BRCA1/BRCA2 germline mutations in locally recurrent breast cancer patients after lumpectomy and radiation therapy: implications for breast-conserving management in patients with BRCA1/BRCA2 mutations.

PURPOSE: Breast cancer patients treated conservatively with lumpectomy and radiation therapy (LRT) have an estimated lifetime risk of local relapse (ipsilateral breast tumor recurrence [IBTR]) of 10% to 15%. For breast cancer patients carrying BRCA1 or BRCA2 (BRCA1/2) mutations, the outcome of treatment with LRT with respect to IBTR has not been determined. In this study, we estimate the frequency of BRCA1/2 mutations in a study of breast cancer patients with IBTR treated with LRT. PATIENTS AND METHODS: Between 1973 and 1994, there were 52 breast cancer patients treated with LRT who developed an IBTR within the prior irradiated breast and who were willing to participate in the current study. From our database, we also identified 52 control breast cancer patients treated with LRT without IBTR. The control patients were individually matched to the index cases with respect to multiple clinical and pathologic parameters. Lymphocyte DNA specimens from all 52 locally recurrent patients and 15 of the matched control patients under age 40 were used as templates for polymerase chain reaction amplification and dye-primer sequencing of exons 2 to 24 of BRCA1, exons 2 to 27 of BRCA2, and flanking intron sequences. RESULTS: After LRT, eight (15%) of 52 breast cancer patients had IBTR with deleterious BRCA1/2 mutations. By age, there were six (40%) of 15 patients with IBTR under age 40 with BRCA1/2 mutations, one (9.0%) of 11 between ages 40 and 49, and one (3.8%) of 26 older than age 49. In comparison to the six (40%) of 15 of patients under age 40 with IBTR found to have BRCA1/2 mutations, only one (6.6%) of 15 matched control patients without IBTR and had a BRCA1/2 mutation (P =.03). The median time to IBTR for patients with BRCA1/2 mutations was 7.8 years compared with 4.7 years for patients without BRCA1/2 mutations (P =.03). By clinical and histologic criteria, these relapses represented second primary tumors developing in the conservatively treated breast. All patients with BRCA1/2 mutations and IBTR underwent successful surgical salvage mastectomy at the time of IBTR and remain alive without evidence of local or systemic progression of disease. CONCLUSION: In this study, we found an elevated frequency of deleterious BRCA1/2 mutations in breast cancer patients treated with LRT who developed late IBTR. The relatively long time to IBTR, as well as the histologic and clinical criteria, suggests that these recurrent cancers actually represent new primary breast cancers. Early onset breast cancer patients experiencing IBTR have a disproportionately high frequency of deleterious BRCA1/2 mutations. This information may be helpful in guiding management in BRCA1 or BRCA2 patients considering breast-conserving therapy.

Local recurrence in the conservatively treated breast cancer patient: a correlation with age and family history.

BACKGROUND: The purpose of this study was to evaluate the relationships among young age at diagnosis, family history status, and local recurrence in breast cancer patients treated with lumpectomy and radiation therapy. METHODS: Between January 1970 and December 1990, 984 early-stage breast cancer patients were treated with conservative surgery and radiation therapy at Yale-New Haven Hospital. All patient data, including demographics, staging information, treatment, and outcome variables were entered into a computerized database. The current study focused on the relationships between young age, family history, and local relapse. A group of 52 patients who experienced a local recurrence in the conservatively treated breast and 52 matched control patients who had not experienced a local recurrence were asked to participate in a study to determine whether local recurrence was associated with family history. Detailed family history interviews were conducted, and pedigrees were analyzed by a genetic counselor who was blind to the clinical history of the patients. RESULTS: As of September 1997, with a median follow-up of 12.3 years for the 984 patients in the database, the overall actuarial 10-year survival is 73%, and the 10-year distant metastasis-free survival is 78%. Of the 984 patients, 112 have experienced a local relapse in the conservatively treated breast, resulting in a 10-year actuarial breast relapse rate of 15%. The 10-year survival after breast relapse is 69%. Patient age tested as a continuous variable correlated strongly with ipsilateral breast tumor relapse. Using age 40 as a cutpoint, patients aged 40 years or less had a significantly higher local relapse rate than patients older than 40 years (P < 0.001). Although the relationship between local relapse and young age was strong, no association was found between family history and local relapse in the detailed family history study. CONCLUSIONS: Young age at diagnosis was a significant prognostic factor for local relapse. In a detailed family history study using a case-control design, no significant differences in family history status were found between patients who had experienced a local relapse and patients who had not.

Revisiting accepted wisdom in the management of breast cancer.

Misconceptions and illusions prevail in the management of breast cancer. Historical review reminds us that medical practice is commonly rooted in tradition rather than proof. The Halsted mastectomy inadvertently served the burgeoning profession of surgery in the early 20th century more than it has benefited women with breast cancer, yet 100 years later the operation continues to thrive. Despite evidence that mastectomy, radiation following lumpectomy, axillary node dissection, or intensive follow-up surveillance have little impact on survival, these practices are adhered to tenaciously. The extent to which current treatment for breast cancer succeeds in prolonging life remains open to question. Many accepted ideas and interventions are perilously disconnected from their true merit. The imperative for doctors to do something sometimes contradicts their pledge to do no harm. Reflection on what is known should guide future action.

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.

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.

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 Paget's 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.

Adjuvant systemic chemotherapy and hormonal therapy. Effect on local recurrence in the conservatively treated breast cancer patient.

BACKGROUND: The purpose of this study is to determine the impact of adjuvant systemic chemotherapy and adjuvant hormonal therapy on local relapse in the conservatively treated breast. MATERIALS AND METHODS: Before December 1989, 548 patients underwent lumpectomy with axillary dissection followed by radiation therapy to the intact breast. Adjuvant systemic therapy was administered as clinically indicated. The majority of patients with pathologically involved lymph nodes received adjuvant systemic therapy, whereas those with pathologically negative lymph nodes received no adjuvant systemic therapy. The majority of patients received a course of radiation therapy either concomitant with or before systemic therapy. In only nine cases was radiation therapy delayed more than 16 weeks after surgery. RESULTS: As of June 1992, the 548 patients had a median follow-up of 6.4 years. In univariate and multivariate Cox regression analysis, patient age and adjuvant systemic chemotherapy were statistically significant independent prognostic factors relating to breast relapse. Those patients who received adjuvant systemic chemotherapy had a lower breast relapse than those who did not. Among patients who received tamoxifen, there was a statistically insignificant trend toward a lower relapse rate compared with those who did not receive tamoxifen. CONCLUSIONS: It appears from this retrospective analysis that patients who received adjuvant systemic therapy, either concomitantly or after their course of radiation therapy, had a lower relapse rate in the conservatively treated breast than those patients who received no adjuvant systemic therapy.

Breast conservation therapy without axillary dissection. A rational treatment strategy in selected patients.

PURPOSE: Patients with early stage breast cancer are being treated with adjuvant systemic therapy with increasing frequency regardless of the pathological status of the axillary lymph nodes. The purpose of this study was to determine the outcome for local regional control in patients treated with radiation therapy to the intact breast and regional lymph nodes without axillary dissection. PATIENTS AND METHODS: The patient population for this study consists of 327 patients with clinical stage I or II invasive breast cancer who were treated by lumpectomy alone without axillary dissection followed by radiation therapy to the intact breast and regional lymph nodes. Outcome for local regional control and survival is reported. RESULTS: As of December 1990, with a median follow-up of more than 10 years, the overall 10-year survival rate was 71%. There were a total of eight regional nodal failures resulting in a 5-year actuarial nodal control rate of 97%. Minimal morbidity was associated with this treatment policy. CONCLUSIONS: For selected patients undergoing breast preservation therapy, lumpectomy alone without axillary dissection followed by radiation therapy to the intact breast and regional lymph nodes results in a high rate of local regional control. Selected patients in whom the results of the axillary lymph node dissection will not influence decisions regarding systemic therapy are candidates for this approach.

Conservative surgery and radiation in the treatment of synchronous ipsilateral breast cancers.

BACKGROUND: Conservative surgery (CS) and radiation therapy (RT) as an alternative to mastectomy is controversial in patients with two or more lesions in the same breast. The authors reviewed their experience with CS and RT in the management of patients with synchronous ipsilateral breast cancer (SIBC). METHODS: Of 1060 patients treated with CS and RT at the authors' facilities before December 1988, 13 (1.2%) presented with SIBC. All lesions were identified macroscopically and confirmed microscopically as carcinoma. After excision, patients were treated with radiation to the breast for a median tumor bed dose of 65 Gy, and regional lymphatics were treated as clinically indicated to a median dose of 48 Gy. These cases were retrospectively reviewed. RESULTS: As of February 1992, with a median follow-up of 71 months, the 5-year actuarial survival rate of the 13 patients was 81%. Three of the 13 (23%) had an ipsilateral breast recurrence, resulting in a 72-month actuarial breast recurrence rate of 25%, compared with a rate of 12% in our singular lesion population. Two of these patients remain alive, no evidence of disease at 135 and 93 months after diagnosis. The third patient had chest wall progression and died with metastatic disease at 64 months. Invasive lobular histology and three separate lesions were identified in two of the three patients with subsequent local recurrence. CONCLUSIONS: The local recurrence rate in conservatively treated patients with SIBC is greater than that seen in patients with single lesions, but because of the small sample size, significant conclusions are not possible. Although the data are limited on this subject, these results support consideration of CS and RT as an option in the management of selected patients who favor a breast conservation management approach.

Prognosis following local recurrence in the conservatively treated breast cancer patient.

At Yale-New Haven Hospital conservative treatment of early stage breast carcinoma with lumpectomy and radiation therapy has been used with increasing frequency since the 1960s. We have reviewed our experience with specific reference to prognosis following local recurrence. Between January 1962 and December 1984 a total of 433 patients were treated with conservative surgery and radiation therapy using standard techniques. As of December 1989, with minimum evaluable follow-up of 5 years and a median follow-up of 8.21 years, there have been a total of 50 ipsilateral breast recurrences resulting in a 5-year actuarial breast recurrence rate of 8%. Extent of disease at the time of local recurrence was clinically categorized as localized (less than 3 cm without dermal involvement) or diffuse (greater than 3 cm and/or with dermal involvement). Seventy-two percent of the recurrences were at or near the original tumor site whereas 28% recurred elsewhere in the breast. At a median follow-up post recurrence of 5.0 years (range 0.3-16.9 years), the 5-year actuarial survival for breast recurrences was 59% and the 5-year disease-free survival was 65%. A number of clinical and pathological features at the time of original diagnosis as well as at the time of local recurrence were tested as possible prognostic indicators for survival following local recurrence. By univariate analysis, significant factors associated with survival following local recurrence included extent of local disease at the time of recurrence (p less than .01), time to local recurrence (p less than .03), with later recurrences doing better, and site of local recurrence (p less than .01), with recurrences elsewhere in the breast doing better. We conclude from this large single institutional experience with a median follow-up post-recurrence of over 5 years that patients experiencing a local recurrence in the conservatively treated breast have a relatively favorable prognosis. The prognostic factors correlating with survival and implications regarding adjuvant systemic therapy at the time of local recurrence are discussed.

Prognostic factors for local recurrence in the conservatively treated breast cancer patient: a cautious interpretation of the data.

Between 1962 and 1984, a total of 433 patients were treated at Yale-New Haven Hospital with conservative surgery and radiation therapy (CS + RT) to the intact breast. As of January 1990, with a minimum assessable follow-up of 5 years and a median follow-up of 8.21 years, there have been a total of 50 breast recurrences resulting in a 5-year actuarial breast recurrence rate of 8%. Of all clinical factors tested, young age was the most significant prognostic factor for local recurrence (P less than .03). In addition, patients with pathologically involved lymph nodes were noted to have a lower local recurrence rate than patients with pathologically negative axillae (P less than .05). These findings were especially notable given the fact that the node-positive group had a higher percentage of T2 tumors and a higher percentage of patients in the young age group. These paradoxical findings, however, may be explained by the fact that 88% of the node-positive patients underwent adjuvant systemic therapy in the form of either systemic chemotherapy or hormonal therapy, while only 8% of node-negative patients underwent any adjuvant systemic therapy. When analyzed as a function of adjuvant therapy, those patients receiving adjuvant therapy had a lower local recurrence rate than those patients not receiving adjuvant therapy (P less than .08). We conclude that adjuvant systemic therapy impacts on the ipsilateral breast recurrence rate in patients treated with CS + RT. The implications of this study in light of the widespread use of adjuvant systemic therapy are discussed.

Mammographically detected breast cancer. Results with conservative surgery and radiation therapy.

At Yale-New Haven Hospital (New Haven, CT) treatment of early stage breast cancer with conservative surgery and radiation therapy (CS & RT) has been utilized with increasing frequency since the 1960s. The authors have reviewed their experience with specific reference to the outcome of those patients whose breast cancer was detected on routine screening mammography. To achieve adequate follow-up, only patients treated before December 1984 are included in this analysis. Of 438 patients treated with CS & RT before December 1984, a total of 41 patients (9%) had nonpalpable lesions detected on routine screening mammography and were treated with CS & RT to the intact breast. Only two patients received adjuvant hormonal therapy and no patients received adjuvant systemic therapy. There has been only one breast failure and one death due to cancer in this group of patients resulting in actuarial survival and breast recurrence-free rates of 100% at 5 years and 92% at 10 years. These results stress the importance of routine screening mammography and raise questions regarding the role of adjuvant systemic therapy in this selected group of patients.

Conservative surgery with radiation therapy in clinical stage I and II breast cancer. Results of a 20-year experience.

Conservative surgery and radiation therapy have been increasingly utilized at Yale-New Haven (Conn) Hospital since the 1960s. This analysis represents our experience from 1962 to 1982, with a total of 281 patients having a minimum assessable follow-up of five years and a median follow-up of 7.4 years. Five- and ten-year actuarial survivals were 83% and 67%, respectively. The actuarial breast recurrence-free rate was 91% at five years and 80% at ten years. Of 31 patients having recurrences in the breast alone, the actuarial five-year survival following recurrence was 48%. Twenty-eight (90%) of these 31 recurrences were salvageable with mastectomy or repeated wedge resection. Patients experiencing an early breast recurrence (less than three years) following initial treatment had a poorer prognosis than patients having recurrences later.

Conservative surgery and radiation therapy in breast carcinoma: local recurrence and prognostic implications.

Conservative surgery with radiation therapy has been used with increasing frequency at Yale-New Haven Hospital since the late 1960's, resulting in a minimum evaluable follow-up time of 5 years on 278 patients treated prior to 1982. The radiation therapy technique generally encompassed treatment to the breast and regional lymph nodes of 4600 cGy with an electron beam boost to the tumor bed of 6400 cGy. Axillary dissection was performed in 19%, adjuvant chemotherapy in 7.3%, and adjuvant hormonal therapy in 5.7%; 65% were clinical Stage I and 35% were clinical Stage II. As of July 1987, with a minimum evaluable follow-up of 5 years and a median follow-up of 7.46 years, the actuarial 5- and 10-year survival for all 278 patients was 83% and 67%, respectively. The breast recurrence-free rate was 91% at 5 years and 80% at 10 years. Whereas the 5-year survival was significantly greater for clinical Stage I patients (91% vs 68%, p = .01), the breast recurrence-free rates did not significantly differ between clinical Stage I & II (93% vs 88%). There were 31 patients who failed in the breast alone as the first site of failure; 67% were at or near the primary site whereas 33% were distinctly removed from the primary site. Salvage mastectomy was performed in 25 patients, repeat wedge resection in two patients, and biopsy only in four patients. Axillary nodes were positive in five (33%) of 15 evaluable patients undergoing axillary dissection at the time of recurrence. The 5-year actuarial survival following local recurrence for the 31 patients was 48% at a mean follow-up of 5.06 years. The local recurrences were further subclassified into localized breast recurrences (LBR), defined clinically as greater than 3 cm and/or with dermal involvement. The 22 patients experiencing localized breast recurrences tended to occur later (median time to recurrence 4.3 years) than the nine patients experiencing a diffuse breast recurrence (median time to recurrence 2.9 years). At last follow-up, three (14%) of the 22 localized breast recurrences had subsequently failed distantly and none had subsequent local failure, whereas four (44%) of nine diffuse breast recurrences had subsequent distant failure and five (55%) of the nine diffuse breast recurrences experienced further local disease. The 5-year actuarial survival following salvage treatment was 90% for the localized breast recurrences and only 13% for the diffuse breast recurrences.

The training and utilization of surgical physician assistants. A retrospective study.

A community hospital's search for qualified surgical house staff in 1975 led to the development of a postgraduate residency program in surgery for physician assistants. Eleven years after its inception, the program's purpose and structure were reviewed, and its alumni, goals, and contributions were evaluated. A 1987 alumni survey provided data to assess the value of residency training to current employment and job satisfaction.

The physician's assistant as resident on surgical service. An example of creative problem solving in surgical manpower.

A residency program for physician assistants (PAs) on a surgical service was undertaken to develop health professionals who could serve in a capacity similar to that of junior surgical residents helping to deliver preoperative and postoperative care under the supervision of surgeons and assisting in operations. As the number of approved surgical residencies and the number of individuals available for residency has decreased, a manpower void is occurring in some institutions in providing in-house services to surgical patients. The use of medical or family practice residents or full-time in-house surgeons is not totally satisfactory. A PA with special training in surgical case management and operative assisting meets many needs previously provided by surgical residents. The surgical PA is, indeed, a surgeon extender and seems, from our three-year experience, to be a good solution to this problem of surgical care in community hospitals. This program also provides an educational mission for the institution and the surgical staff.

Treatment of resistant lateral epicondylitis of the elbow by lengthening of the extensor carpi radialis brevis tendon.

Resistant lateral epicondylitis remains a difficult therapeutic problem. Lengthening of the extensor carpi radialis brevis has proved to be a simple, yet effective, method for treating this problem. Sixteen of the 18 patients in our series are asymptomatic and rated as having excellent results. The result in one patient is rated as good. The one failure in retrospect represented poor patient selection. The results we obtained support the original conclusions of another investigator that this simple surgical approach to the problem can give lasting relief. The procedure can be done on an ambulatory outpatient basis. Minimal postoperative restrictions are involved, and this procedure is appealing in terms of time of disability and cost.