Barbara Ward

Outcome of conservatively managed early-onset breast cancer by BRCA1/2 status.

BACKGROUND Management of early-stage breast cancer in young women with mutations in BRCA1 or BRCA2 remains controversial. This study assessed the long-term risks of ipsilateral and contralateral breast cancer in a cohort of young women who underwent breast-conserving surgery followed by radiotherapy. METHODS Between 1975 and 1998, 290 women with breast cancer diagnosed at age 42 years or younger underwent lumpectomy followed by radiotherapy at our hospital. We recruited 127 of these women for complete sequencing of BRCA1 and BRCA2. Demographic, clinical, pathological, and outcome data were recorded. The primary endpoints were rates of ipsilateral and contralateral breast cancer, in relation to germline BRCA1/2 status. FINDINGS 105 women were classified as having sporadic disease (94 with wild-type or known polymorphisms and 11 with variants of unclear significance) and 22 as having genetic predisposition (deleterious mutations in BRCA1 [15] or BRCA2 [seven]). At 12 years of follow-up, the genetic group had significantly higher rates of ipsilateral (49% vs 21%, p=0.007) and contralateral events (42% vs 9%, p=0.001) than the sporadic group. The majority of events were classified as second primary tumours. No patient in the genetic group had undergone oophorectomy or was taking prophylactic agents such as tamoxifen. INTERPRETATION Patients with germline mutations in BRCA1 or BRCA2 have a high risk of developing late ipsilateral and contralateral second primary tumours. With breast-conserving therapy, chemoprophylaxis or other interventions to reduce the rate of second cancers may be valuable. Alternatively, bilateral mastectomy may be considered, to minimise the risk of second tumours in the breasts.

Ipsilateral breast tumor recurrence as a predictor of distant disease: implications for systemic therapy at the time of local relapse.

PURPOSE To evaluate the prognostic significance of ipsilateral breast tumor recurrence (IBTR) with respect to the subsequent development of distant metastasis. MATERIALS AND METHODS Between January 1970 and December 1989, 973 patients with invasive breast cancer were treated with conservative surgery and radiation therapy at Yale-New Haven Hospital. The median follow-up time as of December 1993 was 8.6 years. A number of prognostic factors were tested as possible predictors of distant metastases, including whether a patient experienced IBTR. IBTRs were broken down by time to recurrence to determine whether the breast recurrence-free interval had any prognostic relevance with respect to the development of distant metastasis. RESULTS As of December 1993, out of the entire population of 973 patients, 73 patients had developed IBTR and 134 had developed distant metastases. The overall actuarial survival rate at 10 years was .71 +/- .02, with a 10-year actuarial breast recurrence-free rate of .84 +/- .02 and a 10-year distant metastasis-free rate of .77 +/- .02. The overall distant metastasis rate was higher in patients who experienced IBTR compared with patients who had never experienced IBTR. Furthermore, the time to IBTR had a significant effect on distant metastases. Of 32 patients who developed an IBTR within 4 years of original diagnosis, 16 (50%) developed distant metastases. In contrast, of 41 patients who developed later breast relapses (> 4 years from original diagnosis), only seven (17%) developed distant metastases (P < .01). Of 32 patients who developed early breast relapse, the 5-year survival rate following breast relapse was .50 +/- .01, compared with a 5-year post-breast relapse survival rate of .78 +/- .10 among 41 patients with later breast relapses (P < .05). CONCLUSION It appears that early IBTR is a significant predictor for distant metastases. Whether early breast tumor relapse is a marker for or cause of distant metastases remains a controversial and unresolved issue. Implications for adjuvant systemic therapy at the time of breast relapse are discussed.

Breast reconstruction in previously irradiated patients using tissue expanders and implants: a potentially unfavorable result.

There exists a paucity of definitive information on the suitability of implant reconstructions in previously irradiated breast cancer patients. This controversial topic prompted a review of our prosthetic reconstructions in this select group of patients. A retrospective study of patients treated between 1976 and 1993 with lumpectomy and radiation therapy for early breast cancer revealed 67 patients with local recurrences. Nine of these patients (10 breasts) underwent a two-stage prosthetic reconstruction following a salvage mastectomy. The average age was 47.9 years. The mean dose of irradiation was 6,070 cGy. The average interval from radiation therapy to placement of a tissue expander was 4.6 years. In one patient (10%) the tissue expander extruded. The average follow-up for 8 patients (9 breasts) who underwent exchange to a permanent prosthesis was 5.1 years. In four reconstructions (40%) there was an uneventful postoperative course. Two cases (20%) were difficult to expand and the final result lacked projection. One patient (10%) developed an infection requiring removal of the permanent prosthesis. Two patients (20%) developed Baker class III or IV capsular contractures. Overall, in our group of 10 implant reconstructions, 60% of the patients resulted in either a complication or an unfavorable result.

Time trend and the age-period-cohort effect on the incidence of histologic types of lung cancer in Connecticut, 1960-1989.

Background. Recent epidemiologic studies have suggested changing patterns of lung cancer incidence by histologic type. The observed time trends have been attributed to a change in the rate of cigarette smoking, changes in exposure to new environmental carcinogens, and changes in the criteria for the histopathologic diagnosis of lung cancer. The current study was designed to examine the incidence patterns of lung cancer by histologic type in Connecticut and to use this information to project the future trend of the disease in this population.

Continuing increase in incidence of germ-cell testis cancer in young adults: Experience from Connecticut, USA, 1935–1992

The current study is designed to examine long‐term trends by histologic types of testis cancer in Connecticut. A regression model was used to identify age, period, or cohort as determinants of the time‐trend on histologic types of testis cancer. The results from this descriptive epidemiologic study show that the overall age‐adjusted incidence rate of testis cancer has increased 3.5‐fold in Connecticut during the past nearly 60 years of cancer registration. The rates for seminoma and nonseminoma have been increasing since the mid‐1950s and increase in a similar manner for those aged 15 to 49. The largest increase was observed in the age groups 20 to 44 for seminoma and 15 to 34 for non‐seminoma. The observed increase was limited to whites. The results from age‐period‐cohort modeling suggest that the observed increase in seminoma before 1950s could be largely attributable to a period effect, while the increase for cohorts born after about 1910 both for seminoma and for non‐seminoma are mainly explained by a strong birth‐cohort effect. Therefore, the observed increase in germ‐cell testis cancer in this population is likely to continue in the coming years. Thus far, the proposed hypotheses, such as exposure to DES in utero, earlier lifetime exposures to viruses, trauma or unusual amounts of heat to the testis, cannot adequately explain the observed incidence patterns of testis cancer. Analytical epidemiologic studies with large sample size are urgently needed to examine the risk factors responsible for the increase.

Reappraisal of the role of axillary lymph node dissection in the conservative treatment of breast cancer.

PURPOSE The purpose of this study was (1) to review systemic therapy practice patterns to assess how information regarding nodal status currently influences systemic therapy decisions, and (2) to review long-term outcome of patients who do not undergo axillary dissection compared with patients who do. METHODS AND MATERIALS For the current practice patterns portion of the study, the records of 292 patients who presented in the past 3 years with invasive breast cancer and underwent conservative surgery were reviewed to determine systemic therapy administered with respect to patient age, primary tumor size, clinical nodal status, and presenting symptoms. For the long-term outcome portion of the study, the records of 955 patients with invasive breast cancer who underwent conservative surgery and radiation therapy before December 1989 were reviewed. Patient characteristics and outcome of those patients who underwent axillary dissection (n = 565, 59%) were compared with a cohort of patients treated during the same era who did not undergo axillary dissection (n = 390, 41%). RESULTS For the current practice-patterns cohort, information regarding nodal status appeared to influence adjuvant systemic therapy for those patients less than 50 years of age and for those patients with palpable masses who were older than 50. Patients older than 50 with nonpalpable mammographically detected tumors have a low probability of nodal involvement and information regarding nodal status rarely changed therapy in this group of patients. In the long-term outcome study, there were no significant differences in the rates of distant metastasis, disease-free survival, or overall survival between those patients who underwent lymph node dissection and those who did not. CONCLUSION For selected patients, axillary lymph node dissection appears to have little influence on subsequent management and long-term outcome. These data suggest that it is time to reassess the role of axillary lymph node dissection in patients who undergo conservative surgery and radiation therapy.

A new peripherally implanted subcutaneous permanent central venous access device for patients requiring chemotherapy.

PURPOSE A peripherally implanted central venous access device (P.A.S. Port; Pharmacia Deltec Inc, St Paul, MN) was evaluated for ease of insertion, functionality, acceptance, and complications in patients who required long-term venous access. A hand-held tracking system (Cath-Finder; Pharmacia Deltec Inc) used to determine catheter tip location was also evaluated. PATIENTS AND METHODS A P.A.S. Port was placed in 47 patients who required long-term intravenous access. The median follow-up duration has been 32 weeks (range, 2 to 112). Total usage has been 2,028 catheter-weeks. The Cath-Finder was used to determine catheter tip location during insertion. Nursing staff and patient satisfaction were polled and functionality and complications were recorded. RESULTS The device was found to be simple to insert, the procedure well tolerated, and, with one exception, the Cath-Finder accurately predicted catheter tip location. There was a 6.4% incidence of transient phlebitis and a 6.4% incidence of symptomatic axillary or subclavian vein thrombosis. There were no infectious complications. Access was simple in all but two obese patients. The device functioned well in all patients, except three in whom blood aspiration was difficult and two in whom fluid administration was slow. The device was well tolerated by all patients and nursing staff satisfaction was high. CONCLUSION This device provides a highly acceptable, additional method of implantable, permanent central venous access for chemotherapy patients with a low complication rate. The successful use of the Cath-Finder and minor extent of the procedure may allow this device to be inserted in a clinic procedure room without sedation and fluoroscopy.

Laryngopharyngoesophagectomy for advanced hypopharyngeal and esophageal squamous cell carcinoma: The yale experience

The 5‐year survival rate for patients with hypopharyngeal squamous cell carcinoma invading the upper esophagus is below 25% regardless of therapy. Most patients with advanced disease—unable to eat or breathe—die within 18 months of diagnosis. Because these patients, on average, have a limited time to live, surgical treatment should aim to maximize the quality of remaining life. Essential to this goal are complete tumor removal and rapid return to oral feeding. Furthermore, short hospital stay and low perioperative morbidity are especially important in these patients.

Subareolar breast cancer: Long-term results with conservative surgery and radiation therapy

PURPOSE It has been suggested that patients presenting with breast cancers within 2 cm of the nipple areolar complex represent a relative contraindication to conservative management due to either a compromised cosmetic result associated with sacrifice of the nipple areolar complex, reluctance to include the entire nipple areolar complex in the conedown field, or increased risk of multicentricity. We have reviewed our experience of conservatively treated patients with specific reference to the subset of patients presenting with tumors within 2 cm of the nipple areolar complex. METHODS AND MATERIALS Between January 1970 and December 1989, 1014 patients with early stage breast cancer were treated at Yale-New Haven Hospital by excisional biopsy with or without axillary lymph node dissection. Of the 1014 charts reviewed, a total of 98 patients fulfilled the criteria of having a central/ subareolar breast cancer. Reexcision was performed on only 16 patients. Following conservative surgery, patients were treated with radiation therapy to the intact breast to a total median dose of 48 Gy with conedown to a total of 64 Gy. adjuvant systemic therapy and regional nodal irradiation were administered as clinically indicated. RESULTS As of December 1993, the median follow-up for the 98 patients in this study was 9.03 years. The majority of patients had presented with either a palpable mass or a mammographically detected lesion. Three patients presented with Pagets disease, five with nipple discharge, and seven with nipple inversion. Ten of the 98 patients had the nipple areolar complex sacrificed at the time of surgery, while the remaining 88 patients had the entire nipple areolar complex included in the conedown field. Four of these 88 patients had the nipple partially blocked during the electron conedown. There were no significant complications associated with including the entire nipple areolar complex within the conedown field to a median dose of 64 Gy. Six of the 98 patients experienced a local recurrence, three experienced a regional recurrence, and nine experienced distant metastasis. The actuarial 10-year survival (0.79 +/- 0.06), distant disease-free survival (0.88 +/- 0.04) and breast recurrence-free survival (0.84 +/- 0.07) were not significantly different from those patients who presented with cancers in other parts of the breast. CONCLUSIONS Patients presenting with subareolar breast cancers within 2 cm of the nipple areolar complex are suitable candidates for conservative surgery and radiation therapy. In the majority of patients in this study, the nipple areolar complex did not need to be sacrificed and could be safely included in the electron conedown field with acceptable complications and cosmesis. A subareolar breast cancer does not represent a relative contraindication to conservative management in patients with early stage breast cancer.

β‐Benzene hexachloride in breast adipose tissue and risk of breast carcinoma

Epidemiologic studies have recently related benzene hexachloride (BHC) to breast carcinoma risk. Experimental studies have also shown that β‐BHC is weakly estrogenic, hence supporting the alleged association. By directly comparing β‐BHC levels in breast adipose tissue from incident breast carcinoma cases and controls, this study examined the hypothesis that exposure to β‐BHC increases the risk of breast carcinoma in females.