OS data for patient, clinician, and public-health stakeholders.