Non-Invasive Breast Cancer

Natural History and Demographics

DCIS represents about 25% of all breast malignancies. It is five times more common than LCIS. The most common subtypes of DCIS are:

The form of DCIS that has the worst prognosis is comedo followed by solid patterns. DCIS is frequently grouped into comedo and non-comedo groups. Most DCIS cases are ER+ with ER positivity between 75% - 85% of all DCIS cases. H2N testing is not presently common, but is being investigated.

The most common clinical presentation of DCIS is microcalcifications on mammogram. LCIS, on the other hand is frequently an incidental finding. LCIS typically does not present mammographically, nor does it present clinical abnormalities.

Approximately 30% of DCIS cases progress to invasive disease at 10 years, if left untreated. Conversely, a patient with LCIS has approximately a 7% risk of invasive disease at 10 years, but the risk is stable at 1% per year of life. Half of the invasive cancers in the setting of LCIS occur in the contralateral breast suggesting that LCIS is a marker for the propensity to develop future invasive disease. The risk of the development of invasive disease in the setting of LCIS is about equal in either breast. LCIS is a proliferative lesion of the lobules, but only 25-50% of those subsequent cancers are invasive lobular cancers. LCIS appears to be a marker for subsequent ductal proliferative lesions (both DCIS and IDC). There are a number of LCIS subtypes known. Of these the pleomorphic LCIS subtype has the worst prognosis.

Risk Factors

The risk factors for local recurrence in DCIS include:

• Decreased margin width (most important factor)
• Increased size of tumor
• High grade disease (comedo-necrosis)
• Young age (≤ 40)
• Comedo necrosis
• Multi-focality

For patients treated with breast conserving surgery (i.e. lumpectomy + radiation therapy), the risk of local recurrence at 14 years is 26% with positive margins and 13% with negative margins.

The Van Nuys Prognostic Classification System was developed to identify DCIS patients who are potentially at low risk for recurrence after radiation alone using margin width, size, grade and age. The system was developed retrospectivelyt and has not been validated in prospective studies or in different data sets.

Diagnostic Workup and Staging

Initial work up and staging studies consist of the H&P, with emphasis on hereditary risk of breast cancer, diagnostic bilateral mammograpms, assessment of ER receptors and a consideration of referral for genetic counselling. Axillary dissections are not needed for DCIS absent clinical indications of nodal involvement. The 2010 NCCN guidelines suggest considering axillary node dissection for mastectomy patients or if the location of the mastectomy will compromise future sentinel node biopsy. DCIS is staged Tis.

DCIS with microinvasion refers to the presence of ≤ 1 mm of invasive disease. If microinvasion is seen, then a sentinel lymph node biopsy would be indicated. In the presence of microinvasion a lymph node biopsy should be performed due to the 4 - 8% lymph node involvement rate. Summary: If microinvasion is present in DCIS, then do the SNB.

DCIS margin status is a changing target. The original NSABP studies on DCIS used a definition of clear margin as "No disease at the inked margin." For patients with DCIS and a < 1 mm margin at excision, there is a 30% probability that there will be residual DCIS present at re-excision. Notably low and intermediate grade DCIS is more likely to be discontinuous. Because of this, margin status may actually be more important in low and intermediate grade disease than in high grade disease. These discontinuous gaps in lesions of DCIS are typically small at < 5 mm in 80% of the cases. For patients with DCIS with an excisional margin of < 1 mm at the fibroglandular border of the breast (ie skin or chest wall), then re-excision is not indicated.

Treatment of DCIS -- Surgery and Radiation

For unifocal DCIS there are two treatment paradigms: Lumpectomy → post operative radiation therapy → tamoxifen/aromatase inhibitors if ER+. Alternatively, a mastectomy may be performed with equivalent outcomes.

For patients electing lumpectomy, a post-excision mammogram should performed to insure that all micro-calcifications were removed at the time of surgery. Specimen radiograph may be take to insure the complete excision of all microcalcifications.

Contra-indications to breast conserving therapy include multi-focal disease, persistently positive margins, poor cosmesis, or an inability to get post-operative radiation therapy (including pregnancy or previous irradiation).

For patients treated with breast conserving surgery to adquate margins of 2 mm or greater, post operative radiation reduces the risk of local recurrence by 50% but there is no evidence of a survival benefit. DCIS recurrences have a rate of around 26% but half of the recurrences are invasive.

Adequate margins have been long debated. The original NSABP studies used the definition of a clear margin as "no disease at the inked margin." A systematic review of published DCIS trials with breast conserving treatment including 4660 patients concluded that a 2 mm margin was superior to a close margin (< 2 mm) and there was no apparent local control benefit in margins > 2 mm.

There is no head to head study of lumpectomy + radiation compared with mastectomy in DCIS. Extrapolations from the NSABP B06 trial of 78 patients found on pathologic review to have only DCIS the local failure rate was found to be 2% for mastectomy, 9% for lumpectomy+radiation therapy and 43% for lumpectomy alone. This is a limited and unplanned analysis of this study done retrospectively. There are four prospective studies that support radiation therapy for local control benefit after lumpectomy in DCIS: They are:

• NSABP B17: Fisher: 2001
  • 818 DCIS patients with negative margins (no cells at inked border) treated with lumpectomy and randomized to RT v. no RT
  • Radiation therapy was 50 Gy to the ipsilateral breast
  • At 10 years the IBTR (i/l breast tumor recurrence) rate was 30.8% in the surgical arm v. 14.9% in the Radiation arm.
  • The rates of both invasive and non-invasive recurrence were cut by 50%
• EORTC 10853: Bijker JCO 2006
  • 1010 DCIS patients with negative margins (no cells at inked border) were randomized to lumpectomy + RT v. lumpectomy alone.
  • Radiation was to the whole breast to 50 Gy.
  • Radiation reduced local failure rates from 16% to 9%
  • Half of all recurrences were invasive cancers
• UKCCCR: Houghton, Lancet 2003
• SeDCIS: Holmber JCO 2008)

Controversy: When is Radiation Required in Post-Lumpectomy DCIS>

The Van Nuys Prognostic Index. The Van Nuys Prognostic Index was published in 2003 by Silverstein. It has not been validated in prospective or retrospective data sets:

The 2003 update by Silverstein reported no statistically significant difference in local relapse free survival with VNPI-Age adujusted scores with or without radiation therapy. For scores in the 7-9 range, a 12 - 15% benefit from radiation therapy. With scores of 10-12 there was still a benefit with radiation therapy but a high risk of recurrence despite radiation therapy. Silverstein's recommendations are: no additional treatment for low VNPI-A scores; Radiation for Group 2 (7 - 9) scores and consider mastectomy for Group 3 (10-12).

Post Lumpectomy Radiation Therapy -- Can some cases be excluded?

There are several trials discussing the need for post-lumpectomy radiation therapy in DCIS. The present (2011) NCCN guidelines for DCIS recommend post lumpectomy radiation therapy as Category 1 evidence based on findings of clinical trials that post lumpectomy radiation therapy reduces ipsilateral breast tumor recurrence by 50% in prospective randomized controlled studies. NCCN considers Category I evidence as "high level evidence (ie randomized controlled studies" and uniform NCCN consensus. The NCCN considers cases in which the ommission of post-lumpectomy radiation therapy is Category 2B (lower level evidence and lack of uniform consensus but no major disagreement).

Reviewing the data, to date, all prospective randomized controlled studies have failed to identify a subset of DCIS patients where radiation therapy can safely be elminated in breast conserving surgery. Although the Van Nuys group has published subsets that appear to be less likely to recur, other groups have failed to replicate this data in prospective studies. For low-intermediate grade DCIS with widely clear margins (5 - 10 mm) an ongoing ECOG study suggests that recurrence rates are low without post-lumpectomy radiation therapy. For high grade disease, post-lumpectomy radiation therapy is necessary.

Several studies have failed to demonstrate the safety of omitting post-lumpectomy radiation therapy:

LCIS

LCIS only lumpectomies can be observed. LCIS recurrences with invasive disease is low and is frequently in the contralateral breast. Paul Chuba published data that LCIS may be a marker for tumor development. Deaths from the few invasive recurrences are extremely rare and the prognosis is favorable. Tamoxifen or raloxafene (P1 Trial) as a risk reduction strategy may be important, as may be bilateral prophylactic mastectomies. LCIS is frequently found incidentally on core needle biopsy and is usually without mammographic or clinical findings. If LCIS is obtained alone as a result of an imaging or clinical finding, further biopsy should be performed to insure the determination of the findings that led to the biopsy. Present literature supports breast conserving surgery in the setting of LCIS and there is no data to suggest that breast conserving surgery is contra-indicated in the setting of LCIS. No special effort to obtain clear LCIS margins are needed. Tamoxifen will reduce by 50% the risk of invasive recurrence in the setting of LCIS in both breasts according to Fisher (Lancet 1999)..

Treatment of DCIS -- Tamoxifen's Role/Hormonal Therapy

For patients with DCIS with ER positive disease, (approximately 75 - 85% of all DCIS) the benefit of tamoxifen has been studied. The results of these studies of tamoxifen after lumpectomy and radiation therapy are mixed.

NSABP B24 looked at lumpectomy + radiation ± tamoxifen and found that at 7 years, the addition of tamoxifen significantly reduced the risk of ipsilateral breast tumor recurrence from 11% to 8%, a 3% improvement. This benefit was seen with respect to invasive recurrences but not noninvasive recurrences.

Contralateral breast tumor recurrence was also reduced with tamoxifen from 4.9% to 2.3% at 7 years. Note that this trial did not require negative margins nor did it test the index lesions for recepter status.

Retrospective analysis of the NSABP B24 trial results for ER negative patients demonstrated that hormonal manipulation benefits were limited to ER positive patients.

There are two concerns about the B24 trial (Fisher): Negative margins were not required and the presence of positive margin patients in the study may have influenced and possibly exaggerated the benefits of tamoxifen. The study did not initially look at ER receptor status although it did in retrospective review. It also enrolled younger women and younger age at diagnosis was associated with higher ipsilateral breast tumor recurrence rates. 30% were under age 50.

The UKCCCR study did not show a benefit with the addtion of tamoxifen with either invasive or noninvasive recurrences. Differences between these studies may be due to cohort ages. NSABP B24 enrolled younger women and the British study enrolled older patients. Younger age has been associated with a higher lifetime risk of recurrence in the B24 study. 30% of the B24 patients were < 50 while only 10% in the UKCCCR study were under 50. There is controversy over which groups benefit from adjuvant tamoxifen in DCIS, but current recommendations and practice are that all ER+ patients get tamoxifen.

The UKCCCR study was a 2 x 2 factoral study with institutional choice as to whether to participate in the 2 x 2 design or only one randomization. This study also looked at the role of radiation therapy with respect to adjuvant treatment with tamoxifen. The study demonstrated that radiation is still useful even with adjuvant tamoxifen. At median follow up of > 4 years, radiation therapy reduced the risk of ipsilateral breast tumor recurrences in women given adjuvant tamoxifen from 18% to 6%.

Conclusions:

• There is controversy about which subgroups will receive a benefit from tamoxifen therapy
• Corrent practice ER positive DCIS patients are all offered adjuvant tamoxifen therapy.
• Radiation therapy is still beneficial for patients with DCIS treated with lumpectomy even with adjuvant tamoxifen.
  UKCCCR reported at median follow up > 4 years Radiation reduced the risk of IBTR in women given tamoxifen from 18% to 6%.

Radiation Therapy Dose and Technique

DCIS breast treatment is to the whole breast to a total dose of 46 - 50 Gy at 1.8 - 2.67 Gy/fraction and a lumpectomy cavity boost to 60 - 66 Gy at 2 Gy / fraction. The 2.67 Gy /fraction dose is recently adopted by the NCCN guidelines and has been reported by the NCIC to a total dose of 46 Gy in 16 fractions. The role of a boost is controversial and is an extrapolation from the EORTC and Lyon boost trials for invasive cancers. The Canadian NCIC scheme did not use a boost, and the role of boost in the hypofractionated regimen is presently being studied by the Trans-Tasmanian group. There is no prospective data for the role of boost in DCIS. In the NSABP B24 trial (lumpectomy/radiation/tamoxifen) boost was given in 44% mainly for close/positive margins.

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Radiation Oncology Synopsis