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The development of interval breast malignancies in patients with BRCA mutations

  1. Ian K. Komenaka M.D.†,*,
  2. Beth-Ann Ditkoff M.D.,
  3. Kathie-Ann Joseph M.D., M.P.H.,
  4. Donna Russo M.S.,
  5. Prakash Gorroochurn Ph.D.,
  6. Marie Ward M.D.,
  7. Elizabeth Horowitz R.-P.A.C.,
  8. Mahmoud B. El-Tamer M.D.,
  9. Freya R. Schnabel M.D.

Article first published online: 12 APR 2004

DOI: 10.1002/cncr.20221

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Cancer

Cancer

Volume 100, Issue 10, pages 2079–2083, 15 May 2004

Additional Information

How to Cite

Komenaka, I. K., Ditkoff, B.-A., Joseph, K.-A., Russo, D., Gorroochurn, P., Ward, M., Horowitz, E., El-Tamer, M. B. and Schnabel, F. R. (2004), The development of interval breast malignancies in patients with BRCA mutations. Cancer, 100: 2079–2083. doi: 10.1002/cncr.20221

Author Information

  1. The Comprehensive Breast Center, Columbia-Presbyterian Medical Center, New York, New York

  1. †

    Fax: (212) 305-1060

*c/o Beth-Ann Ditkoff, M.D., Columbia-Presbyterian Medical Center, Atchley Pavilion, 10th Floor, 161 Fort Washington Avenue, New York, NY 10032

Publication History

  1. Issue published online: 29 APR 2004
  2. Article first published online: 12 APR 2004
  3. Manuscript Accepted: 24 FEB 2004
  4. Manuscript Revised: 2 FEB 2004
  5. Manuscript Received: 27 OCT 2003

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Keywords:

  • interval malignancy;
  • breast carcinoma;
  • BRCA;
  • mutation;
  • screening;
  • breast imaging

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

BACKGROUND

At present, there is no consensus regarding how frequently BRCA mutation carriers should be screened for malignancies using breast imaging techniques. An interval malignancy is defined as a malignancy that becomes evident during the period between annual screening mammography scans; the finding of such a malignancy indicates that the malignancy either went undetected by the last breast imaging scan or developed during the interval since that last scan.

METHODS

The authors retrospectively reviewed the medical charts of all BRCA mutation carriers who were followed by the genetic counselor at the Columbia-Presbyterian Comprehensive Breast Center (New York, NY) between September 1995 and September 2002.

RESULTS

Thirteen BRCA mutation carriers elected to undergo close surveillance and thus were followed at our institution. Three of these 13 patients (23%) did not develop breast carcinoma, 4 (31%) developed breast carcinoma that was detected at the time of annual screening, and 6 (46%) developed palpable interval malignancies in less than 12 months. Among the six patients who developed interval malignancies, the mean time between the last screening mammogram and disease presentation was 5.1 months (range, 2–9 months); the average tumor size in this patient subgroup was 1.7 cm (range, 0.8–3 cm). Two of these six patients had ductal carcinoma in situ, whereas the remaining four had invasive breast carcinoma; three patients had positive lymph nodes at presentation. All six patients who developed interval disease exhibited dense breast tissue on the previous mammogram. Focused breast ultrasonography was able to identify the tumor mass in 3 of 4 patients (75%).

CONCLUSIONS

Nearly half of all BRCA-positive women who chose to undergo close surveillance in the current study developed malignant disease less than a year after exhibiting normal findings on screening mammography. Half of these interval malignancies were positive for lymph node involvement. These results suggest that strong consideration should be given to screening BRCA-positive women at more frequent intervals and to using additional imaging techniques, such as breast ultrasonography and/or breast magnetic resonance imaging, as a part of this screening. Cancer 2004. © 2004 American Cancer Society.

Breast carcinoma is by far the most prevalent malignancy among women.1 Over 210,000 women will be diagnosed with breast carcinoma in 2003. In addition, breast carcinoma is the second most common cause of malignancy-related mortality among women. The widespread incidence of breast carcinoma, together with relevant technologic advances and increased public awareness and concern, has led to increased investigation of breast carcinoma screening and detection practices. As a result, guidelines and standard recommendations for screening asymptomatic women with an average risk of developing breast carcinoma have been published.2, 3 Although mortality reductions attributable to screening mammography have been demonstrated in women age > 50 years, the data regarding mortality reduction among women ages 40–49 years are inconclusive, and the benefit associated with screening in this age group remains controversial.4–6 Nonetheless, in spite of the debate regarding survival benefit, widespread adoption of the published breast carcinoma screening guidelines has led to earlier detection of breast malignancies and to the detection of a larger proportion of these malignancies in a noninvasive stage.6, 7

Over the last decade, with the advent of genetic testing, two major genes associated with increased susceptibility to breast carcinoma—breast cancer susceptibility gene 1 (BRCA1) and breast cancer susceptibility gene 2 (BRCA2)—have been identified. Mutations in these genes confer a 60–85% lifetime risk of developing breast carcinoma. Identification of individuals with this greatly increased risk allows more informed decisions to be made regarding risk reduction options, including chemoprevention and risk-reducing surgery (i.e., prophylactic mastectomy). This limited number of patients with an especially high risk of developing breast carcinoma is further reduced when patients opt to undergo risk-reducing surgery, leaving only those who instead choose close surveillance (with or without chemoprevention) in the high-risk group. For this reason, surveillance recommendations are necessarily based on expert opinion, rather than on prospective data.8

Although there currently is no consensus regarding the frequency of breast imaging screening for asymptomatic BRCA1 or BRCA2 mutation carriers, most guidelines recommend breast imaging beginning at an age 5–10 years younger than the youngest age of diagnosis of an affected relative.9, 10 The conventional 12-month interval between breast imaging scans, however, typically is not shortened for BRCA mutation carriers. Furthermore, there is no consensus regarding the use of multimodality screening (i.e., ultrasonography together with magnetic resonance imaging [MRI]). In an effort to address these issues, we have reviewed the genetic testing database of the Columbia-Presbyterian Comprehensive Breast Center (New York, NY) to investigate the incidence and development of interval malignancies in BRCA mutation carriers.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Approval for the current retrospective study was obtained from both our institutional review board and the Columbia-Presbyterian Cancer Center. The study period extended from September 14, 1995, to August 14, 2002.

Patients considered for BRCA1 and BRCA2 mutation testing were referred by physicians within our institution as well as by physicians at other institutions that did not possess the facilities or capabilities necessary for genetic screening. In general, patients were considered to be candidates for genetic screening if they met the guidelines for genetic counseling and testing as recommended by the American Society of Clinical Oncology.7 In brief, genetic counseling and testing were offered for individuals who had a personal or family history that was suggestive of an inherited breast or ovarian malignancy susceptibility syndrome. The decision to offer BRCA1/2 testing was based on pedigree analysis of features of inherited breast or ovarian malignancy predisposition syndromes. Individuals who were offered testing included those with relatives in at least two generations who had any of the following: 1) early-onset breast carcinoma and/or ovarian malignancy; 2) bilateral breast carcinoma; 3) breast and ovarian malignancies together (i.e., in the same individual); or 4) male breast carcinoma. Individuals with Ashkenazi Jewish ancestry also were offered genetic testing.

BRCA1 and BRCA2 mutation carriers were offered options according to the recommendations of the Cancer Genetics Program at the Columbia-Presbyterian Comprehensive Breast Center. These recommendations were based on (but slightly modified with respect to) the guidelines published in March 1997 by the Cancer Genetics Studies Consortium/National Center for Human Genome Research. The options offered to mutation carriers included careful breast carcinoma screening, chemoprevention, and/or risk-reducing surgery. Risk-reducing surgery involved prophylactic removal of the (remaining) breast(s), with patients also receiving the option to undergo salpingo-oophorectomy. Breast carcinoma screening recommendations included monthly breast self-examination, annual mammography/ultrasonography beginning at an early age (≈25–30 years), clinical breast examination at least every 4–6 months, and consideration for breast MRI. Chemoprevention involved the use of tamoxifen to reduce breast carcinoma risk.

The standard recommendations regarding breast imaging for mutation carriers include the initiation of annual screening mammography at an age 5–10 years younger than the youngest age of diagnosis of an affected relative. The conventional 12-month interval between mammography scans, however, typically is not shortened for mutation carriers. An interval breast malignancy was defined as a malignancy that became evident between annual screening scans and thus represents a case in which the malignancy either went undetected by the last screening mammography scan or developed in the period since that last scan. All patients with BRCA mutations who developed interval breast carcinoma were considered for inclusion in the study group.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

During the time period reviewed, 40 patients were found to be positive for either a BRCA1 or BRCA2 mutation. Two of these 40 patients were male and thus were excluded from consideration for the current study, as there are no standard guidelines for breast imaging in men. In addition, 16 of the 40 patients who exhibited mutations were referred for genetic testing by a physician at an institution other than ours. After testing, all 16 chose to return to their respective referring physicians rather than to change care providers and undergo follow-up at our institution; therefore, data on these 16 individuals were unavailable.

Demographic data on the 22 patients who were followed at our institution are presented in Table 1. The median age of these patients was 46 years (range, 32–59 years). Fourteen patients were BRCA1 mutation carriers, and the remaining eight were BRCA2 mutation carriers.

Table 1. Demographic Characteristics of the 22 BRCA Mutation Carriers in the Current Study
Age (yrs)RaceMutated geneAshkenazi ancestryFamily historyPersonal history

  1. W: white; O: other; B: breast carcinoma; Ov: ovarian malignancy; X: breast and ovarian malignancies; DCIS: ductal carcinoma in situ; Mets: breast carcinoma metastases.

49WBRCA2NoB (second-degree relative)Bilateral
39WBRCA1NoB (first-degree relative); B (first-degree relative); B (second-degree relative)DCIS
48WBRCA2NoB (first-degree relative)Yes
47WBRCA1YesB (first-degree relative); B (first-degree relative)Yes
41WBRCA1NoB (first-degree relative); B (second-degree relative); B (second-degree relative); B (second-degree relative)DCIS
42OBRCA1NoB (first-degree relative); X (first-degree relative)Yes
52OBRCA1NoOv (first-degree relative); X (first-degree relative)Yes
46WBRCA2NoB (first-degree relative); Ov (first-degree relative)DCIS
46WBRCA2NoB (first-degree relative); B (second-degree relative)DCIS
53WBRCA2YesB (first-degree relative); B (second-degree relative); B (second-degree relative)Yes
59WBRCA1YesOv (first-degree relative); Ov (first-degree relative)Yes
46WBRCA2NoB (first-degree relative); B (first-degree relative); B (first-degree relative)Yes
36WBRCA1NoB (first-degree relative); Ov (first-degree relative); Ov (first-degree relative); X (first-degree relative)Yes
51OBRCA1NoOv (first-degree relative)Yes
46WBRCA1NoOv (first-degree relative); Ov (second-degree relative)Mets
49WBRCA1NoB (second-degree relative); Ov (first-degree relative); Ov (second-degree relative)No
43WBRCA1NoB (second-degree relative); B (second-degree relative)Mets
32WBRCA1YesDistant relativesMets
41WBRCA1NoOv (first-degree relative)Yes
36WBRCA2NoB (second-degree relative); B (second-degree relative); Ov (first-degree relative)No
38WBRCA1YesB (first-degree relative); B (second-degree relative)No
40WBRCA2YesB (first-degree relative)No

The outcomes of the 22 patients in the current study population are summarized in Table 2. Three developed metastases from breast carcinoma within 12 months of BRCA mutation detection; all 3 went on to receive systemic therapy but subsequently died of disease. Six patients underwent elective prophylactic mastectomy. Of the 13 patients who chose to undergo breast surveillance screening, 3 (23%) did not develop a new breast malignancy, whereas 4 (31%) developed breast carcinoma that was detected on the annual screening mammography scan; the remaining 6 patients (46%) developed interval malignancies (i.e., breast carcinoma that became evident < 12 months after screening mammography) (Table 3). Chi-square analysis of the observed incidence of interval breast carcinoma versus the expected incidence did not reveal a significant difference (P = 0.5).

Table 2. Outcome Data on the 22 BRCA Mutation Carriers in the Current Study
OutcomeNo. of patients
Prophylactic mastectomy/mastectomies6
Died of breast carcinoma3
Died of other causes0
Interval breast carcinoma6
No interval breast carcinoma7
Table 3. Interval Malignancy Data
Patient no.Intervala(mos)Tumor size (cm)PathologyLymph node status (positive/total)

  • IDC: invasive ductal carcinoma; DCIS: ductal carcinoma in situ; n/a: not applicable (lymph node status was not assessed).

  • a

    Interval between last screening examination and detection of interval breast carcinoma.

130.8IDC, poorly differentiated0/14
282.1DCIS, high graden/a
363.0IDC + DCIS, high grade1/31
491.2IDC, poorly differentiated1/14
52.50.8DCIS, high graden/a
621.4IDC, poorly differentiated1/24
Mean5.11.7  

All six patients who had interval malignancies presented with a palpable mass. The mean pathologic tumor size was 1.7 cm (range, 0.8–3 cm). The mean time between the last screening mammography scan and disease presentation was 5.1 months (range, 2–9 months). Each of these six patients exhibited dense breast tissue on the previous screening mammogram. Focused ultrasonography was able to identify the tumor mass in 3 of 4 patients (75%) at interval disease presentation. The tumor mass was occult to ultrasonography in one patient, and for two patients, ultrasonography was not performed. MRI was not used to screen any of the six patients who had interval malignancies.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES

Compared with the general female population, women who carry BRCA mutations have a greatly increased risk of developing breast carcinoma. For these high-risk individuals, recommendations regarding breast surveillance and imaging are based on expert opinion, because there are no prospective data on which reliable guidelines for preventive screening of this subpopulation can be based. Most physicians recommend a younger age for initial, baseline mammographic scanning of BRCA mutation carriers; however, to date, the most widely used recommendations do not call for a decreased interval between screening mammography scans for these individuals.9, 10

In the current study, nearly half (46%) of all BRCA mutation carriers who chose breast screening surveillance over prophylactic surgery developed interval malignancies. These interval malignancies were diagnosed at a mean of only 5.1 months after the preceding screening scan, with half being diagnosed ≤ 3 months after the most recent screening scan. Two recent studies involving BRCA mutation carriers demonstrated similar findings. Meijers-Heijboer et al.6 found that 50% of BRCA mutation carriers (4 of 8) who chose to undergo close surveillance rather than prophylactic mastectomy developed interval breast carcinoma; these interval malignancies were discovered 2–5 months after normal findings were noted on screening mammography. Similarly, Scheuer et al.11 reported that 6 of 12 patients (50%) developed interval breast carcinoma, which became evident 6–10 months after normal findings were observed on screening mammography. These short periods between screening and the discovery of interval breast carcinoma suggest that annual mammography may be inadequate for screening BRCA mutation carriers.

It is noteworthy that for each patient who went on to develop an interval malignancy, the breast radiologist described the patient's breast tissue as ‘dense’ and noted that its density might limit the sensitivity of the imaging study. The finding that each of these six patients presented with a clinically palpable mass during the period between studies suggests that the frequency of screening and the imaging modality used were inadequate. In the general population, screening mammography has led to decreased tumor size at presentation as well as lower rates of presentation with a palpable mass12; similarly, the identification of BRCA mutation carriers should lead to improved screening practices and, in turn, to earlier detection of disease in this subpopulation.

Sixty-seven percent of all patients with interval breast carcinoma in the current study presented with invasive disease, and 75% of those who presented with invasive disease had lymph node involvement. Both of these rates are clearly higher than what would be considered adequate in a well screened population.13, 14 It is noteworthy that breast ultrasonography was able to identify the interval malignancy in 75% of patients for whom this technique was performed. Given that the screening radiologist remarked on the breast tissue density of each of the six patients who developed interval breast carcinoma, screening of these patients may have been analogous to the screening of younger populations or of other populations with dense breast tissue. Although it is not a standard recommendation, many breast radiologists advocate the adjunct use of ultrasonography for such populations.15–17 All six patients with interval disease had aggressive pathologic characteristics (Table 3), which are consistent with the findings of larger reviews involving BRCA mutation carriers.18–20 Again, these findings suggest that a shorter interval between breast screening visits is necessary for BRCA mutation carriers.

The relatively small size of the study population limited the statistical significance and power of the data that were obtained. In spite of this shortcoming, our findings have several implications. For example, our findings suggest that more frequent breast imaging is necessary for BRCA mutation carriers. In addition, the current study indicates that other breast imaging techniques, such as ultrasonography and possibly even MRI, may be useful in bringing about the earlier detection of breast carcinoma, particularly in patients with dense breast tissue. Although larger reviews are needed to support our findings, we believe that the issues examined clearly require further attention.

In conclusion, nearly half of all BRCA-positive women who chose to undergo close surveillance in the current study developed interval breast carcinoma, which was detected at a mean of only 5 months after the observation of normal findings on screening mammography. In addition, half of these interval malignancies were positive for lymph node involvement. These results suggest that strong consideration should be given to screening BRCA-positive women at more frequent intervals and to using additional imaging techniques, such as breast ultrasonography and/or breast MRI, as a part of this screening process.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
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